The effects of reduced gluten barley diet on humoral and cell-mediated systemic immune responses of gluten-sensitive rhesus macaques.

PubMed

Sestak, Karol; Thwin, Hazel; Dufour, Jason; Aye, Pyone P; Liu, David X; Moehs, Charles P

2015-03-06

Celiac disease (CD) affects approximately 1% of the general population while an estimated additional 6% suffers from a recently characterized, rapidly emerging, similar disease, referred to as non-celiac gluten sensitivity (NCGS). The only effective treatment of CD and NCGS requires removal of gluten sources from the diet. Since required adherence to a gluten-free diet (GFD) is difficult to accomplish, efforts to develop alternative treatments have been intensifying in recent years. In this study, the non-human primate model of CD/NCGS, e.g., gluten-sensitive rhesus macaque, was utilized with the objective to evaluate the treatment potential of reduced gluten cereals using a reduced gluten (RG; 1% of normal gluten) barley mutant as a model. Conventional and RG barleys were used for the formulation of experimental chows and fed to gluten-sensitive (GS) and control macaques to determine if RG barley causes a remission of dietary gluten-induced clinical and immune responses in GS macaques. The impacts of the RG barley diet were compared with the impacts of the conventional barley-containing chow and the GFD. Although remission of the anti-gliadin antibody (AGA) serum responses and an improvement of clinical diarrhea were noted after switching the conventional to the RG barley diet, production of inflammatory cytokines, e.g., interferon-gamma (IFN-γ), tumor necrosis factor (TNF) and interleukin-8 (IL-8) by peripheral CD4+ T helper lymphocytes, persisted during the RG chow treatment and were partially abolished only upon re-administration of the GFD. It was concluded that the RG barley diet might be used for the partial improvement of gluten-induced disease but its therapeutic value still requires upgrading-by co-administration of additional treatments.

The Effects of Reduced Gluten Barley Diet on Humoral and Cell-Mediated Systemic Immune Responses of Gluten-Sensitive Rhesus Macaques

PubMed Central

Sestak, Karol; Thwin, Hazel; Dufour, Jason; Aye, Pyone P.; Liu, David X.; Moehs, Charles P.

2015-01-01

Celiac disease (CD) affects approximately 1% of the general population while an estimated additional 6% suffers from a recently characterized, rapidly emerging, similar disease, referred to as non-celiac gluten sensitivity (NCGS). The only effective treatment of CD and NCGS requires removal of gluten sources from the diet. Since required adherence to a gluten-free diet (GFD) is difficult to accomplish, efforts to develop alternative treatments have been intensifying in recent years. In this study, the non-human primate model of CD/NCGS, e.g., gluten-sensitive rhesus macaque, was utilized with the objective to evaluate the treatment potential of reduced gluten cereals using a reduced gluten (RG; 1% of normal gluten) barley mutant as a model. Conventional and RG barleys were used for the formulation of experimental chows and fed to gluten-sensitive (GS) and control macaques to determine if RG barley causes a remission of dietary gluten-induced clinical and immune responses in GS macaques. The impacts of the RG barley diet were compared with the impacts of the conventional barley-containing chow and the GFD. Although remission of the anti-gliadin antibody (AGA) serum responses and an improvement of clinical diarrhea were noted after switching the conventional to the RG barley diet, production of inflammatory cytokines, e.g., interferon-gamma (IFN-γ), tumor necrosis factor (TNF) and interleukin-8 (IL-8) by peripheral CD4+ T helper lymphocytes, persisted during the RG chow treatment and were partially abolished only upon re-administration of the GFD. It was concluded that the RG barley diet might be used for the partial improvement of gluten-induced disease but its therapeutic value still requires upgrading—by co-administration of additional treatments. PMID:25756783

Sensitive Detection of Francisella tularensis Directly from Whole Blood by Use of the GeneXpert System.

PubMed

Banada, Padmapriya P; Deshpande, Srinidhi; Chakravorty, Soumitesh; Russo, Riccardo; Occi, James; Meister, Gabriel; Jones, Kelly J; Gelhaus, Carl H; Valderas, Michelle W; Jones, Martin; Connell, Nancy; Alland, David

2017-01-01

Francisella tularensis is a potential bioterrorism agent that is highly infectious at very low doses. Diagnosis of tularemia by blood culture and nucleic acid-based diagnostic tests is insufficiently sensitive. Here, we demonstrate a highly sensitive F. tularensis assay that incorporates sample processing and detection into a single cartridge suitable for point-of-care detection. The assay limit of detection (LOD) and dynamic range were determined in a filter-based cartridge run on the GeneXpert system. F. tularensis DNA in buffer or CFU of F. tularensis was spiked into human or macaque blood. To simulate detection in human disease, the assay was tested on blood drawn from macaques infected with F. tularensis Schu S4 at daily intervals. Assay detection was compared to that with a conventional quantitative PCR (qPCR) assay and blood culture. The assay LOD was 0.1 genome equivalents (GE) per reaction and 10 CFU/ml F. tularensis in both human and macaque blood. In infected macaques, the assay detected F. tularensis on days 1 to 4 postinfection in 21%, 17%, 60%, and 83% of macaques, respectively, compared to conventional qPCR positivity rates of 0%, 0%, 30%, and 100% and CFU detection of blood culture at 0%, 0%, 0%, and 10% positive, respectively. Assay specificity was 100%. The new cartridge-based assay can rapidly detect F. tularensis in bloodstream infections directly in whole blood at the early stages of infection with a sensitivity that is superior to that of other methods. The simplicity of the automated testing procedures may make this test suitable for rapid point-of-care detection. Copyright © 2016 American Society for Microbiology.

Baseline and longitudinal change in isometric muscle strength prior to radiographic progression in osteoarthritic and pre-osteoarthritic knees--data from the Osteoarthritis Initiative.

PubMed

Eckstein, F; Hitzl, W; Duryea, J; Kent Kwoh, C; Wirth, W

2013-05-01

To test whether cross-sectional or longitudinal measures of thigh muscle isometric strength differ between knees with and without subsequent radiographic progression of knee osteoarthritis (KOA), with particular focus on pre-osteoarthritic female knees (knees with risk factors but without definite radiographic KOA). Of 4,796 Osteoarthritis Initiative participants, 2,835 knees with Kellgren Lawrence grade (KLG) 0-3 had central X-ray readings, annual quantitative joint space width (JSW) and isometric muscle strength measurements (Good strength chair). Separate slope analysis of covariance (ANCOVA) models were used to determine differences in strength between "progressor" and "non-progressor" knees, after adjusting for age, body mass index, and pain. 466 participant knees exceeded the smallest detectable JSW change during each of two observation intervals (year 2→4 and year 1→3) and were classified as progressors (213 women, 253 men; 128 KLG0/1, 330 KLG2/3); 946 participant knees did not exceed this threshold in either interval and were classified as non-progressors (588 women, 358 from men; 288KLG0/1, 658KLG2/3). Female progressor knees, including those with KLG0/1, tended to have lower extensor and flexor strength at year 2 and at baseline than those without progression, but the difference was not significant after adjusting for confounders. No significant difference was observed in longitudinal change of muscle strength (baseline→year 2) prior to radiographic progression. No significant differences were found for muscle strength in men, and none for change in strength concomitant with progression. This study provides no strong evidence that (changes in) isometric muscle strength precedes or is associated with structural (radiographic) progression of KOA. Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Rituximab treatment for fibrillary glomerulonephritis.

PubMed

Hogan, Jonathan; Restivo, Michaela; Canetta, Pietro A; Herlitz, Leal C; Radhakrishnan, Jai; Appel, Gerald B; Bomback, Andrew S

2014-10-01

Approximately 50% of patients with fibrillary glomerulonephritis (GN) progress to end-stage renal disease (ESRD) within 2 years of diagnosis, and no standard therapy exists. The data on rituximab therapy for fibrillary GN are limited and have inconsistent outcomes. Here, we report the largest case series to date using rituximab for fibrillary GN. Retrospective chart reviews were conducted on 12 patients with fibrillary GN who were treated with rituximab (1 g i.v. × 2 doses or 375 mg/m(2) × 4 doses) at the Center for Glomerular Diseases at Columbia University Medical Center. Non-progression of disease was defined as stable/improved serum creatinine (SCr) with a minimum of 1 year of follow-up. The median SCr was 2.1 (range 0.7-2.7) mg/dL, median estimated glomerular filtration rate (eGFR) 39 (range 21-98) mL/min/1.73 m(2) and median proteinuria 4497 (range 210-7542) mg/day at the time of rituximab initiation. Four patients had received immunosuppression before rituximab, and nine received immunosuppression after rituximab, with four receiving a second rituximab course. Four of 12 patients were non-progressors, 3 of 12 had progressive renal dysfunction without reaching ESRD, and 5 patients reached ESRD. The median follow-up for patients who did not reach ESRD was 38 (range 14-76) months after rituximab treatment. Non-progressors had lower SCr values, higher eGFRs and shorter median duration from diagnosis to treatment than progressors. No serious adverse events were noted. Rituximab therapy was associated with non-progression of renal disease in 4 of 12 patients. At the time of treatment, these non-progressors had better renal function and shorter time from diagnosis to treatment than progressors. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Prognostic value of a CCR5 defective allele in pediatric HIV-1 infection.

PubMed Central

Romiti, M. L.; Colognesi, C.; Cancrini, C.; Mas, A.; Berrino, M.; Salvatori, F.; Orlandi, P.; Jansson, M.; Palomba, E.; Plebani, A.; Bertran, J. M.; Hernandez, M.; de Martino, M.; Amoroso, A.; Tovo, P. A.; Rossi, P.; Espanol, T.; Scarlatti, G.

2000-01-01

BACKGROUND: A deletion of 32 base pairs in the CCR5 gene (delta32 CCR5) has been linked to resistance to HIV-1 infection in exposed adults and to the delay of disease progression in infected adults. MATERIALS AND METHODS: To determine the role of delta32 CCR5 in disease progression of HIV-1 infected children born to seropositive mothers, we studied a polymerase chain reaction in 301 HIV-1 infected, 262 HIV-1 exposed-uninfected and 47 HIV-1 unexposed-uninfected children of Spanish and Italian origin. Infected children were further divided into two groups according to their rate of HIV-1 disease progression: rapid progressors who developed severe clinical and/or immunological conditions within the second year of life, and delayed progressors with any other evolution of disease. Among the latter were the long-term, non-progressors (LTNP) who presented with mild or no symptoms of HIV-1 infection above 8 years of age. Viral phenotype was studied for 45 delayed progressors. RESULTS: No correlation was found between delta32 CCR5 and mother-to-child transmission of HIV-1. However, the frequency of the deletion was substantially higher in LTNP, compared with delayed (p = 0.019) and rapid progressors (p = 0.0003). In children carrying the delta32 CCRS mutation, the presence of MT-2 tropic virus isolate was associated with a severe immune suppression (p = 0.028); whereas, the presence of MT-2 negative viruses correlated with LTNP (p = 0.010). CONCLUSIONS: Given the rapidity and simplicity of the assay, the delta32 CCR5 mutation may be a useful predictive marker to identify children with delayed disease progression who, consequently, may not require immediate antiretroviral treatment. PMID:10803406

Prognostic value of a CCR5 defective allele in pediatric HIV-1 infection.

PubMed

Romiti, M L; Colognesi, C; Cancrini, C; Mas, A; Berrino, M; Salvatori, F; Orlandi, P; Jansson, M; Palomba, E; Plebani, A; Bertran, J M; Hernandez, M; de Martino, M; Amoroso, A; Tovo, P A; Rossi, P; Espanol, T; Scarlatti, G

2000-01-01

A deletion of 32 base pairs in the CCR5 gene (delta32 CCR5) has been linked to resistance to HIV-1 infection in exposed adults and to the delay of disease progression in infected adults. To determine the role of delta32 CCR5 in disease progression of HIV-1 infected children born to seropositive mothers, we studied a polymerase chain reaction in 301 HIV-1 infected, 262 HIV-1 exposed-uninfected and 47 HIV-1 unexposed-uninfected children of Spanish and Italian origin. Infected children were further divided into two groups according to their rate of HIV-1 disease progression: rapid progressors who developed severe clinical and/or immunological conditions within the second year of life, and delayed progressors with any other evolution of disease. Among the latter were the long-term, non-progressors (LTNP) who presented with mild or no symptoms of HIV-1 infection above 8 years of age. Viral phenotype was studied for 45 delayed progressors. No correlation was found between delta32 CCR5 and mother-to-child transmission of HIV-1. However, the frequency of the deletion was substantially higher in LTNP, compared with delayed (p = 0.019) and rapid progressors (p = 0.0003). In children carrying the delta32 CCRS mutation, the presence of MT-2 tropic virus isolate was associated with a severe immune suppression (p = 0.028); whereas, the presence of MT-2 negative viruses correlated with LTNP (p = 0.010). Given the rapidity and simplicity of the assay, the delta32 CCR5 mutation may be a useful predictive marker to identify children with delayed disease progression who, consequently, may not require immediate antiretroviral treatment.

Artifact correction in diffusion MRI of non-human primate brains on a clinical 3T scanner.

PubMed

Zhang, Xiaodong; Kirsch, John E; Zhong, Xiaodong

2016-02-01

Smearing artifacts were observed and investigated in diffusion tensor imaging (DTI) studies of macaque monkeys on a clinical whole-body 3T scanner. Four adult macaques were utilized to evaluate DTI artifacts. DTI images were acquired with a single-shot echo-planar imaging (EPI) sequence using a parallel imaging technique. The smearing artifacts observed on the diffusion-weighted images and fractional anisotropy maps were caused by the incomplete fat suppression due to the irregular macaque frontal skull geometry and anatomy. The artifact can be reduced substantially using a novel three-dimensional (3D) shimming procedure. The smearing artifacts observed on diffusion weighted images and fractional anisotropy (FA) maps of macaque brains can be reduced substantially using a robust 3D shimming approach. The DTI protocol combined with the shimming procedure could be a robust approach to examine brain connectivity and white matter integrity of non-human primates using a conventional clinical setting. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Dietary Gluten-Induced Gut Dysbiosis Is Accompanied by Selective Upregulation of microRNAs with Intestinal Tight Junction and Bacteria-Binding Motifs in Rhesus Macaque Model of Celiac Disease.

PubMed

Mohan, Mahesh; Chow, Cheryl-Emiliane T; Ryan, Caitlin N; Chan, Luisa S; Dufour, Jason; Aye, Pyone P; Blanchard, James; Moehs, Charles P; Sestak, Karol

2016-10-28

The composition of the gut microbiome reflects the overall health status of the host. In this study, stool samples representing the gut microbiomes from 6 gluten-sensitive (GS) captive juvenile rhesus macaques were compared with those from 6 healthy, age- and diet-matched peers. A total of 48 samples representing both groups were studied using V4 16S rRNA gene DNA analysis. Samples from GS macaques were further characterized based on type of diet administered: conventional monkey chow, i.e., wheat gluten-containing diet (GD), gluten-free diet (GFD), barley gluten-derived diet (BOMI) and reduced gluten barley-derived diet (RGB). It was hypothesized that the GD diet would lower the gut microbial diversity in GS macaques. This is the first report illustrating the reduction of gut microbial alpha-diversity ( p < 0.05) following the consumption of dietary gluten in GS macaques. Selected bacterial families (e.g., Streptococcaceae and Lactobacillaceae ) were enriched in GS macaques while Coriobacteriaceae was enriched in healthy animals. Within several weeks after the replacement of the GD by the GFD diet, the composition (beta-diversity) of gut microbiome in GS macaques started to change ( p = 0.011) towards that of a normal macaque. Significance for alpha-diversity however, was not reached by the day 70 when the feeding experiment ended. Several inflammation-associated microRNAs (miR-203, -204, -23a, -23b and -29b) were upregulated ( p < 0.05) in jejunum of 4 biopsied GS macaques fed GD with predicted binding sites on 16S ribosomal RNA of Lactobacillus reuteri (accession number: NR_025911), Prevotella stercorea (NR_041364) and Streptococcus luteciae (AJ297218) that were overrepresented in feces. Additionally, claudin-1, a validated tight junction protein target of miR-29b was significantly downregulated in jejunal epithelium of GS macaques. Taken together, we predict that with the introduction of effective treatments in future studies the diversity of gut microbiomes in GS macaques will approach those of healthy individuals. Further studies are needed to elucidate the regulatory pathways of inflammatory miRNAs in intestinal mucosa of GS macaques and to correlate their expression with gut dysbiosis.

Risk factors associated with the development of overt nephropathy in type 2 diabetes patients: A 12 years observational study

PubMed Central

Viswanathan, Vijay; Tilak, Priyanka; Kumpatla, Satyavani

2012-01-01

Background & objectives: Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal disease in developing countries. Early detection and risk reduction measures can prevent DN. The aim of the study was to determine the risk factors for the development of proteinuria over a period of 12 years of follow up in normoalbuminuric type 2 diabetes patients attending a specialized centre. Methods: Of the 2630 type 2 diabetes subjects newly registered in 1996, 152 (M:F;92:60) normoalbuminuric subjects had baseline and subsequent measurements of anthropometric, haemodynamic and biochemical details spanning 12 years. The subjects were divided into 2 groups based on the renal status during follow up visits. Group 1 (non-progressors) had persistent normoalbuminuria and group 2 (progressors) had persistent proteinuria. Presence of other diabetic complications during follow up and details on antidiabetic and antihypertensive agents were noted. Results: During median follow up of 11 years in subjects with normal renal function at baseline, 44.1 per cent developed proteinuria at follow up. Glucose levels, HbA1c, systolic blood pressure (SBP), triglycerides, and urea levels were significantly higher at baseline among progressors than non-progressors. Progressors had a longer duration of diabetes and significant fall in estimated glomerular filtration rate (eGFR) levels at follow up. In Cox's regression analysis, baseline age, duration of diabetes, baseline HbA1c and mean values of HbA1c, triglycerides, SBP and presence of retinopathy showed significant association with the development of macroalbuminuria. Interpretation & conclusions: Type 2 diabetes patients with uncontrolled diabetes and increase in blood pressure are at high risk of developing nephropathy. Age, long duration of diabetes, elevated BP, poor glycaemic control and presence of retinopathy were significantly associated with the progression of diabetic nephropathy. PMID:22885263

Evolution of human immunodeficiency virus type 1 in perinatally infected infants with rapid and slow progression to disease.

PubMed Central

Salvatori, F; Masiero, S; Giaquinto, C; Wade, C M; Brown, A J; Chieco-Bianchi, L; De Rossi, A

1997-01-01

We addressed the relationship between the origin and evolution of human immunodeficiency virus type 1 (HIV-1) variants and disease outcome in perinatally infected infants by studying the V3 regions of viral variants in samples obtained from five transmitting mothers at delivery and obtained sequentially over the first year of life from their infected infants, two of whom (rapid progressors) rapidly progressed to having AIDS. Phylogenetic analyses disclosed that the V3 sequences from each mother-infant pair clustered together and were clearly distinct from those of the other pairs. Within each pair, the child's sequences formed a monophyletic group, indicating that a single variant initiated the infection in both rapid and slow progressors. Plasma HIV-1 RNA levels increased in all five infants during their first months of life and then declined within the first semester of life only in the three slow progressors. V3 variability increased over time in all infants, but no differences in the pattern of V3 evolution in terms of potential viral phenotype were observed. The numbers of synonymous and nonsynonymous substitutions varied during the first semester of life regardless of viral load, CD4+-cell count, and disease progression. Conversely, during the second semester of life the rate of nonsynonymous substitutions was higher than that of synonymous substitutions in the slow progressors but not in the rapid progressors, thus suggesting a stronger host selective pressure in the former. In view of the proposal that V3 genetic evolution is driven mainly by host immune constraints, these findings suggest that while the immune response to V3 might contribute to regulating viral levels after the first semester of life, it is unlikely to play a determinant role in the initial viral decline soon after birth. PMID:9151863

Glomerular and tubular damage markers in individuals with progressive albuminuria.

PubMed

Nauta, Ferdau L; Scheven, Lieneke; Meijer, Esther; van Oeveren, Wim; de Jong, Paul E; Bakker, Stephan J L; Gansevoort, Ron T

2013-07-01

Albuminuria is associated with risk for renal and cardiovascular disease. It is difficult to predict which persons will progress in albuminuria. This study investigated whether assessment of urinary markers associated with damage to different parts of the nephron may help identify individuals that will progress in albuminuria. Individuals were selected from a prospective community-based cohort study with serial follow-up and defined as "progressors" if they belonged to the quintile of participants with the most rapid annual increase in albuminuria, and reached an albuminuria ≥150 mg/d during follow-up. Patients with known renal disease or macroalbuminuria at baseline were excluded. Each progressor was matched to two control participants, based on baseline albuminuria, age, and sex. Furthermore, damage markers were measured in a separate set of healthy individuals. After a median follow-up of 8.6 years, 183 of 8394 participants met the criteria for progressive albuminuria. Baseline clinical characteristics were comparable between progressors and matched controls (n=366). Both had higher baseline albuminuria than the overall population. Urinary excretion of the glomerular damage marker IgG was significantly higher in progressors, whereas urinary excretion of proximal tubular damage markers and inflammatory markers was lower in these individuals compared with controls. Healthy individuals (n=109) had the lowest values for all urinary damage markers measured. These data suggest that albuminuria associated with markers of glomerular damage is more likely to progress, whereas albuminuria associated with markers of tubulointerstitial damage is more likely to remain stable.

Aiding pest control management of long-tailed macaques (Macaca fascicularis fascicularis) in Malaysia by using molecular markers of mitochondrial DNA

NASA Astrophysics Data System (ADS)

Abdul-Latiff, M. A. B.; Abdul-Patah, P.; Yaakop, S.; Md-Zain, B. M.

2017-10-01

The long-tailed macaques (Macaca fascicularis fascicularis) has been the center of human wildlife conflict in Malaysia since 1970s. This well-adapted and opportunistic primates have been dominating wide range of habitat in Malaysia such as primary and secondary forest, mangrove, as well as human settlements. The conventional practices of translocation by the authorities are threatening the uniqueness of gene pool for this species and ironically contradicting with the ultimate purpose of genetic conservation of this species. The objectives of this study is to determine the level of genetic separation between populations of long-tailed macaques, primarily focusing on populations distributed in northern Peninsular Malaysia. A total of 954 base pairs of control regions mtDNA was sequenced and analyzed from 27 samples of M. fascicularis. The results exhibited a highly homogenous state of populations for long-tailed macaques genetically and this ultimately indicate unsuitable management and planning in terms of pest control management of the species. Authorities are suggested to translocate the species at least within the state boundaries to avoid homogeneity of gene pools for the particular species.

Proinflammatory isoforms of IL-32 as novel and robust biomarkers for control failure in HIV-infected slow progressors

PubMed Central

El-Far, Mohamed; Kouassi, Pascale; Sylla, Mohamed; Zhang, Yuwei; Fouda, Ahmed; Fabre, Thomas; Goulet, Jean-Philippe; van Grevenynghe, Julien; Lee, Terry; Singer, Joel; Harris, Marianne; Baril, Jean-Guy; Trottier, Benoit; Ancuta, Petronela; Routy, Jean-Pierre; Bernard, Nicole; Tremblay, Cécile L.; Angel, Jonathan; Conway, Brian; Côté, Pierre; Gill, John; Johnston, Lynn; Kovacs, Colin; Loutfy, Mona; Logue, Kenneth; Piché, Alain; Rachlis, Anita; Rouleau, Danielle; Thompson, Bill; Thomas, Réjean; Trottier, Sylvie; Walmsley, Sharon; Wobeser, Wendy

2016-01-01

HIV-infected slow progressors (SP) represent a heterogeneous group of subjects who spontaneously control HIV infection without treatment for several years while showing moderate signs of disease progression. Under conditions that remain poorly understood, a subgroup of these subjects experience failure of spontaneous immunological and virological control. Here we determined the frequency of SP subjects who showed loss of HIV control within our Canadian Cohort of HIV+ Slow Progressors and identified the proinflammatory cytokine IL-32 as a robust biomarker for control failure. Plasmatic levels of the proinflammatory isoforms of IL-32 (mainly β and γ) at earlier clinic visits positively correlated with the decline of CD4 T-cell counts, increased viral load, lower CD4/CD8 ratio and levels of inflammatory markers (sCD14 and IL-6) at later clinic visits. We present here a proof-of-concept for the use of IL-32 as a predictive biomarker for disease progression in SP subjects and identify IL-32 as a potential therapeutic target. PMID:26978598

The Dynamics of the Human Infant Gut Microbiome in Development and in Progression towards Type 1 Diabetes

PubMed Central

Kostic, Aleksandar D.; Gevers, Dirk; Siljander, Heli; Vatanen, Tommi; Hyötyläinen, Tuulia; Hämäläinen, Anu-Maaria; Peet, Aleksandr; Tillmann, Vallo; Pöhö, Päivi; Mattila, Ismo; Lähdesmäki, Harri; Franzosa, Eric A.; Vaarala, Outi; de Goffau, Marcus; Harmsen, Hermie; Ilonen, Jorma; Virtanen, Suvi M.; Clish, Clary B.; Orešič, Matej; Huttenhower, Curtis; Knip, Mikael

2015-01-01

SUMMARY Colonization of the fetal and infant gut microbiome results in dynamic changes in diversity, which can impact disease susceptibility. To examine the relationship between human gut microbiome dynamics throughout infancy and type 1 diabetes (T1D), we examined a cohort of 33 infants genetically predisposed to T1D. Modeling trajectories of microbial abundances through infancy revealed a subset of microbial relationships shared across most subjects. Although strain composition of a given species was highly variable between individuals, it was stable within individuals throughout infancy. Metabolic composition and metabolic pathway abundance remained constant across time. A marked drop in alpha-diversity was observed in T1D progressors in the time-window between seroconversion and T1D diagnosis, accompanied by spikes in inflammation-favoring organisms, gene functions, and serum and stool metabolites. This work identifies trends in the development of the human infant gut microbiome along with specific alterations that precede T1D onset and distinguish T1D progressors from non-progressors. PMID:25662751

Progressor: social navigation support through open social student modeling

NASA Astrophysics Data System (ADS)

Hsiao, I.-Han; Bakalov, Fedor; Brusilovsky, Peter; König-Ries, Birgitta

2013-06-01

The increased volumes of online learning content have produced two problems: how to help students to find the most appropriate resources and how to engage them in using these resources. Personalized and social learning have been suggested as potential ways to address these problems. Our work presented in this paper combines the ideas of personalized and social learning in the context of educational hypermedia. We introduce Progressor, an innovative Web-based tool based on the concepts of social navigation and open student modeling that helps students to find the most relevant resources in a large collection of parameterized self-assessment questions on Java programming. We have evaluated Progressor in a semester-long classroom study, the results of which are presented in this paper. The study confirmed the impact of personalized social navigation support provided by the system in the target context. The interface encouraged students to explore more topics attempting more questions and achieving higher success rates in answering them. A deeper analysis of the social navigation support mechanism revealed that the top students successfully led the way to discovering most relevant resources by creating clear pathways for weaker students.

Broad neutralization response in a subset of HIV-1 subtype C-infected viraemic non-progressors from southern India.

PubMed

Nandagopal, Paneerselvam; Bhattacharya, Jayanta; Srikrishnan, Aylur K; Goyal, Rajat; Ravichandran Swathirajan, Chinnambedu; Patil, Shilpa; Saravanan, Shanmugam; Deshpande, Suprit; Vignesh, Ramachandran; Solomon, Sunil Suhas; Singla, Nikhil; Mukherjee, Joyeeta; Murugavel, Kailapuri G

2018-02-05

Broadly neutralizing antibodies (bnAbs) have been considered to be potent therapeutic tools and potential vaccine candidates to enable protection against various clades of human immunodeficiency virus (HIV). The generation of bnAbs has been associated with enhanced exposure to antigen, high viral load and low CD4+ T cell counts, among other factors. However, only limited data are available on the generation of bnAbs in viraemic non-progressors that demonstrate moderate to high viraemia. Further, since HIV-1 subtype C viruses account for more than 50 % of global HIV infections, the identification of bnAbs with novel specificities is crucial to enable the development of potent tools to aid in HIV therapy and prevention. In the present study, we analysed and compared the neutralization potential of responses in 70 plasma samples isolated from ART-naïve HIV-1 subtype C-infected individuals with various disease progression profiles against a panel of 30 pseudoviruses. Among the seven samples that exhibited a neutralization breadth of ≥70 %, four were identified as 'elite neutralizers', and three of these were from viraemic non-progressors while the fourth was from a typical progressor. Analysis of the neutralization specificities revealed that none of the four elite neutralizers were reactive to epitopes in the membrane proximal external region (MPER), CD4-binding site and V1V2 or V3 glycan. However, two of the four elite neutralizers exhibited enhanced sensitivity towards viruses lacking N332 glycan, indicating high neutralization potency. Overall, our findings indicate that the identification of potent neutralization responses with distinct epitope specificities is possible from the as yet unexplored Indian population, which has a high prevalence of HIV-1 subtype C infection.

Partial wave spectroscopic microscopy can predict prostate cancer progression and mitigate over-treatment (Conference Presentation)

NASA Astrophysics Data System (ADS)

Zhang, Di; Graff, Taylor; Crawford, Susan; Subramanian, Hariharan; Thompson, Sebastian; Derbas, Justin R.; Lyengar, Radha; Roy, Hemant K.; Brendler, Charles B.; Backman, Vadim

2016-02-01

Prostate Cancer (PC) is the second leading cause of cancer deaths in American men. While prostate specific antigen (PSA) test has been widely used for screening PC, >60% of the PSA detected cancers are indolent, leading to unnecessary clinical interventions. An alternative approach, active surveillance (AS), also suffer from high expense, discomfort and complications associated with repeat biopsies (every 1-3 years), limiting its acceptance. Hence, a technique that can differentiate indolent from aggressive PC would attenuate the harms from over-treatment. Combining microscopy with spectroscopy, our group has developed partial wave spectroscopic (PWS) microscopy, which can quantify intracellular nanoscale organizations (e.g. chromatin structures) that are not accessible by conventional microscopy. PWS microscopy has previously been shown to predict the risk of cancer in seven different organs (N ~ 800 patients). Herein we use PWS measurement of label-free histologically-normal prostatic epithelium to distinguish indolent from aggressive PC and predict PC risk. Our results from 38 men with low-grade PC indicated that there is a significant increase in progressors compared to non-progressors (p=0.002, effect size=110%, AUC=0.80, sensitivity=88% and specificity=72%), while the baseline clinical characteristics were not significantly different. We further improved the diagnostic power by performing nuclei-specific measurements using an automated system that separates in real-time the cell nuclei from the remaining prostate epithelium. In the long term, we envision that the PWS based prognostication can be coupled with AS without any change to the current procedure to mitigate the harms caused by over-treatment.

Insulin Resistance Predicts Medial Temporal Hypermetabolism in Mild Cognitive Impairment Conversion to Alzheimer Disease

PubMed Central

Willette, Auriel A.; Modanlo, Nina

2015-01-01

Alzheimer disease (AD) is characterized by progressive hypometabolism on [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans. Peripheral insulin resistance (IR) increases AD risk. No studies have examined associations between FDG metabolism and IR in mild cognitive impairment (MCI) and AD, as well as MCI conversion to AD. We studied 26 cognitively normal (CN), 194 MCI (39 MCI-progressors, 148 MCI-stable, 2 years after baseline), and 60 AD subjects with baseline FDG-PET from the Alzheimer’s Disease Neuroimaging Initiative. Mean FDG metabolism was derived for AD-vulnerable regions of interest (ROIs), including lateral parietal and posteromedial cortices, medial temporal lobe (MTL), hippocampus, and ventral prefrontal cortices (vPFC), as well as postcentral gyrus and global cerebrum control regions. The homeostasis model assessment of IR (HOMA-IR) was used to measure IR. For AD, higher HOMA-IR predicted lower FDG in all ROIs. For MCI-progressors, higher HOMA-IR predicted higher FDG in the MTL and hippocampus. Control regions showed no associations. Higher HOMA-IR predicted hypermetabolism in MCI-progressors and hypometabolism in AD in medial temporal regions. Future longitudinal studies should examine the pathophysiologic significance of the shift from MTL hyper- to hypometabolism associated with IR. PMID:25576061

Subregional laminar cartilage MR spin-spin relaxation times (T2) in osteoarthritic knees with and without medial femorotibial cartilage loss - data from the Osteoarthritis Initiative (OAI).

PubMed

Wirth, W; Maschek, S; Beringer, P; Eckstein, F

2017-08-01

To explore whether subregional laminar femorotibial cartilage spin-spin relaxation time (T2) is associated with subsequent radiographic progression and cartilage loss and/or whether one-year change in subregional laminar femorotibial cartilage T2 is associated with concurrent progression in knees with established radiographic OA (ROA). In this case-control study, Osteoarthritis Initiative (OAI) knees with medial femorotibial progression were selected based on one-year loss in both quantitative cartilage thickness Magnetic resonance imaging (MRI) and radiographic joint space width (JSW). Non-progressor knees were matched by sex, Body mass index (BMI), baseline Kellgren-Lawrence-grade (2/3), and pain. Baseline and one-year follow-up superficial and deep cartilage T2 was analyzed in 16 femorotibial subregions using multi-echo spin-echo MRI. 37 knees showed medial femorotibial progression whereas 37 matched controls had no medial or lateral compartment progression. No statistically significant baseline differences between progressor and non-progressor knees in medial femorotibial cartilage T2 were observed in the superficial (48.9 ± 3.0 ms; 95% CI: [47.9, 49.9] vs 47.8 ± 3.6 ms; 95% CI: [46.6, 49.0], P = 0.07) or deep cartilage layer (40.8 ± 3.6 ms; 95% CI: [39.5, 42.0] vs 40.1 ± 4.7 ms; 95% CI: [38.5, 41.6], P = 0.29). Concurrent T2 change was more pronounced in the deep than the superficial cartilage layer. In the medial femorotibial compartment (MFTC), longitudinal change was greater in the deep layer of progressor than non-progressor knees (1.8 ± 4.5 ms; 95% CI: [0.3, 3.3] vs -0.2 ± 1.9 ms; 95% CI: [-0.8, 0.5], P = 0.02), whereas no difference was observed in the superficial layer. Medial compartment cartilage T2 did not appear to be a strong prognostic factor for subsequent structural progression in the same compartment of knees with established ROA, when appropriately controlling for covariates. Yet, deep layer T2 change in the medial compartment occurred concurrent with medial femorotibial progression. Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Biological and genetic evolution of HIV type 1 in two siblings with different patterns of disease progression.

PubMed

Ripamonti, Chiara; Leitner, Thomas; Laurén, Anna; Karlsson, Ingrid; Pastore, Angela; Cavarelli, Mariangela; Antonsson, Liselotte; Plebani, Anna; Fenyö, Eva Maria; Scarlatti, Gabriella

2007-12-01

To investigate the immunological and virological factors that may lead to different patterns of disease progression characteristic of HIV-1-infected children, two HIV-1-infected siblings, a slow and a fast progressor, were followed prospectively before the onset of highly active antiretroviral therapy. Viral coreceptor usage, including the use of CCR5/CXCR4 chimeric receptors, macrophage tropism, and sensitivity to the CC-chemokine RANTES, has been studied. An autologous and heterologous neutralizing antibody response has been documented using peripheral blood mononuclear cells- and GHOST(3) cell line-based assays. Viral evolution was investigated by env C2-V3 region sequence analysis. Although both siblings were infected with HIV-1 of the R5 phenotype, their viruses showed important biological differences. In the fast progressor there was a higher RANTES sensitivity of the early virus, an increased trend to change the mode of CCR5 receptor use, and a larger genetic evolution. Both children developed an autologous neutralizing antibody response starting from the second year with evidence of the continuous emergence of resistant variants. A marked viral genetic and phenotypic evolution was documented in the fast progressor sibling, which is accompanied by a high viral RANTES sensitivity and persistent neutralizing antibodies.

Indian Long-term Non-Progressors Show Broad ADCC Responses with Preferential Recognition of V3 Region of Envelope and a Region from Tat Protein.

PubMed

Kulkarni, Archana; Kurle, Swarali; Shete, Ashwini; Ghate, Manisha; Godbole, Sheela; Madhavi, Vijaya; Kent, Stephen J; Paranjape, Ramesh; Thakar, Madhuri

2017-01-01

HIV-specific antibody-dependent cell cytotoxicity (ADCC) is likely to be important in governing protection from human immunodeficiency virus (HIV) and slowing disease progression. Little is known about the ADCC responses to HIV-1 subtype C. We characterized ADCC responses in HIV-1 subtype C-infected Indian subjects with slow disease progression and identified the dominant antigenic regions recognized by these antibodies. ADCC responses were measured in plasma from 34 long-term non-progressors (LTNPs), who were asymptomatic and maintained CD4 count above 500 cells/mm 3 for the last 7 years in the absence of antiretroviral therapy (ART), and 58 ART naïve progressors with CD4 count <500 cells/mm 3 against overlapping HIV-1 peptides using a flow cytometry-based antibody-dependent natural killer (NK) cell activation assay. The assay measured CD107a expression on NK cells as a marker of antibody-dependent NK cell activation and IFN-γ secretion by NK cells upon activation. The ADCC epitopes were mapped using the matrix of overlapping peptides. Indian LTNPs showed higher and broader ADCC responses compared to the progressors. The Env-C and Tat-specific ADCC responses were associated with lower plasma viral load, whereas the Env-C responses were also associated with higher CD4 counts. Five of 10 LTNP responders targeted epitopes in the V3 region (amino acids 288-330) of Env-C. Additionally, three Tat regions were targeted by ADCC antibodies from LTNPs. ADCC responses were associated with slow HIV progression in Indian subtype C-infected cohort. The frequently recognized peptides from the V3 loop of Env and the novel epitopes from Tat by the LTNPs warrants further study to understand the role of ADCC responses to these regions in control and prevention of HIV-1 infection.

Comparative performance of a licensed anthrax vaccine versus electroporation based delivery of a PA encoding DNA vaccine in rhesus macaques.

PubMed

Livingston, Brian D; Little, Stephen F; Luxembourg, Alain; Ellefsen, Barry; Hannaman, Drew

2010-01-22

DNA vaccination is a promising immunization strategy that could be applied in the development of vaccines for a variety of prophylactic and therapeutic indications. Utilizing anthrax protective antigen as a model antigen, we demonstrate that electroporation mediated delivery enhanced the immunogenicity of DNA vaccines in nonhuman primates over 100-fold as compared to conventional intramuscular injection. Two administrations of a DNA vaccine with electroporation elicited anthrax toxin neutralizing antibody responses in 100% of rhesus macaques. Toxin neutralizing antibodies were sustained for the nearly 1-year study duration and were correlated with protection against subsequent lethal Bacillus anthracis spore challenge. Collectively, electroporation mediated DNA vaccination conferred protection comparable to that observed following vaccination with an FDA approved anthrax vaccine.

An electrocorticographic electrode array for simultaneous recording from medial, lateral, and intrasulcal surface of the cortex in macaque monkeys.

PubMed

Fukushima, Makoto; Saunders, Richard C; Mullarkey, Matthew; Doyle, Alexandra M; Mishkin, Mortimer; Fujii, Naotaka

2014-08-15

Electrocorticography (ECoG) permits recording electrical field potentials with high spatiotemporal resolution over a large part of the cerebral cortex. Application of chronically implanted ECoG arrays in animal models provides an opportunity to investigate global spatiotemporal neural patterns and functional connectivity systematically under various experimental conditions. Although ECoG is conventionally used to cover the gyral cortical surface, recent studies have shown the feasibility of intrasulcal ECoG recordings in macaque monkeys. Here we developed a new ECoG array to record neural activity simultaneously from much of the medial and lateral cortical surface of a single hemisphere, together with the supratemporal plane (STP) of the lateral sulcus in macaque monkeys. The ECoG array consisted of 256 electrodes for bipolar recording at 128 sites. We successfully implanted the ECoG array in the left hemisphere of three rhesus monkeys. The electrodes in the auditory and visual cortex detected robust event related potentials to auditory and visual stimuli, respectively. Bipolar recording from adjacent electrode pairs effectively eliminated chewing artifacts evident in monopolar recording, demonstrating the advantage of using the ECoG array under conditions that generate significant movement artifacts. Compared with bipolar ECoG arrays previously developed for macaque monkeys, this array significantly expands the number of cortical target areas in gyral and intralsulcal cortex. This new ECoG array provides an opportunity to investigate global network interactions among gyral and intrasulcal cortical areas. Published by Elsevier B.V.

Sarcomeric Myosin Expression in the Tongue Body of Humans, Macaques and Rats

PubMed Central

Rahnert, Jill A.; Sokoloff, Alan J.; Burkholder, Thomas J.

2010-01-01

Expression of developmental and unconventional myosin heavy chain (MHC) isoforms in some adult head and neck muscles is thought to reflect specific contractile demands of muscle fibers active during kinematically complex movements. Mammalian tongue muscles are active during oromotor behaviors that encompass a wide range of tongue movement speeds and tongue shape changes (e.g. respiration, oral transport, swallowing, rejection), but the extent to which tongue muscles express developmental and unconventional MHC is not known. Quantitative PCR was used to determine the mRNA content of conventional MHC-beta, MHC-2a, MHC-2b and MHC-2x, the developmental isoforms embryonic MHC and neonatal MHC and the unconventional isoforms atrial/cardiac-α MHC (MHC-alpha), extraocular MHC, masseter MHC and slow tonic MHC in tongue body muscles of the rat, macaque and human. In all species, conventional MHC isoforms predominate. MHC-2b and MHC-2x account for 98% of total MHC mRNA in the rat. MHC-2a, MHC-2x and MHC-beta account for 94% of total MHC mRNA in humans and 96% of total MHC mRNA in macaque. With the exception of MHC-alpha in humans (5%), developmental and unconventional MHC mRNA represents less than 0.3% of total MHC mRNA. We conclude that in these species, there is limited expression of developmental and unconventional MHC and that diversity of tongue body muscle fiber contractile properties is achieved primarily by MHC-beta, MHC-2a, MHC-2x and MHC-2b. Whether expression of MHC-alpha mRNA in tongue is unique to humans or present in other hominoids awaits further investigation. PMID:19907142

Sensitivity study of voxel-based PET image comparison to image registration algorithms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yip, Stephen, E-mail: syip@lroc.harvard.edu; Chen, Aileen B.; Berbeco, Ross

2014-11-01

Purpose: Accurate deformable registration is essential for voxel-based comparison of sequential positron emission tomography (PET) images for proper adaptation of treatment plan and treatment response assessment. The comparison may be sensitive to the method of deformable registration as the optimal algorithm is unknown. This study investigated the impact of registration algorithm choice on therapy response evaluation. Methods: Sixteen patients with 20 lung tumors underwent a pre- and post-treatment computed tomography (CT) and 4D FDG-PET scans before and after chemoradiotherapy. All CT images were coregistered using a rigid and ten deformable registration algorithms. The resulting transformations were then applied to themore » respective PET images. Moreover, the tumor region defined by a physician on the registered PET images was classified into progressor, stable-disease, and responder subvolumes. Particularly, voxels with standardized uptake value (SUV) decreases >30% were classified as responder, while voxels with SUV increases >30% were progressor. All other voxels were considered stable-disease. The agreement of the subvolumes resulting from difference registration algorithms was assessed by Dice similarity index (DSI). Coefficient of variation (CV) was computed to assess variability of DSI between individual tumors. Root mean square difference (RMS{sub rigid}) of the rigidly registered CT images was used to measure the degree of tumor deformation. RMS{sub rigid} and DSI were correlated by Spearman correlation coefficient (R) to investigate the effect of tumor deformation on DSI. Results: Median DSI{sub rigid} was found to be 72%, 66%, and 80%, for progressor, stable-disease, and responder, respectively. Median DSI{sub deformable} was 63%–84%, 65%–81%, and 82%–89%. Variability of DSI was substantial and similar for both rigid and deformable algorithms with CV > 10% for all subvolumes. Tumor deformation had moderate to significant impact on DSI for progressor subvolume with R{sub rigid} = − 0.60 (p = 0.01) and R{sub deformable} = − 0.46 (p = 0.01–0.20) averaging over all deformable algorithms. For stable-disease subvolumes, the correlations were significant (p < 0.001) for all registration algorithms with R{sub rigid} = − 0.71 and R{sub deformable} = − 0.72. Progressor and stable-disease subvolumes resulting from rigid registration were in excellent agreement (DSI > 70%) for RMS{sub rigid} < 150 HU. However, tumor deformation was observed to have negligible effect on DSI for responder subvolumes with insignificant |R| < 0.26, p > 0.27. Conclusions: This study demonstrated that deformable algorithms cannot be arbitrarily chosen; different deformable algorithms can result in large differences of voxel-based PET image comparison. For low tumor deformation (RMS{sub rigid} < 150 HU), rigid and deformable algorithms yield similar results, suggesting deformable registration is not required for these cases.« less

Tracking early decline in cognitive function in older individuals at risk for Alzheimer's disease dementia: the Alzheimer's Disease Cooperative Study Cognitive Function Instrument

PubMed Central

Amariglio, Rebecca E.; Donohue, Michael C.; Marshall, Gad A.; Rentz, Dorene M.; Salmon, David P.; Ferris, Steven H.; Karantzoulis, Stella; Aisen, Paul S.; Sperling, Reisa A.

2015-01-01

Importance Several large-scale Alzheimer's disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. Objective To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. Design, Setting, and Participants Longitudinal study over the course of 48 months at participating Alzheimer's Disease Cooperative Study (ADCS) sites. The study included 468 healthy older individuals (Clinical Dementia Rating Scale [CDR] Global = 0, above cut-off on modified Mini-Mental State Exam and Free and Cued Selective Reminding Test) (mean age= 79.4 years ±3.6). All subjects and their study partners completed the Self and Partner CFI annually. Subjects also underwent concurrent annual neuropsychological assessment and apolipoprotein E (APOE) genotyping. Main outcomes and measures Comparison of CFI scores between clinical progressors (Clinical Dementia Rating Scale [CDR] ≥ 0.5) and non-progressors (CDR remained = 0), as well as between APOE ε4 carriers and non-carriers were performed. Correlations of change between the CFI and neuropsychological performance were assessed longitudinally. Results At 48 months, group differences between clinical progressors and non-progressors were significant for CFI Self, CFI Partner, and CFI Self+Partner total scores. At month 48, APOE ε4 carriers showed greater progression than non-carriers on CFI Partner and CFI Self+Partner scores. Both CFI Self and CFI Partner scores were associated with longitudinal cognitive decline, although findings suggest self report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment. Conclusions and Relevance Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, yet informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease. PMID:25706191

Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia

NASA Astrophysics Data System (ADS)

Shingai, Masashi; Nishimura, Yoshiaki; Klein, Florian; Mouquet, Hugo; Donau, Olivia K.; Plishka, Ronald; Buckler-White, Alicia; Seaman, Michael; Piatak, Michael; Lifson, Jeffrey D.; Dimitrov, Dimiter; Nussenzweig, Michel C.; Martin, Malcolm A.

2013-11-01

Neutralizing antibodies can confer immunity to primate lentiviruses by blocking infection in macaque models of AIDS. However, earlier studies of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies administered to infected individuals or humanized mice reported poor control of virus replication and the rapid emergence of resistant variants. A new generation of anti-HIV-1 monoclonal antibodies, possessing extraordinary potency and breadth of neutralizing activity, has recently been isolated from infected individuals. These neutralizing antibodies target different regions of the HIV-1 envelope glycoprotein including the CD4-binding site, glycans located in the V1/V2, V3 and V4 regions, and the membrane proximal external region of gp41 (refs 9, 10, 11, 12, 13, 14). Here we have examined two of the new antibodies, directed to the CD4-binding site and the V3 region (3BNC117 and 10-1074, respectively), for their ability to block infection and suppress viraemia in macaques infected with the R5 tropic simian-human immunodeficiency virus (SHIV)-AD8, which emulates many of the pathogenic and immunogenic properties of HIV-1 during infections of rhesus macaques. Either antibody alone can potently block virus acquisition. When administered individually to recently infected macaques, the 10-1074 antibody caused a rapid decline in virus load to undetectable levels for 4-7days, followed by virus rebound during which neutralization-resistant variants became detectable. When administered together, a single treatment rapidly suppressed plasma viraemia for 3-5weeks in some long-term chronically SHIV-infected animals with low CD4+ T-cell levels. A second cycle of anti-HIV-1 monoclonal antibody therapy, administered to two previously treated animals, successfully controlled virus rebound. These results indicate that immunotherapy or a combination of immunotherapy plus conventional antiretroviral drugs might be useful as a treatment for chronically HIV-1-infected individuals experiencing immune dysfunction.

An electrocorticographic electrode array for simultaneous recording from medial, lateral, and intrasulcal surface of the cortex in macaque monkeys

PubMed Central

Fukushima, Makoto; Saunders, Richard C.; Mullarkey, Matthew; Doyle, Alexandra M.; Mishkin, Mortimer; Fujii, Naotaka

2014-01-01

Background Electrocorticography (ECoG) permits recording electrical field potentials with high spatiotemporal resolution over a large part of the cerebral cortex. Application of chronically implanted ECoG arrays in animal models provides an opportunity to investigate global spatiotemporal neural patterns and functional connectivity systematically under various experimental conditions. Although ECoG is conventionally used to cover the gyral cortical surface, recent studies have shown the feasibility of intrasulcal ECoG recordings in macaque monkeys. New Method Here we developed a new ECoG array to record neural activity simultaneously from much of the medial and lateral cortical surface of a single hemisphere, together with the supratemporal plane (STP) of the lateral sulcus in macaque monkeys. The ECoG array consisted of 256 electrodes for bipolar recording at 128 sites. Results We successfully implanted the ECoG array in the left hemisphere of three rhesus monkeys. The electrodes in the auditory and visual cortex detected robust event related potentials to auditory and visual stimuli, respectively. Bipolar recording from adjacent electrode pairs effectively eliminated chewing artifacts evident in monopolar recording, demonstrating the advantage of using the ECoG array under conditions that generate significant movement artifacts. Comparison with Existing Methods Compared with bipolar ECoG arrays previously developed for macaque monkeys, this array significantly expands the number of cortical target areas in gyral and intralsulcal cortex. Conclusions This new ECoG array provides an opportunity to investigate global network interactions among gyral and intrasulcal cortical areas. PMID:24972186

Pathological findings and diagnostic implications of a rhesus macaque (Macacca mulatta) model of aerosol exposure to Burkholderia mallei (glanders).

PubMed

Yingst, Samuel L; Facemire, Paul; Chuvala, Lara; Norwood, David; Wolcott, Mark; Huzella, Louis

2015-06-01

Burkholderia mallei is a Gram-negative bacillus that causes a pneumonic disease known as glanders in equids and humans, and a lymphatic infection known as farcy, primarily in equids. With the potential to infect humans by the respiratory route, aerosol exposure can result in severe, occasionally fatal, pneumonia. Today, glanders infections in humans are rare, likely due to less frequent contact with infected equids than in the past. Acutely ill humans often have non-specific clinical signs and in order to diagnose cases, especially in scenarios of multiple cases in an unexpected setting, rapid diagnostics for B. mallei may be critical. The pathogenesis of acute glanders in the rhesus macaque (Macaca mulatta) was studied as an initial effort to improve diagnostic methods. In the study described here, the diagnostic techniques of PCR, culture and histopathology were compared. The results indicated that PCR may provide rapid, non-invasive diagnosis of glanders in some cases. As expected, PCR results were positive in lung tissue in 11/12 acutely infected rhesus macaques, but more importantly in terms of diagnostic algorithm development, PCR results were frequently positive in non-invasive samples such as broncho-alveolar lavage or nasal swabs (7/12) and occasionally in blood (3/12). However, conventional bacterial culture failed to recover bacteria in many of these samples. The study showed that the clinical presentation of aerosol-exposed rhesus macaques is similar to descriptions of human glanders and that PCR has potential for rapid diagnosis of outbreaks, if not individual cases.

Pathological findings and diagnostic implications of a rhesus macaque (Macacca mulatta) model of aerosol exposure to Burkholderia mallei (glanders)

PubMed Central

Yingst, Samuel L.; Chuvala, Lara; Norwood, David; Wolcott, Mark; Huzella, Louis

2015-01-01

Burkholderia mallei is a Gram-negative bacillus that causes a pneumonic disease known as glanders in equids and humans, and a lymphatic infection known as farcy, primarily in equids. With the potential to infect humans by the respiratory route, aerosol exposure can result in severe, occasionally fatal, pneumonia. Today, glanders infections in humans are rare, likely due to less frequent contact with infected equids than in the past. Acutely ill humans often have non-specific clinical signs and in order to diagnose cases, especially in scenarios of multiple cases in an unexpected setting, rapid diagnostics for B. mallei may be critical. The pathogenesis of acute glanders in the rhesus macaque (Macaca mulatta) was studied as an initial effort to improve diagnostic methods. In the study described here, the diagnostic techniques of PCR, culture and histopathology were compared. The results indicated that PCR may provide rapid, non-invasive diagnosis of glanders in some cases. As expected, PCR results were positive in lung tissue in 11/12 acutely infected rhesus macaques, but more importantly in terms of diagnostic algorithm development, PCR results were frequently positive in non-invasive samples such as broncho-alveolar lavage or nasal swabs (7/12) and occasionally in blood (3/12). However, conventional bacterial culture failed to recover bacteria in many of these samples. The study showed that the clinical presentation of aerosol-exposed rhesus macaques is similar to descriptions of human glanders and that PCR has potential for rapid diagnosis of outbreaks, if not individual cases. PMID:25850696

Barrett's Esophagus Methylation Profiles — EDRN Public Portal

Cancer.gov

We propose a nested case-control study of biomarkers in the setting of BE. By bringing together research institutions with large populations of patients with BE, we will perform a multi-center study of FISH and hypermethylation markers as possible prognostic factors in BE. The centers will select from their cohorts who have progressed to HGD or to adenocarcinoma of the esophagus ("progressors"), and who also donated samples prior to the development of cancer, when their histology was felt to be benign. These subjects will be compared to individuals who have been under endoscopic surveillance, but who have not progressed to HGD or EAC ("non-progressors"). Using this approach, we hope to identify promising markers for risk stratification in BE. We expect to be able to make successful application for a prospective study of markers identified in this case-control study.

Association of the HLA-B*52 allele with non-progression to AIDS in Brazilian HIV-1-infected individuals.

PubMed

Teixeira, S L M; de Sá, N B R; Campos, D P; Coelho, A B; Guimarães, M L; Leite, T C N F; Veloso, V G; Morgado, M G

2014-04-01

Several human leukocyte antigen (HLA) class I alleles are associated with the susceptibility to human immunodeficiency virus-1 (HIV-1) infection and/or AIDS progression. Of these, the HLA-B alleles are considered the strongest genetic determinant of disease outcome. We evaluated the influence of the HLA-B alleles on AIDS progression among HIV-1-positive individuals from Rio de Janeiro, Brazil, who were categorized as rapid progressors (RPs), typical progressors (TPs) or long-term non-progressors (LTNPs). In this study, significant differences in HLA-B allele frequencies were observed among the three progression groups for the B*48, B*49 and B*52 alleles. After controlling for other factors associated with AIDS progression, the presence of the B*52 allele was shown to be a significant protective factor (hazard ratio (HR) 0.49 (95% confidence interval (CI) 0.27-0.90) P<0.03). Although no direct association was observed between the presence of the B*27 or B*57 allele and the LTNP profile compared with the TP or RP groups, the adjusted model confirmed that these alleles are protective factors against AIDS progression (HR 0.62 (95% CI 0.38-0.99) P<0.05), as previously described. These data corroborate the existence of significant differences in HLA-B allele frequencies among the distinct AIDS progression profiles and further elucidate the role of HLA alleles in the outcome of HIV infections in diverse populations.

Non-polarized cytokine profile of a long-term non-progressor HIV infected patient.

PubMed

Pina, Ana Flávia; Matos, Vanessa Terezinha Gubert de; Bonin, Camila Mareti; Dal Fabbro, Márcia Maria Ferrairo Janini; Tozetti, Inês Aparecida

The HIV-1 initial viral infection may present diverse clinical and laboratory course and lead to rapid, intermediate, or long-term progression. Among the group of non-progressors, the elite controllers are those who control the infection most effectively, in the absence of antiretroviral therapy (ART). In this paper, the TH1, TH2 and TH17 cytokines profiles are described, as well as clinical and laboratory aspects of an HIV-infected patient with undetectable viral load without antiretroviral therapy. Production of IL-6, IL-10, TNF-α, IFN-γ, and IL-17 was detected; in contrast IL-4 was identified. Host-related factors could help explain such a level of infection control, namely the differentiated modulation of the cellular immune response and a non-polarized cytokine response of the TH1 and TH2 profiles. Copyright © 2018 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.

A Cluster Randomized Controlled Trial of an Adolescent HIV Prevention Program among Bahamian Youth: Effect at 12 Months Post-Intervention

PubMed Central

Chen, Xinguang; Lunn, Sonya; Deveaux, Lynette; Li, Xioaming; Brathwaite, Nanika; Cottrell, Lesley; Stanton, Bonita

2014-01-01

Background Behavioral interventions based on the Protection Motivation Theory (PMT) have been demonstrated to reduce HIV risk behavior among mid- and older adolescents in different settings across the globe but have not been evaluated among Caribbean nations and have received limited evaluation among pre-adolescents. Objective To determine 1) the effectiveness among pre-adolescents in The Bahamas of a PMT-based HIV prevention program “Focus on Youth in the Caribbean” (FOYC) and 2) the role of the targeted PMT constructs in intervention effect. Methods 1,360 sixth grade youth (10-11 years of age) from 15 urban schools in New Providence, The Bahamas were randomized by school to receive either FOYC or a control condition. Data collected at baseline, six and 12 months post intervention were analyzed. A five-step scheme was used to assess sexual behavior progression, ranging from “1” = “a virgin without intention to have sex” to” 5″ = “having sex without a condom”. Group-based trajectory analysis was utilized in assessing the program effect. Results Two sexual behavior progression patterns were detected: slow progressors and quick progressors. Receiving FOYC reduced the likelihood for adolescents to become quick progressors (adjusted OR = 0.77, 95% CI: 0.64-1.00). The observed effectiveness was especially impacted by a subset of the targeted PMT constructs. Conclusion FOYC effectively delays sexual risk among Bahamian pre-adolescents. The group-based trajectory analysis provides an analytical approach for assessing interventions among adolescents with low rates and diverse progression patterns of sexual activity. PMID:19116781

Characterization of broadly neutralizing antibody responses to HIV-1 in a cohort of long term non-progressors.

PubMed

González, Nuria; McKee, Krisha; Lynch, Rebecca M; Georgiev, Ivelin S; Jimenez, Laura; Grau, Eulalia; Yuste, Eloísa; Kwong, Peter D; Mascola, John R; Alcamí, José

2018-01-01

Only a small fraction of HIV-1-infected patients develop broadly neutralizing antibodies (bNAbs), a process generally associated to chronic antigen stimulation. It has been described that rare aviremic HIV-1-infected patients can generate bNAbs but this issue remains controversial. To address this matter we have assessed bNAb responses in a large cohort of long-term non-progressors (LTNPs) with low or undetectable viremia. Samples from the LTNP cohort of the Spanish AIDS Research Network (87 elite and 42 viremic controllers) and a control population of 176 viremic typical-progressors (TPs) were screened for bNAbs using Env-recombinant viruses. bNAb specificities were studied by ELISA using mutated gp120, neutralization assays with mutated viruses, and peptide competition. Epitope specificities were also elucidated from the serum pattern of neutralization against a panel of diverse HIV-1 isolates. Broadly neutralizing sera were found among 9.3% LTNPs, both elite (7%) and viremic controllers (14%). Within the broadly neutralizing sera, CD4 binding site antibodies were detected by ELISA in 4/12 LTNPs (33%), and 16/33 of TPs (48%). Anti-MPER antibodies were detected in 6/12 LTNPs (50%) and 14/33 TPs (42%) whereas glycan-dependent HIV-1 bNAbs were more frequent in LTNPs (11/12, 92%) as compared to TPs (12/33, 36%). A good concordance between standard serum mapping and neutralization-based mapping was observed. LTNPs, both viremic and elite controllers, showed broad humoral immune responses against HIV-1, including activity against many major epitopes involved in bNAbs-mediated protection.

Glomerular and Tubular Damage Markers in Individuals with Progressive Albuminuria

PubMed Central

Nauta, Ferdau L.; Scheven, Lieneke; Meijer, Esther; van Oeveren, Wim; de Jong, Paul E.; Bakker, Stephan J.L.

2013-01-01

Summary Background and objectives Albuminuria is associated with risk for renal and cardiovascular disease. It is difficult to predict which persons will progress in albuminuria. This study investigated whether assessment of urinary markers associated with damage to different parts of the nephron may help identify individuals that will progress in albuminuria. Design, setting, participants, & measurements Individuals were selected from a prospective community-based cohort study with serial follow-up and defined as “progressors” if they belonged to the quintile of participants with the most rapid annual increase in albuminuria, and reached an albuminuria ≥150 mg/d during follow-up. Patients with known renal disease or macroalbuminuria at baseline were excluded. Each progressor was matched to two control participants, based on baseline albuminuria, age, and sex. Furthermore, damage markers were measured in a separate set of healthy individuals. Results After a median follow-up of 8.6 years, 183 of 8394 participants met the criteria for progressive albuminuria. Baseline clinical characteristics were comparable between progressors and matched controls (n=366). Both had higher baseline albuminuria than the overall population. Urinary excretion of the glomerular damage marker IgG was significantly higher in progressors, whereas urinary excretion of proximal tubular damage markers and inflammatory markers was lower in these individuals compared with controls. Healthy individuals (n=109) had the lowest values for all urinary damage markers measured. Conclusions These data suggest that albuminuria associated with markers of glomerular damage is more likely to progress, whereas albuminuria associated with markers of tubulointerstitial damage is more likely to remain stable. PMID:23539232

B-virus from pet macaque monkeys: an emerging threat in the United States?

PubMed Central

Ostrowski, S. R.; Leslie, M. J.; Parrott, T.; Abelt, S.; Piercy, P. E.

1998-01-01

Of primary concern when evaluating macaque bites are bacterial and B-virus infections. B-virus infection is highly prevalent (80% to 90%) in adult macaques and may cause a potentially fatal meningoencephalitis in humans. We examined seven nonoccupational exposure incidents involving 24 persons and eight macaques. Six macaques were tested for herpes B; four (67%) were seropositive. A common observation was that children were more than three times as likely to be bitten than adults. The virus must be assumed to be a potential health hazard in macaque bite wounds; this risk makes macaques unsuitable as pets. PMID:9452406

Macacine Herpesvirus 1 in Long-Tailed Macaques, Malaysia, 2009–2011

PubMed Central

Lee, Mei-Ho; Rostal, Melinda K.; Hughes, Tom; Sitam, Frankie; Lee, Chee-Yen; Japning, Jeffrine; Harden, Mallory E.; Griffiths, Anthony; Basir, Misliah; Wolfe, Nathan D.; Daszak, Peter

2015-01-01

Macacine herpesvirus 1 (MaHV1; B virus) naturally infects macaques (Macaca spp.) and can cause fatal encephalitis in humans. In Peninsular Malaysia, wild macaques are abundant, and translocation is used to mitigate human–macaque conflict. Most adult macaques are infected with MaHV1, although the risk for transmission to persons who handle them during capture and translocation is unknown. We investigated MaHV1 shedding among 392 long-tailed macaques (M. fascicularis) after capture and translocation by the Department of Wildlife and National Parks in Peninsular Malaysia, during 2009–2011. For detection of MaHV1 DNA, PCR was performed on urogenital and oropharyngeal swab samples. Overall, 39% of macaques were shedding MaHV1 DNA; rates of DNA detection did not differ between sample types. This study demonstrates that MaHV1 was shed by a substantial proportion of macaques after capture and transport and suggests that persons handling macaques under these circumstances might be at risk for exposure to MaHV1. PMID:26080081

Human-wildlife conflict: proximate predictors of aggression between humans and rhesus macaques in India.

PubMed

Beisner, Brianne A; Heagerty, Allison; Seil, Shannon K; Balasubramaniam, Krishna N; Atwill, Edward R; Gupta, Brij K; Tyagi, Praveen C; Chauhan, Netrapal P S; Bonal, B S; Sinha, P R; McCowan, Brenda

2015-02-01

Macaques live in close contact with humans across South and Southeast Asia, and direct interaction is frequent. Aggressive contact is a concern in many locations, particularly among populations of rhesus and longtail macaques that co-inhabit urbanized cities and towns with humans. We investigated the proximate factors influencing the occurrence of macaque aggression toward humans as well as human aggression toward macaques to determine the extent to which human behavior elicits macaque aggression and vice versa. We conducted a 3-month study of four free-ranging populations of rhesus macaques in Dehradun, India from October-December 2012, using event sampling to record all instances of human-macaque interaction (N = 3120). Our results show that while human aggression was predicted by the potential for economic losses or damage, macaque aggression was influenced by aggressive or intimidating behavior by humans as well as recent rates of conspecific aggression. Further, adult female macaques participated in aggression more frequently than expected, whereas adult and subadult males participated as frequently as expected. Our analyses demonstrate that neither human nor macaque aggression is unprovoked. Rather, both humans and macaques are responding to one another's behavior. Mitigation of human-primate conflict, and indeed other types of human-wildlife conflict in such coupled systems, will require a holistic investigation of the ways in which each participant is responding to, and consequently altering, the behavior of the other. © 2015 Wiley Periodicals, Inc.

Baseline and Longitudinal Change in Isometric Muscle Strength Prior to Radiographic Progression in Osteoarthritic and Pre-Osteoarthritic Knees- Data from the Osteoarthritis Initiative

PubMed Central

Eckstein, Felix; Hitzl, Wolfgang; Duryea, Jeff; Kwoh, C. Kent; Wirth, Wolfgang

2013-01-01

OBJECTIVE To test whether cross-sectional or longitudinal measures of thigh muscle isometric strength differ between knees with and without subsequent radiographic progression of knee osteoarthritis (KOA), with particular focus on pre-osteoarthritic female knees (knees with risk factors but without definite radiographic KOA). METHODS Of 4796 Osteoarthritis Initiative participants, 2835 knees with Kellgren Lawrence grade (KLG) 0–3 had central X-ray readings, annual quantitative joint space width (JSW) and isometric muscle strength measurements (Good strength chair). Separate slope ANCOVA models were used to determine differences in strength between “progressor” and “non- progressor” knees, after adjusting for age, body mass index, and pain. RESULTS 466 participant knees exceeded the smallest detectable JSW change during each of two observation intervals (year 2→4 and year 1→3) and were classified as progressors (213 women, 253 men; 128 KLG0/1, 330 KLG2/3); 946 participant knees did not exceed this threshold in either interval and were classified as non-progressors (588 women, 358 from men; 288KLG0/1, 658KLG2/3). Female progressor knees, including those with KLG0/1, tended to have lower extensor and flexor strength at year2 and at baseline than those without progression, but the difference was not significant after adjusting for confounders. No significant difference was observed in longitudinal change of muscle strength (baseline→year2) prior to radiographic progression. No significant differences were found for muscle strength in men, and none for change in strength concomitant with progression. CONCLUSION This study provides no strong evidence that (changes in) isometric muscle strength precedes or is associated with structural (radiographic) progression of KOA. PMID:23473978

Fast progressive lower motor neuron disease is an ALS variant: A two-centre tract of interest-based MRI data analysis.

PubMed

Müller, Hans-Peter; Agosta, Federica; Riva, Nilo; Spinelli, Edoardo G; Comi, Giancarlo; Ludolph, Albert C; Filippi, Massimo; Kassubek, Jan

2018-01-01

The criteria for assessing upper motor neuron pathology in pure lower motor neuron disease (LMND) still remain a major issue of debate with respect to the clinical classification as an amyotrophic lateral sclerosis (ALS) variant. The study was designed to investigate white matter damage by a hypothesis-guided tract-of-interest-based approach in patients with LMND compared with healthy controls and ´classical´ ALS patients in order to identify in vivo brain structural changes according to the neuropathologically defined ALS affectation pattern. Data were pooled from two previous studies at two different study sites (Ulm, Germany and Milano, Italy). DTI-based white matter integrity mapping was performed by voxelwise statistical comparison and by a tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 65 LMND patients (clinically differentiated in fast and slow progressors) vs. 92 matched controls and 101 ALS patients with a 'classical' phenotype to identify white matter structural alterations. The analysis of white matter structural connectivity by regional FA reductions demonstrated the characteristic alteration patterns along the CST and also in frontal and prefrontal brain areas in LMND patients compared to controls and ALS. Fast progressing LMND showed substantial involvement, like in ALS, while slow progressors showed less severe alterations. In the tract-specific analysis according to the ALS-staging pattern, fast progressing LMND showed significant alterations of ALS-related tract systems as compared to slow progressors and controls. This study showed an affectation pattern for corticoefferent fibers in LMND with fast disease progression as defined for ALS, that way confirming the hypothesis that fast progressing LMND is a phenotypical variant of ALS.

Single neuropsychological test scores associated with rate of cognitive decline in early Alzheimer disease.

PubMed

Parikh, Mili; Hynan, Linda S; Weiner, Myron F; Lacritz, Laura; Ringe, Wendy; Cullum, C Munro

2014-01-01

Alzheimer disease (AD) characteristically begins with episodic memory impairment followed by other cognitive deficits; however, the course of illness varies, with substantial differences in the rate of cognitive decline. For research and clinical purposes it would be useful to distinguish between persons who will progress slowly from persons who will progress at an average or faster rate. Our objective was to use neurocognitive performance features and disease-specific and health information to determine a predictive model for the rate of cognitive decline in participants with mild AD. We reviewed the records of a series of 96 consecutive participants with mild AD from 1995 to 2011 who had been administered selected neurocognitive tests and clinical measures. Based on Clinical Dementia Rating (CDR) of functional and cognitive decline over 2 years, participants were classified as Faster (n = 45) or Slower (n = 51) Progressors. Stepwise logistic regression analyses using neurocognitive performance features, disease-specific, health, and demographic variables were performed. Neuropsychological scores that distinguished Faster from Slower Progressors included Trail Making Test - A, Digit Symbol, and California Verbal Learning Test (CVLT) Total Learned and Primacy Recall. No disease-specific, health, or demographic variable predicted rate of progression; however, history of heart disease showed a trend. Among the neuropsychological variables, Trail Making Test - A best distinguished Faster from Slower Progressors, with an overall accuracy of 68%. In an omnibus model including neuropsychological, disease-specific, health, and demographic variables, only Trail Making Test - A distinguished between groups. Several neuropsychological performance features were associated with the rate of cognitive decline in mild AD, with baseline Trail Making Test - A performance best separating those who declined at an average or faster rate from those who showed slower progression.

Rates of glaucomatous visual field change in a large clinical population.

PubMed

Chauhan, Balwantray C; Malik, Rizwan; Shuba, Lesya M; Rafuse, Paul E; Nicolela, Marcelo T; Artes, Paul H

2014-06-10

To determine the rate of glaucomatous visual field change in routine clinical care. Mean deviation (MD) rate was computed in one randomly selected eye of all glaucoma patients and suspects with ≥5 examinations in a tertiary eye-care center. Proportions of "fast" (MD rate, <-1 to -2 dB/y) and "catastrophic" (<-2 dB/y) progressors were determined. The MD rates were computed in tertile groups by the number of examinations, baseline age, and MD. The MD rates were compared to the Canadian Glaucoma Study (CGS), a prospective study with IOP interventions mandated by visual field progression, by pairwise matching of patients by baseline MD. There were 2324 patients with median (interquartile range) baseline age and MD of 65 (56, 74) years and -2.44 (-5.44, -0.86) dB, and follow-up of 7.1 (4.8, 10.2) years with 8 (6, 11) examinations. The median MD rate was -0.05 (0.13, -0.30) dB/y, while the mean follow-up IOP was 17.1 (15.0, 19.7) mm Hg. The MD rate was progressively worse, with a doubling of fast and catastrophic progressors, with each tertile of increasing age. Worse MD rate was associated with lower follow-up IOP. Neither MD rate nor the number of fast and catastrophic progressors was significantly different in clinical care patients matched to CGS patients. Most patients under routine glaucoma care demonstrate slow rates of visual field progression. The MD rate in the current study was similar to an interventional prospective study, but considerably less negative compared to published studies with similar design. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Population dynamics of rhesus macaques and associated foamy virus in Bangladesh

PubMed Central

Feeroz, Mostafa M; Soliven, Khanh; Small, Christopher T; Engel, Gregory A; Andreina Pacheco, M; Yee, JoAnn L; Wang, Xiaoxing; Kamrul Hasan, M; Oh, Gunwha; Levine, Kathryn L; Rabiul Alam, SM; Craig, Karen L; Jackson, Dana L; Lee, Eun-Gyung; Barry, Peter A; Lerche, Nicholas W; Escalante, Ananias A; Matsen IV, Frederick A; Linial, Maxine L; Jones-Engel, Lisa

2013-01-01

Foamy viruses are complex retroviruses that have been shown to be transmitted from nonhuman primates to humans. In Bangladesh, infection with simian foamy virus (SFV) is ubiquitous among rhesus macaques, which come into contact with humans in diverse locations and contexts throughout the country. We analyzed microsatellite DNA from 126 macaques at six sites in Bangladesh in order to characterize geographic patterns of macaque population structure. We also included in this study 38 macaques owned by nomadic people who train them to perform for audiences. PCR was used to analyze a portion of the proviral gag gene from all SFV-positive macaques, and multiple clones were sequenced. Phylogenetic analysis was used to infer long-term patterns of viral transmission. Analyses of SFV gag gene sequences indicated that macaque populations from different areas harbor genetically distinct strains of SFV, suggesting that geographic features such as forest cover play a role in determining the dispersal of macaques and SFV. We also found evidence suggesting that humans traveling the region with performing macaques likely play a role in the translocation of macaques and SFV. Our studies found that individual animals can harbor more than one strain of SFV and that presence of more than one SFV strain is more common among older animals. Some macaques are infected with SFV that appears to be recombinant. These findings paint a more detailed picture of how geographic and sociocultural factors influence the spectrum of simian-borne retroviruses. PMID:26038465

Adapting to Florida's riverine woodlands: the population status and feeding ecology of the Silver River rhesus macaques and their interface with humans.

PubMed

Riley, Erin P; Wade, Tiffany W

2016-04-01

The study of primates living in novel environments represents an interesting context in which to examine patterns of behavioral and ecological flexibility. Our research focused on an understudied, anthropogenically introduced primate population living in Florida, USA: the Silver River rhesus macaques (Macaca mulatta). To better understand how this population has adapted to life in Florida's riparian woodlands, we collected data on the diet and size of the rhesus macaque population and its encounters with boaters along the Silver River from January to May 2013. Using scan sampling and all-occurrences sampling, we collected 166 h of diet data and 105 h of human-macaque encounter data, respectively. We confirmed previous reports that four social groups comprise the Silver River macaque population, totaling 118 individuals. The Silver River macaques predominantly consumed leaves and other vegetative plant parts (87.5 %), with ash trees serving as a staple food (66.5 % of feeding records). Although human-macaque encounters were frequent (80 % of 611 boats observed), only a small proportion of boats (11.5 %) provisioned the macaques. Motorized boats (e.g., pontoon and motor boats) were more likely to provision, while kayaks and canoes were more likely to move in close proximity of the macaques situated at the river's edge. Our results indicate that the Silver River macaques have adjusted to life in the New World by adopting a temperate-dwelling feeding strategy and by incorporating locally available foods (e.g., sedges) into their diet. They have also learned that the river's edge provides opportunities to receive provisions from boaters. However, because the rate of provisioning is low, these foods likely play a filler fallback role. Given that provisioning and direct contact between macaques and boaters are infrequent but proximity to the macaques is a concern, our findings have important implications for the management of the human-macaque interface along the Silver River and beyond.

Identification of an Enterocytozoon bieneusi-like microsporidian parasite in simian-immunodeficiency-virus-inoculated macaques with hepatobiliary disease.

PubMed Central

Mansfield, K. G.; Carville, A.; Shvetz, D.; MacKey, J.; Tzipori, S.; Lackner, A. A.

1997-01-01

Enterocytozoon bieneusi is a common opportunistic pathogen of human patients with acquired immune deficiency syndrome (AIDS) causing significant morbidity and mortality. In a retrospective analysis utilizing conventional histochemical techniques, in situ hybridization, polymerase chain reaction, and ultrastructural examination, we identified 18 simian-immunodeficiency-virus-infected macaques (16 Macaca mulatta, 1 M. nemestrina, and 1 M. cyclopis) with Enterocytozoon infection of the hepatobiliary system and small intestine. The organisms were readily identified in the bile ducts and gall bladder by special stains and by in situ hybridization using a probe directed against the small subunit ribosomal RNA of human origin E. bieneusi. Infection of the biliary system was associated with a nonsuppurative and proliferative cholecystitis and choledochitis. Hepatic involvement was characterized by bridging portal fibrosis and nodular hepatocellular regeneration accompanied by marked bile ductular and septal duct hyperplasia. Ultrastructurally, all developmental stages of the organism were found in direct contact with the host cell cytoplasm; spores and sporoblasts contained a double layer of polar tubes. Sequencing of a 607-bp segment of the small subunit ribosomal RNA revealed 97 and 100% identity to two clones of small subunit ribosomal RNA derived from E. bieneusi of human origin. Extensive morphological and genetic similarities between the simian and human enterocytozoons suggest that experimentally infected macaques may serve as a useful model of microsporidial infection in AIDS. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:9094995

Characterization of 47 MHC class I sequences in Filipino cynomolgus macaques

PubMed Central

Campbell, Kevin J.; Detmer, Ann M.; Karl, Julie A.; Wiseman, Roger W.; Blasky, Alex J.; Hughes, Austin L.; Bimber, Benjamin N.; O’Connor, Shelby L.; O’Connor, David H.

2009-01-01

Cynomolgus macaques (Macaca fascicularis) provide increasingly common models for infectious disease research. Several geographically distinct populations of these macaques from Southeast Asia and the Indian Ocean island of Mauritius are available for pathogenesis studies. Though host genetics may profoundly impact results of such studies, similarities and differences between populations are often overlooked. In this study we identified 47 full-length MHC class I nucleotide sequences in 16 cynomolgus macaques of Filipino origin. The majority of MHC class I sequences characterized (39 of 47) were unique to this regional population. However, we discovered eight sequences with perfect identity and six sequences with close similarity to previously defined MHC class I sequences from other macaque populations. We identified two ancestral MHC haplotypes that appear to be shared between Filipino and Mauritian cynomolgus macaques, notably a Mafa-B haplotype that has previously been shown to protect Mauritian cynomolgus macaques against challenge with a simian/human immunodeficiency virus, SHIV89.6P. We also identified a Filipino cynomolgus macaque MHC class I sequence for which the predicted protein sequence differs from Mamu-B*17 by a single amino acid. This is important because Mamu-B*17 is strongly associated with protection against simian immunodeficiency virus (SIV) challenge in Indian rhesus macaques. These findings have implications for the evolutionary history of Filipino cynomolgus macaques as well as for the use of this model in SIV/SHIV research protocols. PMID:19107381

Reduced TCOF1 mRNA level in a rhesus macaque with Treacher Collins-like syndrome: further evidence for haploinsufficiency of treacle as the cause of disease.

PubMed

Shows, Kathryn H; Ward, Christy; Summers, Laura; Li, Lin; Ziegler, Gregory R; Hendrickx, Andrew G; Shiang, Rita

2006-02-01

Mutations in the human gene TCOF1 cause a mandibulofacial dysostosis known as Treacher Collins syndrome (TCS). An infant rhesus macaque (Macaca mulatta) that displayed the TCS phenotype was identified at the California National Primate Research Center. The TCOF1 coding region was cloned from a normal rhesus macaque and sequenced. The rhesus macaque homolog of TCOF1 is 91.6% identical in cDNA sequence and 93.8% identical in translated protein sequence compared to human TCOF1. Sequencing of TCOF1 in the TCS-affected rhesus macaque showed no mutations within the coding region or splice sites; however, real-time quantitative PCR showed an 87% reduction of spleen TCOF1 mRNA level in the TCS affected macaque when compared with normal macaque spleen.

Human exposure to herpesvirus B-seropositive macaques, Bali, Indonesia.

PubMed

Engel, Gregory A; Jones-Engel, Lisa; Schillaci, Michael A; Suaryana, Komang Gde; Putra, Artha; Fuentes, Agustin; Henkel, Richard

2002-08-01

Herpesvirus B (Cercopithecine herpesvirus 1) has been implicated as the cause of approximately 40 cases of meningoencephalitis affecting persons in direct or indirect contact with laboratory macaques. However, the threat of herpesvirus B in nonlaboratory settings worldwide remains to be addressed. We investigated the potential for exposure to herpesvirus B in workers at a "monkey forest" (a temple that has become a tourist attraction because of its monkeys) in Bali, Indonesia. In July 2000, 105 workers at the Sangeh Monkey Forest in Central Bali were surveyed about contact with macaques (Macaca fascicularis). Nearly half of those interviewed had either been bitten or scratched by a macaque. Prevalence of injury was higher in those who fed macaques. Serum from 31 of 38 Sangeh macaques contained antibodies to herpesvirus B. We conclude that workers coming into contact with macaques at the Sangeh Monkey Forest are at risk for exposure to herpesvirus B.

Human Exposure to Herpesvirus B–Seropositive Macaques, Bali, Indonesia

PubMed Central

Engel, Gregory A.; Schillaci, Michael A.; Suaryana, Komang Gde; Putra, Artha; Fuentes, Agustin; Henkel, Richard

2002-01-01

Herpesvirus B (Cercopithecine herpesvirus 1) has been implicated as the cause of approximately 40 cases of meningoencephalitis affecting persons in direct or indirect contact with laboratory macaques. However, the threat of herpesvirus B in nonlaboratory settings worldwide remains to be addressed. We investigated the potential for exposure to herpesvirus B in workers at a “monkey forest” (a temple that has become a tourist attraction because of its monkeys) in Bali, Indonesia. In July 2000, 105 workers at the Sangeh Monkey Forest in Central Bali were surveyed about contact with macaques (Macaca fascicularis). Nearly half of those interviewed had either been bitten or scratched by a macaque. Prevalence of injury was higher in those who fed macaques. Serum from 31 of 38 Sangeh macaques contained antibodies to herpesvirus B. We conclude that workers coming into contact with macaques at the Sangeh Monkey Forest are at risk for exposure to herpesvirus B. PMID:12141963

Possible use of heterospecific food-associated calls of macaques by sika deer for foraging efficiency.

PubMed

Koda, Hiroki

2012-09-01

Heterospecific communication signals sometimes convey relevant information for animal survival. For example, animals use or eavesdrop on heterospecific alarm calls concerning common predators. Indeed, most observations have been reported regarding anti-predator strategies. Use of heterospecific signals has rarely been observed as part of a foraging strategy. Here, I report empirical evidence, collected using playback experiments, showing that Japanese sika deer, Cevus nippon, use heterospecific food calls of Japanese macaques, Macaca fuscata yakui, for foraging efficiency. The deer and macaques both inhabit the wild forest of Yakushima Island with high population densities and share many food items. Anecdotal observations suggest that deer often wait to browse fruit falls under the tree where a macaque group is foraging. Furthermore, macaques frequently produce food calls during their foraging. If deer effectively obtain fruit from the leftovers of macaques, browsing fruit fall would provide a potential benefit to the deer, and, further, deer are likely to associate macaque food calls with feeding activity. The results showed that playback of macaque food calls under trees gathered significantly more deer than silence control periods. These results suggest that deer can associate macaque food calls with foraging activities and use heterospecific calls for foraging efficiency. Copyright © 2012 Elsevier B.V. All rights reserved.

Simian immunodeficiency virus SIVmac239 infection and simian human immunodeficiency virus SHIV89.6P infection result in progression to AIDS in cynomolgus macaques of Asian origin.

PubMed

Okamura, Tomotaka; Tsujimura, Yusuke; Soma, Shogo; Takahashi, Ichiro; Matsuo, Kazuhiro; Yasutomi, Yasuhiro

2016-12-01

Simian immunodeficiency virus (SIV) infection models in cynomolgus macaques are important for analysis of the pathogenesis of immunodeficiency virus and for studies on the efficacy of new vaccine candidates. However, very little is known about the pathogenesis of SIV or simian human immunodeficiency virus (SHIV) in cynomolgus macaques from different Asian countries. In the present study, we analysed the infectivity and pathogenicity of CCR5-tropic SIVmac and those of dual-tropic SHIV89.6P inoculated into cynomolgus macaques in Indonesian, Malaysian or Philippine origin. The plasma viral loads in macaques infected with either SIVmac239 or SHIV89.6P were maintained at high levels. CD4+ T cell levels in macaques infected with SIVmac239 gradually decreased. All of the macaques infected with SHIV89.6P showed greatly reduced CD4+ T-cell numbers within 6 weeks of infection. Eight of the 11 macaques infected with SIVmac239 were killed due to AIDS symptoms after 2-4.5 years, while four of the five macaques infected with SHIV89.6P were killed due to AIDS symptoms after 1-3.5 years. We also analysed cynomolgus macaques infected intrarectally with repeated low, medium or high doses of SIVmac239, SIVmac251 or SHIV89.6P. Infection was confirmed by quantitative RT-PCR at more than 5000, 300 and 500 TCID50 for SIVmac239, SIVmac251 and SHIV89.6P, respectively. The present study indicates that cynomolgus macaques of Asian origin are highly susceptible to SIVmac and SHIV infection by both intravenous and mucosal routes. These models will be useful for studies on virus pathogenesis, vaccination and therapeutics against human immunodeficiency virus/AIDS.

Identification of rhesus macaque genital microbiota by 16S pyrosequencing shows similarities to human bacterial vaginosis: implications for use as an animal model for HIV vaginal infection.

PubMed

Spear, Gregory T; Gilbert, Douglas; Sikaroodi, Masoumeh; Doyle, Lara; Green, Linda; Gillevet, Patrick M; Landay, Alan L; Veazey, Ronald S

2010-02-01

The composition of the lower genital tract microbiota in women is believed to affect the risk of sexually acquiring HIV. Since macaque genital microbiota could similarly impact vaginal infection with SIV we identified microbiota in 11 rhesus macaques using multitag pyrosequencing of the 16S rRNA gene. The microbiota was polymicrobial with a median of nine distinct bacterial taxa per macaque (range 3-16 taxa, each constituting 1% or more of the sequences). Taxa frequently found included Peptoniphilus, Sneathia, Porphyromonas, Mobiluncus, Atopobacter, Dialister, Thioreductor, Prevotella, and Streptococcus, many of which are also frequently found in women with bacterial vaginosis. Lactobacillus sequences (mostly L. johnsonii) were found in only four macaques but were not predominant in any (median of 0% of sequences, range 0-39%). All macaques were resampled 6 months after the first time point to determine the stability of the microbiota. The microbiota remained polymicrobial with a median of 10 taxa (range 6-18). Microbial patterns remained similar for six of the macaques, changed substantially in two, and had a mixed pattern in three. Significant sialidase enzyme activity, a marker of bacteria vaginosis in women, was detected in genital fluid from 9/11 and 8/11 macaques from the first and second time points, respectively. These results show that the macaque lower genital microbiota resembled a bacteria vaginosis-type microbiota in women and suggest that the microbiota of macaques in captivity promote rather than protect against vaginal infection with SIV. These results also suggest macaques could be used as an animal model to study some aspects of bacterial vaginosis.

Identification and characterization of short tandem repeats in the Tibetan macaque genome based on resequencing data.

PubMed

Liu, San-Xu; Hou, Wei; Zhang, Xue-Yan; Peng, Chang-Jun; Yue, Bi-Song; Fan, Zhen-Xin; Li, Jing

2018-07-18

The Tibetan macaque, which is endemic to China, is currently listed as a Near Endangered primate species by the International Union for Conservation of Nature (IUCN). Short tandem repeats (STRs) refer to repetitive elements of genome sequence that range in length from 1-6 bp. They are found in many organisms and are widely applied in population genetic studies. To clarify the distribution characteristics of genome-wide STRs and understand their variation among Tibetan macaques, we conducted a genome-wide survey of STRs with next-generation sequencing of five macaque samples. A total of 1 077 790 perfect STRs were mined from our assembly, with an N50 of 4 966 bp. Mono-nucleotide repeats were the most abundant, followed by tetra- and di-nucleotide repeats. Analysis of GC content and repeats showed consistent results with other macaques. Furthermore, using STR analysis software (lobSTR), we found that the proportion of base pair deletions in the STRs was greater than that of insertions in the five Tibetan macaque individuals (P<0.05, t-test). We also found a greater number of homozygous STRs than heterozygous STRs (P<0.05, t-test), with the Emei and Jianyang Tibetan macaques showing more heterozygous loci than Huangshan Tibetan macaques. The proportion of insertions and mean variation of alleles in the Emei and Jianyang individuals were slightly higher than those in the Huangshan individuals, thus revealing differences in STR allele size between the two populations. The polymorphic STR loci identified based on the reference genome showed good amplification efficiency and could be used to study population genetics in Tibetan macaques. The neighbor-joining tree classified the five macaques into two different branches according to their geographical origin, indicating high genetic differentiation between the Huangshan and Sichuan populations. We elucidated the distribution characteristics of STRs in the Tibetan macaque genome and provided an effective method for screening polymorphic STRs. Our results also lay a foundation for future genetic variation studies of macaques.

Genetic characteristics and antimicrobial resistance of Escherichia coli from Japanese macaques (Macaca fuscata) in rural Japan.

PubMed

Ogawa, Keiko; Yamaguchi, Keiji; Suzuki, Masatsugu; Tsubota, Toshio; Ohya, Kenji; Fukushi, Hideto

2011-04-01

Escherichia coli was isolated from wild and captive Japanese macaques (Macaca fuscata) to investigate the risk of zoonotic infections and the prevalence of antimicrobial-resistant Escherichia coli in the wild macaque population in Shimokita Peninsula, a rural area of Japan. We collected 265 fresh fecal samples from wild macaques and 20 samples from captive macaques in 2005 and 2006 for E. coli isolation. The predominant isolates were characterized by serotyping, virulence gene profiling, plasmid profiling, pulsed-field gel electrophoresis (PFGE), and microbial sensitivity tests. In total, 248 E. coli strains were isolated from 159 fecal samples from wild macaques, and 42 E. coli were isolated from 17 samples from captive macaques. None of the virulence genes eae, stx, elt, and est were detected in any of the isolates. The relatedness between wild- and captive-derived isolates was low by serotyping, PFGE, and plasmid profiling. Serotypes O8:H6, O8:H34, O8:H42, O8:HUT, O103:H27, O103:HNM, and OUT:H27 were found in wild macaque feces; serotypes O157:H42 and O119:H21 were recovered from captive macaques. O-and H-serotypes of the 26 isolates were not typed by commercial typing antisera and were named OUT and HUT, respectively. Twenty-eight isolates had no flagellar antigen, and their H-serotypes were named HNM. Similarity of PFGE patterns between wild-derived isolates and captive-derived isolates was <70%. No plasmid profile was shared between wild-derived and captive-derived isolates. The prevalence of antimicrobial-resistant E. coli was 6.5% (n=62) in wild macaques, and these isolates were resistant to cephalothin. We conclude that wild Japanese macaques in Shimokita Peninsula were unlikely to act as a reservoir of pathogenic E. coli for humans and that antimicrobial-resistant E. coli in wild macaques may be derived from humans.

Risk and Resilience: Early Manipulation of Macaque Social Experience and Persistent Behavioral and Neurophysiological Outcomes

ERIC Educational Resources Information Center

Stevens, Hanna E.; Leckman, James F.; Coplan, Jeremy D.; Suomi, Stephen J.

2009-01-01

A literature review on macaque monkeys finds that peer rearing of young macaques and rearing of young macaques by mothers that are undergoing variable foraging conditions result in emotional and neurophysiological disturbance. Certain genotypes contribute to resilience to this disturbance. The findings have implications to child mental health and…

Investigation of cadmium contamination using hair of the Japanese macaque, Macaca fuscata, from Shimokita Peninsula, Aomori Prefecture in Japan.

PubMed

Mochizuki, Mariko; Anahara, Reiko; Mano, Tomoki; Nakayama, Yuri; Kobori, Mutsumi; Omi, Toshinori; Matsuoka, Shiro; Ueda, Fukiko

2012-09-01

The cadmium (Cd) contents in hair of macaques (n = 45, Macaca fuscata) living on the Shimokita Peninsula were investigated. The mean Cd contents in the hair of Japanese (n = 34, 5.01 μg/g) and macaques (3.05 μg/g) tendency to be higher than those of animals living other areas. The Cd contents of hair of wild macaques were significantly (p < 0.01) lower than that of humans, although three were no significant difference between Cd contents of humans and that of the macaque in captivity. The hair of the macaque was suggested as a useful sample for measurement of Cd contamination in the environment.

The Laplacian spectrum of neural networks

PubMed Central

de Lange, Siemon C.; de Reus, Marcel A.; van den Heuvel, Martijn P.

2014-01-01

The brain is a complex network of neural interactions, both at the microscopic and macroscopic level. Graph theory is well suited to examine the global network architecture of these neural networks. Many popular graph metrics, however, encode average properties of individual network elements. Complementing these “conventional” graph metrics, the eigenvalue spectrum of the normalized Laplacian describes a network's structure directly at a systems level, without referring to individual nodes or connections. In this paper, the Laplacian spectra of the macroscopic anatomical neuronal networks of the macaque and cat, and the microscopic network of the Caenorhabditis elegans were examined. Consistent with conventional graph metrics, analysis of the Laplacian spectra revealed an integrative community structure in neural brain networks. Extending previous findings of overlap of network attributes across species, similarity of the Laplacian spectra across the cat, macaque and C. elegans neural networks suggests a certain level of consistency in the overall architecture of the anatomical neural networks of these species. Our results further suggest a specific network class for neural networks, distinct from conceptual small-world and scale-free models as well as several empirical networks. PMID:24454286

The most common Chinese rhesus macaque MHC class I molecule shares peptide binding repertoire with the HLA-B7 supertype

PubMed Central

Solomon, Christopher; Southwood, Scott; Hoof, Ilka; Rudersdorf, Richard; Peters, Bjoern; Sidney, John; Pinilla, Clemencia; Marcondes, Maria Cecilia Garibaldi; Ling, Binhua; Marx, Preston; Sette, Alessandro

2010-01-01

Of the two rhesus macaque subspecies used for AIDS studies, the Simian immunodeficiency virus-infected Indian rhesus macaque (Macaca mulatta) is the most established model of HIV infection, providing both insight into pathogenesis and a system for testing novel vaccines. Despite the Chinese rhesus macaque potentially being a more relevant model for AIDS outcomes than the Indian rhesus macaque, the Chinese-origin rhesus macaques have not been well-characterized for their major histocompatibility complex (MHC) composition and function, reducing their greater utilization. In this study, we characterized a total of 50 unique Chinese rhesus macaques from several varying origins for their entire MHC class I allele composition and identified a total of 58 unique complete MHC class I sequences. Only nine of the sequences had been associated with Indian rhesus macaques, and 28/58 (48.3%) of the sequences identified were novel. From all MHC alleles detected, we prioritized Mamu-A1*02201 for functional characterization based on its higher frequency of expression. Upon the development of MHC/peptide binding assays and definition of its associated motif, we revealed that this allele shares peptide binding characteristics with the HLA-B7 supertype, the most frequent supertype in human populations. These studies provide the first functional characterization of an MHC class I molecule in the context of Chinese rhesus macaques and the first instance of HLA-B7 analogy for rhesus macaques. Electronic supplementary material The online version of this article (doi:10.1007/s00251-010-0450-3) contains supplementary material, which is available to authorized users. PMID:20480161

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caly, Leon; Kassouf, Vicki T.; Moseley, Gregory W.

Nuclear import of the accessory protein Vpr is central to infection by human immunodeficiency virus (HIV). We previously identified the Vpr F72L mutation in a HIV-infected, long-term non-progressor, showing that it resulted in reduced Vpr nuclear accumulation and altered cytoplasmic localisation. Here we demonstrate for the first time that the effects of nuclear accumulation of the F72L mutation are due to impairment of microtubule-dependent-enhancement of Vpr nuclear import. We use high resolution imaging approaches including fluorescence recovery after photobleaching and other approaches to document interaction between Vpr and the dynein light chain protein, DYNLT1, and impaired interaction of the F72Lmore » mutant with DYNLT1. The results implicate MTs/DYNLT1 as drivers of Vpr nuclear import and HIV infection, with important therapeutic implications. - Highlights: • HIV-1 Vpr utilizes the microtubule network to traffic towards the nucleus. • Mechanism relies on interaction between Vpr and dynein light chain protein DYNLT1. • Long-term non-progressor derived mutation (F72L) impairs this interaction. • Key residues in the vicinity of F72 contribute to interaction with DYNLT1.« less

Correction of Refractive Errors in Rhesus Macaques (Macaca mulatta) Involved in Visual Research

PubMed Central

Mitchell, Jude F; Boisvert, Chantal J; Reuter, Jon D; Reynolds, John H; Leblanc, Mathias

2014-01-01

Macaques are the most common animal model for studies in vision research, and due to their high value as research subjects, often continue to participate in studies well into old age. As is true in humans, visual acuity in macaques is susceptible to refractive errors. Here we report a case study in which an aged macaque demonstrated clear impairment in visual acuity according to performance on a demanding behavioral task. Refraction demonstrated bilateral myopia that significantly affected behavioral and visual tasks. Using corrective lenses, we were able to restore visual acuity. After correction of myopia, the macaque's performance on behavioral tasks was comparable to that of a healthy control. We screened 20 other male macaques to assess the incidence of refractive errors and ocular pathologies in a larger population. Hyperopia was the most frequent ametropia but was mild in all cases. A second macaque had mild myopia and astigmatism in one eye. There were no other pathologies observed on ocular examination. We developed a simple behavioral task that visual research laboratories could use to test visual acuity in macaques. The test was reliable and easily learned by the animals in 1 d. This case study stresses the importance of screening macaques involved in visual science for refractive errors and ocular pathologies to ensure the quality of research; we also provide simple methodology for screening visual acuity in these animals. PMID:25427343

Correction of refractive errors in rhesus macaques (Macaca mulatta) involved in visual research.

PubMed

Mitchell, Jude F; Boisvert, Chantal J; Reuter, Jon D; Reynolds, John H; Leblanc, Mathias

2014-08-01

Macaques are the most common animal model for studies in vision research, and due to their high value as research subjects, often continue to participate in studies well into old age. As is true in humans, visual acuity in macaques is susceptible to refractive errors. Here we report a case study in which an aged macaque demonstrated clear impairment in visual acuity according to performance on a demanding behavioral task. Refraction demonstrated bilateral myopia that significantly affected behavioral and visual tasks. Using corrective lenses, we were able to restore visual acuity. After correction of myopia, the macaque's performance on behavioral tasks was comparable to that of a healthy control. We screened 20 other male macaques to assess the incidence of refractive errors and ocular pathologies in a larger population. Hyperopia was the most frequent ametropia but was mild in all cases. A second macaque had mild myopia and astigmatism in one eye. There were no other pathologies observed on ocular examination. We developed a simple behavioral task that visual research laboratories could use to test visual acuity in macaques. The test was reliable and easily learned by the animals in 1 d. This case study stresses the importance of screening macaques involved in visual science for refractive errors and ocular pathologies to ensure the quality of research; we also provide simple methodology for screening visual acuity in these animals.

Human behavior and opportunities for parasite transmission in communities surrounding long-tailed macaque populations in Bali, Indonesia.

PubMed

Lane-DeGraaf, Kelly E; Putra, I G A Arta; Wandia, I Nengah; Rompis, Aida; Hollocher, Hope; Fuentes, Agustin

2014-02-01

Spatial overlap and shared resources between humans and wildlife can exacerbate parasite transmission dynamics. In Bali, Indonesia, an agricultural-religious temple system provides sanctuaries for long-tailed macaques (Macaca fascicularis), concentrating them in areas in close proximity to humans. In this study, we interviewed individuals in communities surrounding 13 macaque populations about their willingness to participate in behaviors that would put them at risk of exposure to gastrointestinal parasites to understand if age, education level, or occupation are significant determinants of exposure behaviors. These exposure risk behaviors and attitudes include fear of macaques, direct contact with macaques, owning pet macaques, hunting and eating macaques, and overlapping water uses. We find that willingness to participate in exposure risk behaviors are correlated with an individual's occupation, age, and/or education level. We also found that because the actual risk of infection varies across populations, activities such as direct macaque contact and pet ownership, could be putting individuals at real risk in certain contexts. Thus, we show that human demographics and social structure can influence willingness to participate in behaviors putting them at increased risk for exposure to parasites. © 2013 Wiley Periodicals, Inc.

Age-Associated Pathology in Rhesus Macaques (Macaca mulatta)

PubMed Central

Simmons, H. A.

2018-01-01

The rhesus macaque (Macaca mulatta) is one of the most extensively used nonhuman primate models for human diseases. This article presents a literature review focusing on major organ systems and age-associated conditions in humans and primates, combined with information from the Wisconsin National Primate Research Center Electronic Health Record database to highlight and contrast age-associated lesions in geriatric rhesus macaques with younger cohorts. Rhesus macaques are excellent models for age-associated conditions, including diabetes, osteoarthritis, endometriosis, visual accommodation, hypertension, osteoporosis, and amyloidosis. Adenocarcinoma of the large intestine (ileocecocolic junction, cecum, and colon) is the most common spontaneous neoplasm in the rhesus macaque. A combination of cross-sectional and longitudinal studies is required to truly define mechanisms of maturation, aging, and the pathology of age-associated conditions in macaques and thus humans. The rhesus macaque is and will continue to be an appropriate and valuable model for investigation of the mechanisms and treatment of age-associated diseases. PMID:26864889

Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study.

PubMed

Herrick, Ariane L; Peytrignet, Sebastien; Lunt, Mark; Pan, Xiaoyan; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan J; Dinsdale, Graham; Brown, Edith; Czirják, László; Distler, Jörg H W; Distler, Oliver; Fligelstone, Kim; Gregory, William J; Ochiel, Rachel; Vonk, Madelon C; Ancuţa, Codrina; Ong, Voon H; Farge, Dominique; Hudson, Marie; Matucci-Cerinic, Marco; Balbir-Gurman, Alexandra; Midtvedt, Øyvind; Jobanputra, Paresh; Jordan, Alison C; Stevens, Wendy; Moinzadeh, Pia; Hall, Frances C; Agard, Christian; Anderson, Marina E; Diot, Elisabeth; Madhok, Rajan; Akil, Mohammed; Buch, Maya H; Chung, Lorinda; Damjanov, Nemanja S; Gunawardena, Harsha; Lanyon, Peter; Ahmad, Yasmeen; Chakravarty, Kuntal; Jacobsen, Søren; MacGregor, Alexander J; McHugh, Neil; Müller-Ladner, Ulf; Riemekasten, Gabriela; Becker, Michael; Roddy, Janet; Carreira, Patricia E; Fauchais, Anne Laure; Hachulla, Eric; Hamilton, Jennifer; İnanç, Murat; McLaren, John S; van Laar, Jacob M; Pathare, Sanjay; Proudman, Susanna M; Rudin, Anna; Sahhar, Joanne; Coppere, Brigitte; Serratrice, Christine; Sheeran, Tom; Veale, Douglas J; Grange, Claire; Trad, Georges-Selim; Denton, Christopher P

2018-04-01

Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. NCT02339441. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

A prospective blood RNA signature for tuberculosis disease risk

PubMed Central

Zak, Daniel E.; Penn-Nicholson, Adam; Scriba, Thomas J.; Thompson, Ethan; Suliman, Sara; Amon, Lynn M.; Mahomed, Hassan; Erasmus, Mzwandile; Whatney, Wendy; Hussey, Gregory D.; Abrahams, Deborah; Kafaar, Fazlin; Hawkridge, Tony; Verver, Suzanne; Hughes, E. Jane; Ota, Martin; Sutherland, Jayne; Howe, Rawleigh; Dockrell, Hazel M.; Boom, W. Henry; Thiel, Bonnie; Ottenhoff, Tom H.M.; Mayanja-Kizza, Harriet; Crampin, Amelia C; Downing, Katrina; Hatherill, Mark; Valvo, Joe; Shankar, Smitha; Parida, Shreemanta K; Kaufmann, Stefan H.E.; Walzl, Gerhard; Aderem, Alan; Hanekom, Willem A.

2016-01-01

Background Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease may lead to interventions that impact the epidemic. Methods Healthy, M. tuberculosis infected South African adolescents were followed for 2 years; blood was collected every 6 months. A prospective signature of risk was derived from whole blood RNA-Sequencing data by comparing participants who ultimately developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex qRT-PCR, the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. The latter participants were household contacts of adults with active pulmonary tuberculosis disease. Findings Of 6,363 adolescents screened, 46 progressors and 107 matched controls were identified. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% confidence interval, 63·2–68·9) and a specificity of 80·6% (79·2–82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA-Seq and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6–64·3) and a specificity of 82·8% (76·7–86) in 12 months preceding tuberculosis. Interpretation The whole blood tuberculosis risk signature prospectively identified persons at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. Funding Bill and Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union and the South African Medical Research Council (detail at end of text). PMID:27017310

Cryopreservation of Cynomolgus Macaque (Macaca fascicularis) Sperm by Using a Commercial Egg-YolkFree Freezing Medium.

PubMed

Yan, Yaping; Ao, Lei; Wang, Hong; Duan, Yanchao; Chang, Shaohui; Chen, Bingbing; Zhi, Dalong; Li, Sujuan; Niu, Yuyu; Ji, Weizhi; Si, Wei

2016-11-01

Conventional TRISegg yolk (TEY) freezing medium for the cryopreservation of NHP sperm has the risk of contamination due to widespread zoonotic diseases. This study was aimed at determining the optimal glycerol concentration, freezing rate, and holding time in liquid N2 vapor for the cryopreservation of cynomolgus macaque sperm by using a commercial egg-yolkfree freezing medium (SC medium) designed for human sperm cryopreservation. Sperm motility and acrosomal integrity after freezing were assessed. Sperm in SC medium (dilution ratio, 3:1) frozen at cooling rates of 67 and 183C/min in liquid N2 vapor showed higher post-thaw motility than did samples frozen at 435C/min. At the cooling rate of 183C/min and dilution in SC medium at a 3:1 ratio, post-thaw motility was higher after a holding time of 10 min than after 30 min (recommended by the manufacturer). In addition, post-thaw motility of sperm frozen in SC medium was higher with dilution ratios of 3:1, 4.5:1, and 6:1 compared with 9:1, 10.5:1, and 12:1, and the sample diluted 12:1 showed the lowest percentage of thawed sperm with intact acrosomes. Sperm showed higher post-thaw motility after freezing in TEY than in SC medium; acrosomal integrity did not differ between the 2 media. Our results indicated that cynomolgus macaque sperm can be cryopreserved successfully by using a commercial egg-yolkfree freezing medium, which provides an option for genetic preservation with decreased zoonotic risk in this important NHP species.

Experimental SSM-CVB3 infection in macaques.

PubMed

Han, Tiesuo; He, Wenqi; Song, Deguang; Zhao, Kui; Wu, Chenchen; Gao, Feng; Lu, Huijun; Gai, Xianying; Wang, Xinrui; Li, Fei; Ji, Cuicui; Lin, Xijuan

2012-02-01

To evaluate the pathogenicity of SSM-CVB3 in a macaque model. The clinical symptoms of macaques were recorded; hematological, biochemical and histopathological evaluations were completed; viral titers and neutralization titers (NT-titers) in sera were tested; and the mRNA levels of SSM-CVB3, coxsackievirus and adenovirus receptor (CAR) and decay accelerating factor (DAF) were determined. After SSM-CVB3 infection, the macaques showed a lack of activity, a poor appetite, a higher body temperature, and severe diarrhea. The macaques also developed hematuria and albuminuria at 4 to 10 days post-inoculation. Virus titers (5.1-6.5 LogTCID(50)/mL) were higher at 6 to 10 days post-inoculation, and NT-titers (6.5-7.3 Log2) reached plateaus at 8 to 14 days post-inoculation. The infected macaques developed serious anemia with decreased RBC and WBC, but the percentages of LYM were increased. The levels of CK, CK-MB, AST and ALT in the sera were 84-169 U/L, 87.6-271.1 U/L, 43-87 U/L and 43-82 U/L, respectively, and all of those were higher than normal. Histological analysis showed obvious cardiac, hepatic and renal damages in the infected macaques and the mRNA contents of SSM-CVB3, CAR and DAF in the heart, liver and kidneys of infected macaques were higher (P<0.05). This was the first report on experimental SSM-CVB3 infections in macaques with serious hepatic and renal damage, except for myocarditis. The information obtained from this study suggests that the SSM-CVB3 strain and this macaque model could be used for studying CVB3-induced cardiac, hepatic or renal diseases. Copyright © 2011 Elsevier Inc. All rights reserved.

Immunohistochemical characterization of slow and fast myosin heavy chain composition of muscle fibres in the styloglossus muscle of the human and macaque (Macaca rhesus).

PubMed

Sokoloff, Alan J; Yang, Betty; Li, Haiyan; Burkholder, Thomas J

2007-06-01

Muscle fibre contractile diversity is thought to be increased by the hybridization of multiple myosin heavy chain (MHC) isoforms in single muscle fibres. Reports of hybrid fibres composed of MHCI and MHCII isoforms in human, but not macaque, tongue muscles, suggest a human adaptation for increased tongue muscle contractile diversity. Here we test whether hybrid fibres composed of MHCI and MHCII are unique to human tongue muscles or are present as well in the macaque. MHC composition of the macaque and human styloglossus was characterized with antibodies that allowed identification of three muscle fibre phenotypes, a slow phenotype composed of MHCI, a fast phenotype composed of MHCII and a hybrid phenotype composed of MHCI and MHCII. The fast phenotype constitutes 68.5% of fibres in the macaque and 43.4% of fibres in the human (P<0.0001). The slow phenotype constitutes 20.2% of fibres in the macaque and 39.3% of fibres in the human (P<0.0001). The hybrid phenotype constitutes 11.2% of fibres in the macaque and 17.3% of fibres in the human (P=0.0002). Macaques and humans do not differ in fiber size (cross-sectional area, diameter). However, measures of fibre size differ by phenotype such that fast>hybrid>slow (P<0.05). These data demonstrate differences in the relative percent of muscle fibre phenotypes in the macaque and human styloglossus but also demonstrate that all three phenotypes are present in both species. These data suggest a similar range of mechanical properties in styloglossus muscle fibres of the macaque and human.

A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge.

PubMed

Andrews, Chasity D; Yueh, Yun Lan; Spreen, William R; St Bernard, Leslie; Boente-Carrera, Mar; Rodriguez, Kristina; Gettie, Agegnehu; Russell-Lodrigue, Kasi; Blanchard, James; Ford, Susan; Mohri, Hiroshi; Cheng-Mayer, Cecilia; Hong, Zhi; Ho, David D; Markowitz, Martin

2015-01-14

Long-acting GSK1265744 (GSK744 LA) is a strand transfer inhibitor of the HIV/SIV (simian immunodeficiency virus) integrase and was shown to be an effective preexposure prophylaxis (PrEP) agent in a low-dose intrarectal SHIV (simian-human immunodeficiency virus) rhesus macaque challenge model. We examined the pharmacokinetics and efficacy of GSK744 LA as PrEP against repeat high-dose intravaginal SHIV challenge in female rhesus macaques treated with Depo-Provera (depot medroxyprogesterone acetate), which promotes viral transmission vaginally. When Depo-Provera-treated female rhesus macaques were dosed with GSK744 LA (50 mg/kg) monthly, systemic and tissue drug concentrations were lower than previously observed in male rhesus macaques. GSK744 concentrations were fivefold lower on average in cervical tissues than in rectal tissues. Eight female rhesus macaques were treated with GSK744 LA at week 0, and four female rhesus macaques served as controls. All animals received a high-dose challenge of SHIV162P3 at week 1. No infection was detected in GSK744 LA-treated rhesus macaques, whereas viremia was detected 1 to 2 weeks after SHIV challenge in all control animals. The GSK744 LA-treated rhesus macaques were given a second administration of drug at week 4 and further challenged at weeks 5 and 7. GSK744 LA treatment protected six of eight female rhesus macaques against three high-dose SHIV challenges, whereas all control animals became infected after the first challenge (P = 0.0003, log-rank test). These results support further clinical development of GSK744 LA for PrEP. Copyright © 2015, American Association for the Advancement of Science.

The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences

PubMed Central

Xue, Cheng; Raveendran, Muthuswamy; Harris, R. Alan; Fawcett, Gloria L.; Liu, Xiaoming; White, Simon; Dahdouli, Mahmoud; Rio Deiros, David; Below, Jennifer E.; Salerno, William; Cox, Laura; Fan, Guoping; Ferguson, Betsy; Horvath, Julie; Johnson, Zach; Kanthaswamy, Sree; Kubisch, H. Michael; Liu, Dahai; Platt, Michael; Smith, David G.; Sun, Binghua; Vallender, Eric J.; Wang, Feng; Wiseman, Roger W.; Chen, Rui; Muzny, Donna M.; Gibbs, Richard A.; Yu, Fuli; Rogers, Jeffrey

2016-01-01

Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research, have the largest natural geographic distribution of any nonhuman primate, and have been the focus of much evolutionary and behavioral investigation. Consequently, rhesus macaques are one of the most thoroughly studied nonhuman primate species. However, little is known about genome-wide genetic variation in this species. A detailed understanding of extant genomic variation among rhesus macaques has implications for the use of this species as a model for studies of human health and disease, as well as for evolutionary population genomics. Whole-genome sequencing analysis of 133 rhesus macaques revealed more than 43.7 million single-nucleotide variants, including thousands predicted to alter protein sequences, transcript splicing, and transcription factor binding sites. Rhesus macaques exhibit 2.5-fold higher overall nucleotide diversity and slightly elevated putative functional variation compared with humans. This functional variation in macaques provides opportunities for analyses of coding and noncoding variation, and its cellular consequences. Despite modestly higher levels of nonsynonymous variation in the macaques, the estimated distribution of fitness effects and the ratio of nonsynonymous to synonymous variants suggest that purifying selection has had stronger effects in rhesus macaques than in humans. Demographic reconstructions indicate this species has experienced a consistently large but fluctuating population size. Overall, the results presented here provide new insights into the population genomics of nonhuman primates and expand genomic information directly relevant to primate models of human disease. PMID:27934697

Chronic alcohol consumption results in higher simian immunodeficiency virus replication in mucosally inoculated rhesus macaques.

PubMed

Poonia, Bhawna; Nelson, Steve; Bagby, Greg J; Zhang, Ping; Quniton, Lee; Veazey, Ronald S

2005-10-01

The influence of alcohol consumption on HIV pathogenesis is not well understood. In this study we used the simian immunodeficiency virus (SIV)/macaque model of HIV infection to study the influence of chronic binge alcohol consumption on SIV infection. Rhesus macaques were fed alcohol or isocaloric amounts of sucrose via indwelling intragastric catheters and then inoculated with SIVmac251 by the rectal route. Real-time RT-PCR for SIV gag mRNA showed significantly higher plasma viral copies in alcohol-consuming macaques at 4 and 6 weeks pi, compared with sucrose controls. The viral copies were 1 to 2 logs higher in these animals. The percentage of CD8+ lymphocytes in the duodenum of alcohol-consuming macaques was significantly lower than in sucrose-consuming macaques both before infection as well as at different time points postinfection. Also, the percentage of CD4(+)CD3+ lymphocytes in the intestines was significantly higher in alcohol-consuming macaques before infection. These findings suggest that a higher percentage of SIV target cells (CD4) in the gut coupled with lower percentages of CD8 cells, which could be important in controlling virus replication, may be responsible for the higher SIV loads observed in alcohol-consuming macaques.

Chronic alcohol consumption results in higher simian immunodeficiency virus replication in mucosally inoculated rhesus macaques.

PubMed

Poonia, Bhawna; Nelson, Steve; Bagby, Greg J; Zhang, Ping; Quniton, Lee; Veazey, Ronald S

2006-06-01

The influence of alcohol consumption on HIV pathogenesis is not well understood. In this study we used the SIV/macaque model of HIV infection to study the influence of chronic binge alcohol consumption on simian immunodeficiency virus (SIV) infection. Rhesus macaques were fed alcohol or isocaloric amounts of sucrose via indwelling intragastric catheters and then inoculated with SIVmac251 by the rectal route. Real-time RTPCR for SIV gag mRNA showed significantly higher plasma viral copies in alcohol-consuming macaques at 4 and 6 weeks pi, compared with sucrose controls. The viral copies were 1 to 2 logs higher in these animals. The percentage of CD8+ lymphocytes in the duodenum of alcohol-consuming macaques was significantly lower than in sucrose-consuming macaques both before infection as well as at different time points postinfection. Also, the percentage of CD4+CD3+ lymphocytes in the intestines was significantly higher in alcohol-consuming macaques before infection. These findings suggest that a higher percentage of SIV target cells (CD4) in the gut coupled with lower percentages of CD8 cells, which could be important in controlling virus replication, may be responsible for the higher SIV loads observed in alcohol-consuming macaques.

Preference for facial averageness: Evidence for a common mechanism in human and macaque infants

PubMed Central

Damon, Fabrice; Méary, David; Quinn, Paul C.; Lee, Kang; Simpson, Elizabeth A.; Paukner, Annika; Suomi, Stephen J.; Pascalis, Olivier

2017-01-01

Human adults and infants show a preference for average faces, which could stem from a general processing mechanism and may be shared among primates. However, little is known about preference for facial averageness in monkeys. We used a comparative developmental approach and eye-tracking methodology to assess visual attention in human and macaque infants to faces naturally varying in their distance from a prototypical face. In Experiment 1, we examined the preference for faces relatively close to or far from the prototype in 12-month-old human infants with human adult female faces. Infants preferred faces closer to the average than faces farther from it. In Experiment 2, we measured the looking time of 3-month-old rhesus macaques (Macaca mulatta) viewing macaque faces varying in their distance from the prototype. Like human infants, macaque infants looked longer to faces closer to the average. In Experiments 3 and 4, both species were presented with unfamiliar categories of faces (i.e., macaque infants tested with adult macaque faces; human infants and adults tested with infant macaque faces) and showed no prototype preferences, suggesting that the prototypicality effect is experience-dependent. Overall, the findings suggest a common processing mechanism across species, leading to averageness preferences in primates. PMID:28406237

Sexual partner preference in female Japanese macaques.

PubMed

Vasey, Paul L

2002-02-01

Whether animals ever exhibit a preference for same-sex sexual partners is a subject of debate. Japanese macaques represent excellent models for examining issues related to sexual preference in animals because females, in certain populations, routinely engage in both heterosexual and homosexual behavior over the course of their life spans. Multiple lines of evidence indicate that female homosexual behavior in Japanese macaques is a sexual behavior, not a sociosexual one. Additional evidence indicates that female Japanese macaques do not engage in homosexual behavior simply because acceptable male mates are unavailable or unmotivated to copulate. Patterns of sexual partner choice by female Japanese macaques that are the focus of intersexual competition indicate that females of this species choose same-sex sexual partners even when they are simultaneously presented with a motivated, opposite-sex alternative. Thus, in some populations of Japanese macaques, females prefer certain same-sex sexual partners relative to certain male mates, and vice versa. Taken together, this evidence suggests that female Japanese macaques are best characterized as bisexual in orientation, not preferentially homosexual or preferentially heterosexual.

Glial cell morphological and density changes through the lifespan of rhesus macaques.

PubMed

Robillard, Katelyn N; Lee, Kim M; Chiu, Kevin B; MacLean, Andrew G

2016-07-01

How aging impacts the central nervous system (CNS) is an area of intense interest. Glial morphology is known to affect neuronal and immune function as well as metabolic and homeostatic balance. Activation of glia, both astrocytes and microglia, occurs at several stages during development and aging. The present study analyzed changes in glial morphology and density through the entire lifespan of rhesus macaques, which are physiologically and anatomically similar to humans. We observed apparent increases in gray matter astrocytic process length and process complexity as rhesus macaques matured from juveniles through adulthood. These changes were not attributed to cell enlargement because they were not accompanied by proportional changes in soma or process volume. There was a decrease in white matter microglial process length as rhesus macaques aged. Aging was shown to have a significant effect on gray matter microglial density, with a significant increase in aged macaques compared with adults. Overall, we observed significant changes in glial morphology as macaques age indicative of astrocytic activation with subsequent increase in microglial density in aged macaques. Copyright © 2016 Elsevier Inc. All rights reserved.

X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feng, Youjun; Graduate School, Chinese Academy of Sciences, Beijing; Qi, Jianxun

2006-01-01

X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide. Simian immunodeficiency virus (SIV) in the rhesus macaque is regarded as a classic animal model, playing a crucial role in HIV vaccine strategies and therapeutics by characterizing various cytotoxic T-lymphocyte (CTL) responses in macaque monkeys. However, the availability of well documented structural reports focusing on rhesus macaque major histocompatibility complex class I (MHC I) molecules remains extremely limited. Here, a complex of the rhesus macaque MHC I molecule (Mamu-A*02) with human β{sub 2}m and an immunodominant SIV-Gag nonapeptide, GESNLKSLY (GY9), has been crystallized. The crystal diffractsmore » X-rays to 2.7 Å resolution and belongs to space group C2, with unit-cell parameters a = 124.11, b = 110.45, c = 100.06 Å, and contains two molecules in the asymmetric unit. The availability of the structure, which is being solved by molecular replacement, will provide new insights into rhesus macaque MHC I (Mamu-A*02) presenting pathogenic SIV peptides.« less

Attenuation of Pathogenic Immune Responses during Infection with Human and Simian Immunodeficiency Virus (HIV/SIV) by the Tetracycline Derivative Minocycline

PubMed Central

Drewes, Julia L.; Szeto, Gregory L.; Engle, Elizabeth L.; Liao, Zhaohao; Shearer, Gene M.; Zink, M. Christine; Graham, David R.

2014-01-01

HIV immune pathogenesis is postulated to involve two major mechanisms: 1) chronic innate immune responses that drive T cell activation and apoptosis and 2) induction of immune regulators that suppress T cell function and proliferation. Both arms are elevated chronically in lymphoid tissues of non-natural hosts, which ultimately develop AIDS. However, these mechanisms are not elevated chronically in natural hosts of SIV infection that avert immune pathogenesis despite similarly high viral loads. In this study we investigated whether minocycline could modulate these pathogenic antiviral responses in non-natural hosts of HIV and SIV. We found that minocycline attenuated in vitro induction of type I interferon (IFN) and the IFN-stimulated genes indoleamine 2,3-dioxygenase (IDO1) and TNF-related apoptosis inducing ligand (TRAIL) in human plasmacytoid dendritic cells and PBMCs exposed to aldrithiol-2 inactivated HIV or infectious influenza virus. Activation-induced TRAIL and expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in isolated CD4+ T cells were also reduced by minocycline. Translation of these in vitro findings to in vivo effects, however, were mixed as minocycline significantly reduced markers of activation and activation-induced cell death (CD25, Fas, caspase-3) but did not affect expression of IFNβ or the IFN-stimulated genes IDO1, FasL, or Mx in the spleens of chronically SIV-infected pigtailed macaques. TRAIL expression, reflecting the mixed effects of minocycline on activation and type I IFN stimuli, was reduced by half, but this change was not significant. These results show that minocycline administered after infection may protect against aspects of activation-induced cell death during HIV/SIV immune disease, but that in vitro effects of minocycline on type I IFN responses are not recapitulated in a rapid progressor model in vivo. PMID:24732038

Transmission of Ebola virus from pigs to non-human primates.

PubMed

Weingartl, Hana M; Embury-Hyatt, Carissa; Nfon, Charles; Leung, Anders; Smith, Greg; Kobinger, Gary

2012-01-01

Ebola viruses (EBOV) cause often fatal hemorrhagic fever in several species of simian primates including human. While fruit bats are considered natural reservoir, involvement of other species in EBOV transmission is unclear. In 2009, Reston-EBOV was the first EBOV detected in swine with indicated transmission to humans. In-contact transmission of Zaire-EBOV (ZEBOV) between pigs was demonstrated experimentally. Here we show ZEBOV transmission from pigs to cynomolgus macaques without direct contact. Interestingly, transmission between macaques in similar housing conditions was never observed. Piglets inoculated oro-nasally with ZEBOV were transferred to the room housing macaques in an open inaccessible cage system. All macaques became infected. Infectious virus was detected in oro-nasal swabs of piglets, and in blood, swabs, and tissues of macaques. This is the first report of experimental interspecies virus transmission, with the macaques also used as a human surrogate. Our finding may influence prevention and control measures during EBOV outbreaks.

Isolation and Characterization of a Neuropathogenic Simian Immunodeficiency Virus Derived from a Sooty Mangabey

PubMed Central

Novembre, Francis J.; De Rosayro, Juliette; O’Neil, Shawn P.; Anderson, Daniel C.; Klumpp, Sherry A.; McClure, Harold M.

1998-01-01

Transfusion of blood from a simian immunodeficiency virus (SIV)- and simian T-cell lymphotropic virus-infected sooty mangabey (designated FGb) to rhesus and pig-tailed macaques resulted in the development of neurologic disease in addition to AIDS. To investigate the role of SIV in neurologic disease, virus was isolated from a lymph node of a pig-tailed macaque (designated PGm) and the cerebrospinal fluid of a rhesus macaque (designated ROn2) and passaged to additional macaques. SIV-related neuropathogenic effects were observed in 100% of the pig-tailed macaques inoculated with either virus. Lesions in these animals included extensive formation of SIV RNA-positive giant cells in the brain parenchyma and meninges. Based upon morphology, the majority of infected cells in both lymphoid and brain tissue appeared to be of macrophage lineage. The virus isolates replicated very well in pig-tailed and rhesus macaque peripheral blood mononuclear cells (PBMC) with rapid kinetics. Differential replicative abilities were observed in both PBMC and macrophage populations, with viruses growing to higher titers in pig-tailed macaque cells than in rhesus macaque cells. An infectious molecular clone of virus derived from the isolate from macaque PGm (PGm5.3) was generated and was shown to have in vitro replication characteristics similar to those of the uncloned virus stock. While molecular analyses of this virus revealed its similarity to SIV isolates from sooty mangabeys, significant amino acid differences in Env and Nef were observed. This virus should provide an excellent system for investigating the mechanism of lentivirus-induced neurologic disease. PMID:9765429

Genetic characterization of rhesus macaques (Macaca mulatta) in Nepal.

PubMed

Kyes, Randall C; Jones-Engel, Lisa; Chalise, Mukesh K; Engel, Gregory; Heidrich, John; Grant, Richard; Bajimaya, Shyam S; McDonough, John; Smith, David Glenn; Ferguson, Betsy

2006-05-01

Indian-origin rhesus macaques (Macaca mulatta) have long served as an animal model for the study of human disease and behavior. Given the current shortage of Indian-origin rhesus, many researchers have turned to rhesus macaques from China as a substitute. However, a number of studies have identified marked genetic differences between the Chinese and Indian animals. We investigated the genetic characteristics of a third rhesus population, the rhesus macaques of Nepal. Twenty-one rhesus macaques at the Swoyambhu Temple in Kathmandu, Nepal, were compared with more than 300 Indian- and Chinese-origin rhesus macaques. The sequence analyses of two mitochondrial DNA (mtDNA) loci, from the HVS I and 12 S rRNA regions, showed that the Nepali animals were more similar to Indian-origin than to Chinese-origin animals. The distribution of alleles at 24 short tandem repeat (STR) loci distributed across 17 chromosomes also showed greater similarity between the Nepali and Indian-origin animals. Finally, an analysis of seven major histocompatibility complex (MHC) alleles showed that the Nepali animals expressed Class I alleles that are common to Indian-origin animals, including Mamu-A*01. All of these analyses also revealed a low level of genetic diversity within this Nepali rhesus sample. We conclude that the rhesus macaques of Nepal more closely resemble rhesus macaques of Indian origin than those of Chinese origin. As such, the Nepali rhesus may offer an additional resource option for researchers who wish to maintain research protocols with animals that possess key genetic features characteristic of Indian-origin rhesus macaques. 2005 Wiley-Liss, Inc.

Activity of wild Japanese macaques in Yakushima revealed by camera trapping: Patterns with respect to season, daily period and rainfall

PubMed Central

Otani, Yosuke; Hongo, Shun; Honda, Takeaki; Okamura, Hiroki; Higo, Yuma

2018-01-01

Animals are subject to various scales of temporal environmental fluctuations, among which daily and seasonal variations are two of the most widespread and significant ones. Many biotic and abiotic factors change temporally, and climatic factors are particularly important because they directly affect the cost of thermoregulation. The purpose of the present study was to determine the activity patterns of wild Japanese macaques (Macaca fuscata) with a special emphasis on the effect of thermal conditions. We set 30 camera traps in the coniferous forest of Yakushima and monitored them for a total of 8658 camera-days between July 2014 and July 2015. Over the one-year period, temperature had a positive effect, and rainfall had a negative effect on the activity of macaques during the day. Capture rate was significantly higher during the time period of one hour after sunrise and during midday. During winter days, macaques concentrated their activity around noon, and activity shifted from the morning toward the afternoon. This could be interpreted as macaques shifting their activity to warmer time periods within a single day. Japanese macaques decreased their activity during the time before sunrise in seasons with lower temperatures. It was beneficial for macaques to be less active during cooler time periods in a cold season. Even small amounts of rainfall negatively affected the activity of Japanese macaques, with capture rates decreasing significantly even when rainfall was only 0.5–1 mm/min. In conclusion, thermal conditions significantly affected the activity of wild Japanese macaques at various time scales. PMID:29293657

Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

USGS Publications Warehouse

Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

2013-01-01

Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in vCJD-infected human and macaque blood.

Identification of MHC class I sequences in Chinese-origin rhesus macaques

PubMed Central

Karl, Julie A.; Wiseman, Roger W.; Campbell, Kevin J.; Blasky, Alex J.; Hughes, Austin L.; Ferguson, Betsy; Read, Daniel S.

2010-01-01

The rhesus macaque (Macaca mulatta) is an excellent model for human disease and vaccine research. Two populations exhibiting distinctive morphological and physiological characteristics, Indian- and Chinese-origin rhesus macaques, are commonly used in research. Genetic analysis has focused on the Indian macaque population, but the accessibility of these animals for research is limited. Due to their greater availability, Chinese rhesus macaques are now being used more frequently, particularly in vaccine and biodefense studies, although relatively little is known about their immunogenetics. In this study, we discovered major histocompatibility complex (MHC) class I cDNAs in 12 Chinese rhesus macaques and detected 41 distinct Mamu-A and Mamu-B sequences. Twenty-seven of these class I cDNAs were novel, while six and eight of these sequences were previously reported in Chinese and Indian rhesus macaques, respectively. We then performed microsatellite analysis on DNA from these 12 animals, as well as an additional 18 animals, and developed sequence specific primer PCR (PCR-SSP) assays for eight cDNAs found in multiple animals. We also examined our cohort for potential admixture of Chinese and Indian origin animals using a recently developed panel of single nucleotide polymorphisms (SNPs). The discovery of 27 novel MHC class I sequences in this analysis underscores the genetic diversity of Chinese rhesus macaques and contributes reagents that will be valuable for studying cellular immunology in this population. PMID:18097659

Estimation of Shear Wave Speed in the Rhesus Macaques Uterine Cervix

PubMed Central

Huang, Bin; Drehfal, Lindsey C.; Rosado-Mendez, Ivan M.; Guerrero, Quinton W.; Palmeri, Mark L.; Simmons, Heather A.; Feltovich, Helen; Hall, Timothy J.

2016-01-01

Cervical softness is a critical parameter in pregnancy. Clinically, preterm birth is associated with premature cervical softening and post-dates birth is associated with delayed cervical softening. In practice, the assessment of softness is subjective, based on digital examination. Fortunately, objective, quantitative techniques to assess softness and other parameters associated with microstructural cervical change are emerging. One of these is shear wave speed (SWS) estimation. In principle, this allows objective characterization of stiffness because waves travel more slowly in softer tissue. We are studying SWS in humans and rhesus macaques, the latter in order to accelerate translation from bench to bedside. For the current study, we estimated SWS in ex vivo cervices of rhesus macaques, n=24 nulliparous (never given birth) and n=9 multiparous (delivered at least 1 baby). Misoprostol (a prostaglandin used to soften human cervices prior to gynecological procedures) was administered to 13 macaques prior to necropsy (nulliparous: 7, multiparous: 6). SWS measurements were made at predetermined locations from the distal to proximal end of the cervix on both the anterior and posterior cervix, with 5 repeat measures at each location. The intent was to explore macaque cervical microstructure, including biological and spatial variability, to elucidate the similarities and differences between the macaque and the human cervix in order to facilitate future in vivo studies. We found that SWS is dependent on location in the normal nonpregnant macaque cervix, as in the human cervix. Unlike the human cervix, we detected no difference between ripened and unripened rhesus macaque cervix samples, nor nulliparous versus multiparous samples, although we observed a trend toward stiffer tissue in nulliparous samples. We found rhesus macaque cervix to be much stiffer than human, which is important for technique refinement. These findings are useful for guiding study of cervical microstructure in both humans and macaques. PMID:26886979

Retrospective Analysis of the Incidence of Retained Placenta in 3 Large Colonies of NHP

PubMed Central

Bauer, Cassondra; Harrison, Tara

2016-01-01

During 1999 through 2014, retained placenta was the most common cause of clinical admission for reproductive complications in breeding colonies of baboons (approximate colony size, 2000 animals), cynomolgus macaques (approximately 1000), and rhesus macaques (approximately 500) at the Southwest National Primate Research Center. Retained placentas occurred in 2.7% of baboons, 3.3% of cynomolgus macaques, and 1.0% of rhesus macaques. Apparent risk factors for retained placenta included stillbirth or abortion and at least one prior cesarean section. There was a significant association between stillbirth and retained placenta in all species. Cesarean sections were performed routinely for baboons to meet research objectives but occurred only as needed for cynomolgus and rhesus macaques. Having had at least one prior cesarean section was an incidence factor for retained placenta in 37.0% of baboons and 4.7% of cynomolgus macaques; none of the rhesus macaques with retained placentas had undergone cesarean section previously. More than 90% of dams with retained placenta returned to a successful reproductive life or assignment to a nonbreeding research protocol. Advances in reproductive management will benefit from prospective studies that capture additional data from all members of a breeding group prior to reproductive complications. PMID:27053569

Retrospective Analysis of the Incidence of Retained Placenta in 3 Large Colonies of NHP.

PubMed

Bauer, Cassondra; Harrison, Tara

2016-04-01

During 1999 through 2014, retained placenta was the most common cause of clinical admission for reproductive complications in breeding colonies of baboons (approximate colony size, 2000 animals), cynomolgus macaques (approximately 1000), and rhesus macaques (approximately 500) at the Southwest National Primate Research Center. Retained placentas occurred in 2.7% of baboons, 3.3% of cynomolgus macaques, and 1.0% of rhesus macaques. Apparent risk factors for retained placenta included stillbirth or abortion and at least one prior cesarean section. There was a significant association between stillbirth and retained placenta in all species. Cesarean sections were performed routinely for baboons to meet research objectives but occurred only as needed for cynomolgus and rhesus macaques. Having had at least one prior cesarean section was an incidence factor for retained placenta in 37.0% of baboons and 4.7% of cynomolgus macaques; none of the rhesus macaques with retained placentas had undergone cesarean section previously. More than 90% of dams with retained placenta returned to a successful reproductive life or assignment to a nonbreeding research protocol. Advances in reproductive management will benefit from prospective studies that capture additional data from all members of a breeding group prior to reproductive complications.

Annual variations in sexual hormones and births' frequency in female stump-tailed macaques (Macaca arctoides).

PubMed

Mondragón-Ceballos, R; García-Granados, M D; Matamoros-Trejo, G; Hernández-López, L E

2018-03-01

Although the breeding seasonality in Macaca arctoides have been studied over a long period of time, it is still controversial whether reproduction in this primate tend to increase during certain months of the year as it happens in most of the macaque species. Many authors have classified Macaca arctoides as not being seasonal species. Nonetheless, there were no reports, about seasonal variations of female sexual hormones to demonstrate that asseveration. Therefore, in the present study we collect 1611 fecal samples from June 2009 to November 2010 from 10 female stump-tailed macaques to measure 17β-estradiol and progesterone concentrations. Also, we included the birth frequency per year, in order to identify if sexual hormones peaked at a certain period of the year, thus, births would be occurring six months later according to the gestation length of stump-tailed macaques. Our results indicate two mating seasons per year in stump-tailed macaques: one in July-August and a second one in November. The distribution of the birth frequency, throughout the year support these results. We conclude that stump-tail macaques have a discrete seasonality no different than most of macaques' species. Copyright © 2017 Elsevier Inc. All rights reserved.

A Microneedle Patch for Measles and Rubella Vaccination Is Immunogenic and Protective in Infant Rhesus Macaques.

PubMed

Joyce, Jessica C; Carroll, Timothy D; Collins, Marcus L; Chen, Min-Hsin; Fritts, Linda; Dutra, Joseph C; Rourke, Tracy L; Goodson, James L; McChesney, Michael B; Prausnitz, Mark R; Rota, Paul A

2018-04-26

New methods to increase measles and rubella (MR) vaccination coverage are needed to achieve global and regional MR elimination goals. Here, we developed microneedle (MN) patches designed to administer MR vaccine by minimally trained personnel, leave no biohazardous sharps waste, remove the need for vaccine reconstitution, and provide thermostability outside the cold chain. This study evaluated the immunogenicity of MN patches delivering MR vaccine to infant rhesus macaques. Protective titers of measles neutralizing antibodies (>120 mIU/mL) were detected in 100% of macaques in the MN group and 75% of macaques in the subcutaneous (SC) injection group. Rubella neutralizing antibody titers were >10 IU/mL for all groups. All macaques in the MN group were protected from challenge with wild-type measles virus, whereas 75% were protected in the SC group. However, vaccination by the MN or SC route was unable to generate protective immune responses to measles in infant macaques pretreated with measles immunoglobulin to simulate maternal antibody. These results show, for the first time, that MR vaccine delivered by MN patch generated protective titers of neutralizing antibodies to both measles and rubella in infant rhesus macaques and afforded complete protection from measles virus challenge.

Depressive-like behavioral profiles in captive-bred single- and socially-housed rhesus and cynomolgus macaques: a species comparison

PubMed Central

Camus, Sandrine M. J.; Rochais, Céline; Blois-Heulin, Catherine; Li, Qin; Hausberger, Martine; Bezard, Erwan

2014-01-01

Background: To unravel the causes of major depressive disorder (MDD), the third leading cause of disease burden around the world, ethological animal models have recently been proposed. Our previous studies highlighted a depressive-like profile among single- and socially-housed farm-bred cynomolgus macaques. Although phylogenetically close, cynomolgus and rhesus macaques, the two most commonly used macaque species in biomedical research, differ on several levels such as patterns of aggression, reconciliation, temperament, or dominance styles. The question of whether one captive macaque species was more vulnerable than another in the development of a pathological profile reminiscent of MDD symptoms was explored. Methods: Behavioral data (including body postures, orientations, gaze directions, inter-individual distances, and locations in the cage) were collected in farming conditions. Using an unbiased validated ethological scan-sampling method, followed by multiple correspondence and hierarchical clustering analyses, 40 single- and 35 socially-housed rhesus macaques were assessed. Independently, for each housing condition, inter-species comparisons were made with previously acquired data on farm-bred cynomolgus monkeys. Results: Consistent with our previous studies, we found depressive-like characteristics (e.g., inactivity, low level of investigation and maintenance, long time spent inactive while facing the wall) among single- and socially-housed rhesus macaques. Species-specificities were reported in non-depressive time budgets and in the prevalence of the pathological profiles. Conclusions: Our results suggest that rhesus may be more vulnerable to developing a despair-like state than cynomolgus macaques, both in single- and in social-housing conditions. Therefore, rhesus macaques are more suitable for use as a “spontaneous” model of depressive disorders. PMID:24600363

Disseminated Hemangiosarcoma in a Juvenile Rhesus Macaque (Macaca mulatta)

PubMed Central

Beck, Amanda P; Gray, Stanton B; Chaffee, Beth K

2016-01-01

Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported in rhesus macaques. This report describes the clinicopathologic features of a 1-y-old rhesus macaque with spontaneous disseminated hemangiosarcoma that originally presented as a focal cutaneous mass. Histopathologic examination of multiple tumor foci revealed regions in which the neoplastic cells formed diffuse sheets, as well as the well-defined vascular channels typically associated with hemangiosarcoma. Multiple endothelial cell immunomarkers were used to confirm the diagnosis in this rhesus macaque. The tumor exhibited staining properties consistent with those seen in domestic animals and humans. In addition, to our knowledge, this animal represents the youngest case of any form of spontaneous hemangiosarcoma reported in the rhesus macaque to date. PMID:27298251

Disseminated Hemangiosarcoma in a Juvenile Rhesus Macaque (Macaca mulatta).

PubMed

Beck, Amanda P; Gray, Stanton B; Chaffee, Beth K

2016-01-01

Hemangiosarcoma is a malignant tumor of vascular endothelial origin that is sporadically reported in rhesus macaques. This report describes the clinicopathologic features of a 1-y-old rhesus macaque with spontaneous disseminated hemangiosarcoma that originally presented as a focal cutaneous mass. Histopathologic examination of multiple tumor foci revealed regions in which the neoplastic cells formed diffuse sheets, as well as the well-defined vascular channels typically associated with hemangiosarcoma. Multiple endothelial cell immunomarkers were used to confirm the diagnosis in this rhesus macaque. The tumor exhibited staining properties consistent with those seen in domestic animals and humans. In addition, to our knowledge, this animal represents the youngest case of any form of spontaneous hemangiosarcoma reported in the rhesus macaque to date.

Somatostatin-immunoreactive senile plaque-like structures in the frontal cortex and nucleus accumbens of aged tree shrews and Japanese macaques.

PubMed

Yamashita, Akiko; Fuchs, Eberhard; Taira, Masato; Yamamoto, Takamitsu; Hayashi, Motoharu

2012-06-01

Previously, we demonstrated decreased expression of somatostatin mRNA in aged macaque brain, particularly in the prefrontal cortex. To investigate whether or not this age-dependent decrease in mRNA is related to morphological changes, we analyzed somatostatin cells in the cerebra of aged Japanese macaques and compared them with those in rats and tree shrews, the latter of which are closely related to primates. Brains of aged macaques, tree shrews, and rats were investigated by immunohistochemistry with special emphasis on somatostatin. We observed degenerating somatostatin-immunoreactive cells in the cortices of aged macaques and tree shrews. Somatostatin-immunoreactive senile plaque-like structures were found in areas 6 and 8 and in the nucleus accumbens of macaques, as well as in the nucleus accumbens and the cortex of aged tree shrews, where amyloid accumulations were observed. Somatostatin degenerations may be related to amyloid accumulations and may play roles in impairments of cognitive functions during aging. © 2012 John Wiley & Sons A/S.

The genetic composition of populations of cynomolgus macaques (Macaca fascicularis) used in biomedical research.

PubMed

Kanthaswamy, S; Ng, J; Satkoski Trask, J; George, D A; Kou, A J; Hoffman, L N; Doherty, T B; Houghton, P; Smith, D G

2013-06-01

The genetic composition of cynomolgus macaques used in biomedical research is not as well-characterized as that of rhesus macaques. Populations of cynomolgus macaques from Sumatra, Corregidor, Mauritius, Singapore, Cambodia, and Zamboanga were analyzed using 24 STRs. The Sumatran and Cambodian populations exhibited the highest allelic diversity, while the Mauritian population exhibited the lowest. Sumatran cynomolgus macaques were the most genetically similar to all others, consistent with an Indonesian origin of the species. The high diversity among Cambodian animals may result from interbreeding with rhesus macaques. The Philippine and Mauritian samples were the most divergent from other populations, the former due to separation from the Sunda Shelf by deepwater and the latter due to anthropogenic translocation and extreme founder effects. Investigators should verify their research subjects' origin, ancestry, and pedigree to minimize risks to biomedical experimentation from genetic variance stemming from close kinship and mixed ancestry as these can obscure treatment effects. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

High Infection Rates for Adult Macaques after Intravaginal or Intrarectal Inoculation with Zika Virus

PubMed Central

Nalca, Aysegul; Rossi, Franco D.; Miller, Lynn J.; Wiley, Michael R.; Perez-Sautu, Unai; Washington, Samuel C.; Norris, Sarah L.; Wollen-Roberts, Suzanne E.; Shamblin, Joshua D.; Kimmel, Adrienne E.; Bloomfield, Holly A.; Valdez, Stephanie M.; Sprague, Thomas R.; Principe, Lucia M.; Bellanca, Stephanie A.; Cinkovich, Stephanie S.; Lugo-Roman, Luis; Cazares, Lisa H.; Pratt, William D.; Palacios, Gustavo F.; Bavari, Sina; Pitt, M. Louise; Nasar, Farooq

2017-01-01

Unprotected sexual intercourse between persons residing in or traveling from regions with Zika virus transmission is a risk factor for infection. To model risk for infection after sexual intercourse, we inoculated rhesus and cynomolgus macaques with Zika virus by intravaginal or intrarectal routes. In macaques inoculated intravaginally, we detected viremia and virus RNA in 50% of macaques, followed by seroconversion. In macaques inoculated intrarectally, we detected viremia, virus RNA, or both, in 100% of both species, followed by seroconversion. The magnitude and duration of infectious virus in the blood of macaques suggest humans infected with Zika virus through sexual transmission will likely generate viremias sufficient to infect competent mosquito vectors. Our results indicate that transmission of Zika virus by sexual intercourse might serve as a virus maintenance mechanism in the absence of mosquito-to-human transmission and could increase the probability of establishment and spread of Zika virus in regions where this virus is not present. PMID:28548637

Establishment of an immortal cynomolgus macaque fibroblast cell line for propagation of cynomolgus macaque cytomegalovirus (CyCMV).

PubMed

Ambagala, Aruna P; Marsh, Angie K; Chan, Jacqueline K; Mason, Rosemarie; Pilon, Richard; Fournier, Jocelyn; Sandstrom, Paul; Willer, David O; MacDonald, Kelly S

2013-05-01

Cynomolgus macaques are widely used as an animal model in biomedical research. We have established an immortalized cynomolgus macaque fibroblast cell line (MSF-T) by transducing primary dermal fibroblasts isolated from a 13-year-old male cynomolgus macaque with a retrovirus vector expressing human telomerase reverse transcriptase (hTERT). The MSF-T cells showed increased telomerase enzyme activity and reached over 200 in vitro passages compared to the non-transduced dermal fibroblasts, which reached senescence after 43 passages. The MSF-T cell line is free of mycoplasma contamination and is permissive to the newly identified cynomolgus macaque cytomegalovirus (CyCMV). CyCMV productively infects MSF-T cells and induces down-regulation of MHC class I expression. The MSF-T cell line will be extremely useful for the propagation of CyCMV and other cynomolgus herspesviruses in host-derived fibroblast cells, allowing for the retention of host-specific viral genes. Moreover, this cell line will be beneficial for many in vitro experiments related to this animal model.

Differential cross-reactivity of monoclonal antibody OPD4 (anti-CD45RO) in macaques.

PubMed

Wang, Xiaolei; Pahar, Bapi; Rasmussen, Terri; Alvarez, Xavier; Dufour, Jason; Rasmussen, Kelsi; Lackner, Andrew A; Veazey, Ronald S

2008-01-01

Immunologic research in nonhuman primates is occasionally limited by the availability of reagents that cross-react in nonhuman primates. One major limitation has been the lack of a monoclonal antibody to CD45RO. Although the monoclonal antibody UCHL-1 is used to detect CD45RO isoforms in humans, it does not react with nonhuman primates, mandating the use of alternative strategies to define "memory" T cell responses in nonhuman primates. The current study examined the reactivity and specificity of another antibody against CD45RO, clone OPD4, in macaques. Here we demonstrate that OPD4 specifically labels memory CD4+ T cells in approximately 44% of rhesus macaques (Macaca mulatta) of Indian but not Chinese origin. In contrast, tissues from pigtail macaques (Macaca nemestrina) react with this clone, indicating that OPD4 may be useful for examining memory CD4+ T cells in certain macaques, but its utility may be limited in other species or even among individual macaques.

Differential cross-reactivity of monoclonal antibody OPD4 (anti-CD45RO) in macaques

PubMed Central

Wang, Xiaolei; Pahar, Bapi; Rasmussen, Terri; Alvarez, Xavier; Dufour, Jason; Rasmussen, Kelsi; Lackner, Andrew A.; Veazey, Ronald S.

2008-01-01

Immunologic research in nonhuman primates is occasionally limited by the availability of reagents that cross react in nonhuman primates. One major limitation has been the lack of a monoclonal antibody to CD45RO. Although the monoclonal antibody UCHL-1 is used to detect CD45RO isoforms in humans, it does not react with nonhuman primates, mandating the use of alternative strategies to define “memory” T cell responses in nonhuman primates. The current study examined the reactivity and specificity of another antibody against CD45RO, clone OPD4, in macaques. Here we demonstrate that OPD4 specifically labels memory CD4+ T cells in ~44% of rhesus macaques (Macaca mulatta) of Indian, but not Chinese origin. In contrast, tissues from pigtail macaques (Macaca nemestrina) react with this clone, indicating that OPD4 may be useful for examining memory CD4+ T cells in certain macaques, but its utility may be limited in other species or even among individual macaques. PMID:18304631

High Infection Rates for Adult Macaques after Intravaginal or Intrarectal Inoculation with Zika Virus.

PubMed

Haddow, Andrew D; Nalca, Aysegul; Rossi, Franco D; Miller, Lynn J; Wiley, Michael R; Perez-Sautu, Unai; Washington, Samuel C; Norris, Sarah L; Wollen-Roberts, Suzanne E; Shamblin, Joshua D; Kimmel, Adrienne E; Bloomfield, Holly A; Valdez, Stephanie M; Sprague, Thomas R; Principe, Lucia M; Bellanca, Stephanie A; Cinkovich, Stephanie S; Lugo-Roman, Luis; Cazares, Lisa H; Pratt, William D; Palacios, Gustavo F; Bavari, Sina; Pitt, M Louise; Nasar, Farooq

2017-08-01

Unprotected sexual intercourse between persons residing in or traveling from regions with Zika virus transmission is a risk factor for infection. To model risk for infection after sexual intercourse, we inoculated rhesus and cynomolgus macaques with Zika virus by intravaginal or intrarectal routes. In macaques inoculated intravaginally, we detected viremia and virus RNA in 50% of macaques, followed by seroconversion. In macaques inoculated intrarectally, we detected viremia, virus RNA, or both, in 100% of both species, followed by seroconversion. The magnitude and duration of infectious virus in the blood of macaques suggest humans infected with Zika virus through sexual transmission will likely generate viremias sufficient to infect competent mosquito vectors. Our results indicate that transmission of Zika virus by sexual intercourse might serve as a virus maintenance mechanism in the absence of mosquito-to-human transmission and could increase the probability of establishment and spread of Zika virus in regions where this virus is not present.

Protective Role of BST2 Polymorphisms in Mother-to-Child Transmission of HIV-1 and Adult AIDS Progression.

PubMed

Kamada, Anselmo J; Bianco, Anna M; Zupin, Luisa; Girardelli, Martina; Matte, Maria C C; Medeiros, Rúbia Marília de; Almeida, Sabrina Esteves de Matos; Rocha, Marineide M; Segat, Ludovica; Chies, José A B; Kuhn, Louise; Crovella, Sergio

2016-07-01

Bone marrow stromal cell antigen-2 (BST-2)/Tetherin is a restriction factor that prevents Human immunodeficiency virus type 1 (HIV-1) release from infected cells and mediates pro-inflammatory cytokine production. This study investigated the risk conferred by single nucleotide polymorphisms (rs919266, rs9192677, and rs9576) at BST-2 coding gene (BST2) in HIV-1 mother-to-child transmission and in disease progression. Initially, 101 HIV-1+ pregnant women and 331 neonates exposed to HIV-1 from Zambia were enrolled. Additional BST2 single nucleotide polymorphism analyses were performed in 2 cohorts with acquired immunodeficiency syndrome (AIDS) progression: an adult Brazilian cohort (37 rapid, 30 chronic and 21 long-term non-progressors) and an Italian pediatric cohort (21 rapid and 67 slow progressors). The rs9576A allele was nominally associated with protection during breastfeeding (P = 0.019) and individuals carrying rs919266 GA showed slower progression to AIDS (P = 0.033). Despite the influence of rs919266 and rs9576 on BST2 expression being still undetermined, a preventive role by BST2 polymorphisms was found during HIV-1 infection.

Gastrointestinal Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques Is Characterized by Proinflammatory Dysregulation of the Interleukin-6-Janus Kinase/Signal Transducer and Activator of Transcription3 Pathway

PubMed Central

Mohan, Mahesh; Aye, Pyone P.; Borda, Juan T.; Alvarez, Xavier; Lackner, Andrew A.

2007-01-01

Gastrointestinal disease and inflammation are common sequelae of human and simian immunodeficiency virus (SIV) infection. Nevertheless, the molecular mechanisms that lead to gastrointestinal dysfunction remain unclear. We investigated regulation of the interleukin (IL)-6-JAK-STAT3 pathway in jejunum and colon, collected at necropsy, from 10 SIV-infected macaques with diarrhea (group 1), 10 non-SIV-infected macaques with diarrhea (group 2), and 7 control uninfected macaques (group 3). All group 1 and 2 macaques had chronic diarrhea, wasting, and colitis, but group 1 animals had more frequent and severe lesions in the jejunum. A significant increase in IL-6 and SOCS-3 gene expression along with constitutive STAT3 activation was observed in the colon of all group 1 and 2 macaques and in the jejunum of only group 1 macaques compared to controls. Further, in colon, histopathology severity scores correlated significantly with IL-6 (groups 1 and 2) and SOCS-3 (group 2) gene expression. In jejunum, a similar correlation was observed only in group 1 animals. Phosphorylated STAT3 (p-STAT3) was localized to lymphocytes (CD3+) and macrophages (CD68+), with fewer CD3+ lymphocytes expressing p-STAT3 in group 1 macaques. Despite high SOCS-3 expression, STAT3 remained constitutively active, providing a possible explanation for persistent intestinal inflammation and immune activation that may favor viral replication and disease progression. PMID:18055558

ABO blood group phenotype frequency estimation using molecular phenotyping in rhesus and cynomolgus macaques.

PubMed

Kanthaswamy, S; Ng, J; Oldt, R F; Valdivia, L; Houghton, P; Smith, D G

2017-11-01

A much larger sample (N = 2369) was used to evaluate a previously reported distribution of the A, AB and B blood group phenotypes in rhesus and cynomolgus macaques from six different regional populations. These samples, acquired from 15 different breeding and research facilities in the United States, were analyzed using a real-time quantitative polymerase chain reaction (qPCR) assay that targets single nucleotide polymorphisms (SNPs) responsible for the macaque A, B and AB phenotypes. The frequency distributions of blood group phenotypes of the two species differ significantly from each other and significant regional differentiation within the geographic ranges of each species was also observed. The B blood group phenotype was prevalent in rhesus macaques, especially those from India, while the frequencies of the A, B and AB phenotypes varied significantly among cynomolgus macaques from different geographic regions. The Mauritian cynomolgus macaques, despite having originated in Indonesia, showed significant (P ≪ .01) divergence from the Indonesian animals at the ABO blood group locus. Most Mauritian animals belonged to the B blood group while the Indonesian animals were mostly A. The close similarity in blood group frequency distributions between the Chinese rhesus and Indochinese cynomolgus macaques demonstrates that the introgression between these two species extends beyond the zone of intergradation in Indochina. This study underscores the importance of ABO blood group phenotyping of the domestic supply of macaques and their biospecimens. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Using Machine Learning to Discover Latent Social Phenotypes in Free-Ranging Macaques

PubMed Central

Madlon-Kay, Seth; Brent, Lauren J. N.; Heller, Katherine A.; Platt, Michael L.

2017-01-01

Investigating the biological bases of social phenotypes is challenging because social behavior is both high-dimensional and richly structured, and biological factors are more likely to influence complex patterns of behavior rather than any single behavior in isolation. The space of all possible patterns of interactions among behaviors is too large to investigate using conventional statistical methods. In order to quantitatively define social phenotypes from natural behavior, we developed a machine learning model to identify and measure patterns of behavior in naturalistic observational data, as well as their relationships to biological, environmental, and demographic sources of variation. We applied this model to extensive observations of natural behavior in free-ranging rhesus macaques, and identified behavioral states that appeared to capture periods of social isolation, competition over food, conflicts among groups, and affiliative coexistence. Phenotypes, represented as the rate of being in each state for a particular animal, were strongly and broadly influenced by dominance rank, sex, and social group membership. We also identified two states for which variation in rates had a substantial genetic component. We discuss how this model can be extended to identify the contributions to social phenotypes of particular genetic pathways. PMID:28754001

The Travelling-Wave Primate System: A New Solution for Magnetic Resonance Imaging of Macaque Monkeys at 7 Tesla Ultra-High Field.

PubMed

Herrmann, Tim; Mallow, Johannes; Plaumann, Markus; Luchtmann, Michael; Stadler, Jörg; Mylius, Judith; Brosch, Michael; Bernarding, Johannes

2015-01-01

Neuroimaging of macaques at ultra-high field (UHF) is usually conducted by combining a volume coil for transmit (Tx) and a phased array coil for receive (Rx) tightly enclosing the monkey's head. Good results have been achieved using vertical or horizontal magnets with implanted or near-surface coils. An alternative and less costly approach, the travelling-wave (TW) excitation concept, may offer more flexible experimental setups on human whole-body UHF magnetic resonance imaging (MRI) systems, which are now more widely available. Goal of the study was developing and validating the TW concept for in vivo primate MRI. The TW Primate System (TWPS) uses the radio frequency shield of the gradient system of a human whole-body 7 T MRI system as a waveguide to propagate a circularly polarized B1 field represented by the TE11 mode. This mode is excited by a specifically designed 2-port patch antenna. For receive, a customized neuroimaging monkey head receive-only coil was designed. Field simulation was used for development and evaluation. Signal-to-noise ratio (SNR) was compared with data acquired with a conventional monkey volume head coil consisting of a homogeneous transmit coil and a 12-element receive coil. The TWPS offered good image homogeneity in the volume-of-interest Turbo spin echo images exhibited a high contrast, allowing a clear depiction of the cerebral anatomy. As a prerequisite for functional MRI, whole brain ultrafast echo planar images were successfully acquired. The TWPS presents a promising new approach to fMRI of macaques for research groups with access to a horizontal UHF MRI system.

Cryopreservation of Cynomolgus Macaque (Macaca fascicularis) Sperm by Using a Commercial Egg-Yolk–Free Freezing Medium

PubMed Central

Yan, Yaping; Ao, Lei; Wang, Hong; Duan, Yanchao; Chang, Shaohui; Chen, Bingbing; Zhi, Dalong; Li, Sujuan; Niu, Yuyu; Ji, Weizhi; Si, Wei

2016-01-01

Conventional TRIS–egg yolk (TEY) freezing medium for the cryopreservation of NHP sperm has the risk of contamination due to widespread zoonotic diseases. This study was aimed at determining the optimal glycerol concentration, freezing rate, and holding time in liquid N2 vapor for the cryopreservation of cynomolgus macaque sperm by using a commercial egg-yolk–free freezing medium (SC medium) designed for human sperm cryopreservation. Sperm motility and acrosomal integrity after freezing were assessed. Sperm in SC medium (dilution ratio, 3:1) frozen at cooling rates of –67° and –183°C/min in liquid N2 vapor showed higher post-thaw motility than did samples frozen at –435 °C/min. At the cooling rate of –183 °C/min and dilution in SC medium at a 3:1 ratio, post-thaw motility was higher after a holding time of 10 min than after 30 min (recommended by the manufacturer). In addition, post-thaw motility of sperm frozen in SC medium was higher with dilution ratios of 3:1, 4.5:1, and 6:1 compared with 9:1, 10.5:1, and 12:1, and the sample diluted 12:1 showed the lowest percentage of thawed sperm with intact acrosomes. Sperm showed higher post-thaw motility after freezing in TEY than in SC medium; acrosomal integrity did not differ between the 2 media. Our results indicated that cynomolgus macaque sperm can be cryopreserved successfully by using a commercial egg-yolk–free freezing medium, which provides an option for genetic preservation with decreased zoonotic risk in this important NHP species. PMID:27931311

The Travelling-Wave Primate System: A New Solution for Magnetic Resonance Imaging of Macaque Monkeys at 7 Tesla Ultra-High Field

PubMed Central

Herrmann, Tim; Mallow, Johannes; Plaumann, Markus; Luchtmann, Michael; Stadler, Jörg; Mylius, Judith; Brosch, Michael; Bernarding, Johannes

2015-01-01

Introduction Neuroimaging of macaques at ultra-high field (UHF) is usually conducted by combining a volume coil for transmit (Tx) and a phased array coil for receive (Rx) tightly enclosing the monkey’s head. Good results have been achieved using vertical or horizontal magnets with implanted or near-surface coils. An alternative and less costly approach, the travelling-wave (TW) excitation concept, may offer more flexible experimental setups on human whole-body UHF magnetic resonance imaging (MRI) systems, which are now more widely available. Goal of the study was developing and validating the TW concept for in vivo primate MRI. Methods The TW Primate System (TWPS) uses the radio frequency shield of the gradient system of a human whole-body 7 T MRI system as a waveguide to propagate a circularly polarized B1 field represented by the TE11 mode. This mode is excited by a specifically designed 2-port patch antenna. For receive, a customized neuroimaging monkey head receive-only coil was designed. Field simulation was used for development and evaluation. Signal-to-noise ratio (SNR) was compared with data acquired with a conventional monkey volume head coil consisting of a homogeneous transmit coil and a 12-element receive coil. Results The TWPS offered good image homogeneity in the volume-of-interest Turbo spin echo images exhibited a high contrast, allowing a clear depiction of the cerebral anatomy. As a prerequisite for functional MRI, whole brain ultrafast echo planar images were successfully acquired. Conclusion The TWPS presents a promising new approach to fMRI of macaques for research groups with access to a horizontal UHF MRI system. PMID:26066653

Characterization of full-length MHC class II sequences in Indonesian and Vietnamese cynomolgus macaques.

PubMed

Creager, Hannah M; Becker, Ericka A; Sandman, Kelly K; Karl, Julie A; Lank, Simon M; Bimber, Benjamin N; Wiseman, Roger W; Hughes, Austin L; O'Connor, Shelby L; O'Connor, David H

2011-09-01

In recent years, the use of cynomolgus macaques in biomedical research has increased greatly. However, with the exception of the Mauritian population, knowledge of the MHC class II genetics of the species remains limited. Here, using cDNA cloning and Sanger sequencing, we identified 127 full-length MHC class II alleles in a group of 12 Indonesian and 12 Vietnamese cynomolgus macaques. Forty two of these were completely novel to cynomolgus macaques while 61 extended the sequence of previously identified alleles from partial to full length. This more than doubles the number of full-length cynomolgus macaque MHC class II alleles available in GenBank, significantly expanding the allele library for the species and laying the groundwork for future evolutionary and functional studies.

Mycobacterium kansasii Isolated from Tuberculinpositive Rhesus Macaques (Macaca mulatta) in the Absence of Disease.

PubMed

Shipley, Steven T; Johnson, David K; Roodgar, Morteza; Smith, David Glenn; Montgomery, Charles A; Lloyd, Steven M; Higgins, James A; Kriel, Edwin H; Klein, Hilton J; Porter, William P; Nazareno, Jerome B; Houghton, Paul W; Panda, Aruna; DeTolla, Louis J

2017-08-01

Mycobacterial infections are of primary health concern in NHP colonies in biomedical research. NHP are constantly monitored and screened for Mycobacterium spp. We report 6 Chinese-origin rhesus macaques infected with Mycobacterium kansasii that exhibited positive tuberculin skin tests in the absence of disease. Two of these macaques were being used for research purposes; the remaining 4 macaques were residing at the contract quarantine company. Histopathology and acid-fast staining of fixed tissues from all macaques showed that all were free of disease. Thoracic radiographs were negative for any signs of disease or infection. Samples from bronchial lavage and tissues including lung, spleen, hilar and mesenteric lymph nodes tested negative by PCR assay for Mycobacterium spp. One of the research macaques tested culture-positive for M. kansasii and a poorly characterized M. avium complex organism. One macaque from the contract quarantine facility tested culture positive for M. kansasii. Genomic testing and target gene RNA expression analysis of the 2 M. kansasii isolates were performed to evaluate possible kinship and affected genes that might contribute to susceptibility to mycobacterial infection. Genotyping of the 2 isolates revealed 2 genetically distinct strains (strains 1 and 4). The presence of positive tuberculin skin tests in the absence of disease raises serious concerns regarding diagnostic methods used for infected NHP.

Allogeneic lymphocytes persist and traffic in feral MHC-matched mauritian cynomolgus macaques.

PubMed

Greene, Justin M; Burwitz, Benjamin J; Blasky, Alex J; Mattila, Teresa L; Hong, Jung Joo; Rakasz, Eva G; Wiseman, Roger W; Hasenkrug, Kim J; Skinner, Pamela J; O'Connor, Shelby L; O'Connor, David H

2008-06-11

Thus far, live attenuated SIV has been the most successful method for vaccinating macaques against pathogenic SIV challenge; however, it is not clear what mechanisms are responsible for this protection. Adoptive transfer studies in mice have been integral to understanding live attenuated vaccine protection in models like Friend virus. Previous adoptive transfers in primates have failed as transferred cells are typically cleared within hours after transfer. Here we describe adoptive transfer studies in Mauritian origin cynomolgus macaques (MCM), a non-human primate model with limited MHC diversity. Cells transferred between unrelated MHC-matched macaques persist for at least fourteen days but are rejected within 36 hours in MHC-mismatched macaques. Cells trafficked from the blood to peripheral lymphoid tissues within 12 hours of transfer. MHC-matched MCM provide the first viable primate model for adoptive transfer studies. Because macaques infected with SIV are the best model for HIV/AIDS pathogenesis, we can now directly study the correlates of protective immune responses to AIDS viruses. For example, plasma viral loads following pathogenic SIV challenge are reduced by several orders of magnitude in macaques previously immunized with attenuated SIV. Adoptive transfer of lymphocyte subpopulations from vaccinated donors into SIV-naïve animals may define the immune mechanisms responsible for protection and guide future vaccine development.

Manual lateralization in macaques: handedness, target laterality and task complexity.

PubMed

Regaiolli, Barbara; Spiezio, Caterina; Vallortigara, Giorgio

2016-01-01

Non-human primates represent models to understand the evolution of handedness in humans. Despite several researches have been investigating non-human primates handedness, few studies examined the relationship between target position, hand preference and task complexity. This study aimed at investigating macaque handedness in relation to target laterality and tastiness, as well as task complexity. Seven pig-tailed macaques (Macaca nemestrina) were involved in three different "two alternative choice" tests: one low-level task and two high-level tasks (HLTs). During the first and the third tests macaques could select a preferred food and a non-preferred food, whereas by modifying the design of the second test, macaques were presented with no-difference alternative per trial. Furthermore, a simple-reaching test was administered to assess hand preference in a social context. Macaques showed hand preference at individual level both in simple and complex tasks, but not in the simple-reaching test. Moreover, target position seemed to affect hand preference in retrieving an object in the low-level task, but not in the HLT. Additionally, individual hand preference seemed to be affected from the tastiness of the item to be retrieved. The results suggest that both target laterality and individual motivation might influence hand preference of macaques, especially in simple tasks.

A Putative Multiple-Demand System in the Macaque Brain.

PubMed

Mitchell, Daniel J; Bell, Andrew H; Buckley, Mark J; Mitchell, Anna S; Sallet, Jerome; Duncan, John

2016-08-17

In humans, cognitively demanding tasks of many types recruit common frontoparietal brain areas. Pervasive activation of this "multiple-demand" (MD) network suggests a core function in supporting goal-oriented behavior. A similar network might therefore be predicted in nonhuman primates that readily perform similar tasks after training. However, an MD network in nonhuman primates has not been described. Single-cell recordings from macaque frontal and parietal cortex show some similar properties to human MD fMRI responses (e.g., adaptive coding of task-relevant information). Invasive recordings, however, come from limited prespecified locations, so they do not delineate a macaque homolog of the MD system and their positioning could benefit from knowledge of where MD foci lie. Challenges of scanning behaving animals mean that few macaque fMRI studies specifically contrast levels of cognitive demand, so we sought to identify a macaque counterpart to the human MD system using fMRI connectivity in 35 rhesus macaques. Putative macaque MD regions, mapped from frontoparietal MD regions defined in humans, were found to be functionally connected under anesthesia. To further refine these regions, an iterative process was used to maximize their connectivity cross-validated across animals. Finally, whole-brain connectivity analyses identified voxels that were robustly connected to MD regions, revealing seven clusters across frontoparietal and insular cortex comparable to human MD regions and one unexpected cluster in the lateral fissure. The proposed macaque MD regions can be used to guide future electrophysiological investigation of MD neural coding and in task-based fMRI to test predictions of similar functional properties to human MD cortex. In humans, a frontoparietal "multiple-demand" (MD) brain network is recruited during a wide range of cognitively demanding tasks. Because this suggests a fundamental function, one might expect a similar network to exist in nonhuman primates, but this remains controversial. Here, we sought to identify a macaque counterpart to the human MD system using fMRI connectivity. Putative macaque MD regions were functionally connected under anesthesia and were further refined by iterative optimization. The result is a network including lateral frontal, dorsomedial frontal, and insular and inferior parietal regions closely similar to the human counterpart. The proposed macaque MD regions can be useful in guiding electrophysiological recordings or in task-based fMRI to test predictions of similar functional properties to human MD cortex. Copyright © 2016 Mitchell et al.

The Variability of Estimated Glomerular Filtration Rate Decline in Alport Syndrome.

PubMed

Langsford, David; Tang, Mila; Djurdjev, Ognjenka; Er, Lee; Levin, Adeera

2016-01-01

A progressive trajectory toward renal failure is common in patients with Alport syndrome. Genotype-phenotype correlations have been well described; however, the natural history of the trajectory toward renal failure is not well described. The objective of this study is to describe the natural history of renal function decline in a cohort of Alport syndrome patients. Retrospective observational cohort study. British Columbia, Canada, chronic renal disease registry 1995-2012. 37 biopsy proven Alport syndrome or hematuria with family history of Alport syndrome. Serial estimated glomerular filtration rate (eGFR) Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient's eGFR measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2 /y decline), stable state (0-2 mL/min/1.73 m2 /y decline), and regressors (>2 mL/min/1.73 m2 /y incline). In this retrospective observational cohort study, participants were identified through a chronic renal disease registry in British Columbia, Canada, from 1995 to 2012. Inclusion criteria were biopsy proven or hematuria with a family history of Alport syndrome. Individual patients and family group members were studied. Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient's serial estimated glomerular filtration rate (eGFR) measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m 2 /y decline), stable state (0-2 mL/min/1.73 m 2 /y decline), and regressors (>2 mL/min/1.73 m 2 /y incline). Histological or genetic evidence of Alport syndrome is not available in all patients. Median follow-up time was 48.2 months of 37 patients (78% male), with a median age of 36 (interquartile range [IQR], 18-47) and a median age of renal replacement therapy commencement (n = 23) of 38 (IQR = 20-52). Renal function changes were found to be heterogeneous overall, intra-individual and within families. Portion of progressors in eGFR 45-60 mL/min/1.73 m 2 was 73.7% (SD, 10.3), whereas 23.6% (SD, 11.0) remained stable. Within eGFR 30-45 mL/min/1.73 m 2 , 45.6% (SD, 7.0) were progressors, whereas 53.4% (SD, 7.4) remained stable. A large portion of eGFR 15-30 mL/min/1.73 m 2 patients were stable (54.8%; SD, 8.4), whereas 25.7% (SD, 7.1) progressed and 19.5% (SD, 5.6) regressed. The renal decline in Alport syndrome patients is heterogeneous which has implications for designing clinical trials of interventions.

The Variability of Estimated Glomerular Filtration Rate Decline in Alport Syndrome

PubMed Central

Langsford, David; Tang, Mila; Djurdjev, Ognjenka; Er, Lee; Levin, Adeera

2016-01-01

Background: A progressive trajectory toward renal failure is common in patients with Alport syndrome. Genotype-phenotype correlations have been well described; however, the natural history of the trajectory toward renal failure is not well described. Objective: The objective of this study is to describe the natural history of renal function decline in a cohort of Alport syndrome patients. Design: Retrospective observational cohort study. Setting: British Columbia, Canada, chronic renal disease registry 1995-2012. Patients: 37 biopsy proven Alport syndrome or hematuria with family history of Alport syndrome. Measurements: Serial estimated glomerular filtration rate (eGFR) Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient’s eGFR measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2 /y decline), stable state (0-2 mL/min/1.73 m2 /y decline), and regressors (>2 mL/min/1.73 m2 /y incline). Methods: In this retrospective observational cohort study, participants were identified through a chronic renal disease registry in British Columbia, Canada, from 1995 to 2012. Inclusion criteria were biopsy proven or hematuria with a family history of Alport syndrome. Individual patients and family group members were studied. Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient’s serial estimated glomerular filtration rate (eGFR) measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2/y decline), stable state (0-2 mL/min/1.73 m2/y decline), and regressors (>2 mL/min/1.73 m2/y incline). Limitations: Histological or genetic evidence of Alport syndrome is not available in all patients. Results: Median follow-up time was 48.2 months of 37 patients (78% male), with a median age of 36 (interquartile range [IQR], 18-47) and a median age of renal replacement therapy commencement (n = 23) of 38 (IQR = 20-52). Renal function changes were found to be heterogeneous overall, intra-individual and within families. Portion of progressors in eGFR 45-60 mL/min/1.73 m2 was 73.7% (SD, 10.3), whereas 23.6% (SD, 11.0) remained stable. Within eGFR 30-45 mL/min/1.73 m2, 45.6% (SD, 7.0) were progressors, whereas 53.4% (SD, 7.4) remained stable. A large portion of eGFR 15-30 mL/min/1.73 m2 patients were stable (54.8%; SD, 8.4), whereas 25.7% (SD, 7.1) progressed and 19.5% (SD, 5.6) regressed. Conclusions: The renal decline in Alport syndrome patients is heterogeneous which has implications for designing clinical trials of interventions. PMID:28781883

Prevention of Rectal SHIV Transmission in Macaques by Daily or Intermittent Prophylaxis with Emtricitabine and Tenofovir

PubMed Central

García-Lerma, J. Gerardo; Otten, Ron A; Qari, Shoukat H; Jackson, Eddie; Cong, Mian-er; Masciotra, Silvina; Luo, Wei; Kim, Caryn; Adams, Debra R; Monsour, Michael; Lipscomb, Jonathan; Johnson, Jeffrey A; Delinsky, David; Schinazi, Raymond F; Janssen, Robert; Folks, Thomas M; Heneine, Walid

2008-01-01

Background In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. Methods and Findings We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. Conclusions This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities. PMID:18254653

Development of Broadly Neutralizing Antibodies and Their Mapping by Monomeric gp120 in Human Immunodeficiency Virus Type 1-Infected Humans and Simian-Human Immunodeficiency Virus SHIVSF162P3N-Infected Macaques.

PubMed

Jia, Manxue; Lu, Hong; Markowitz, Martin; Cheng-Mayer, Cecilia; Wu, Xueling

2016-04-01

To improve our understanding of the similarities and differences between neutralizing antibodies elicited by simian-human immunodeficiency virus (SHIV)-infected rhesus macaques and human immunodeficiency virus type 1 (HIV-1)-infected humans, we examined the plasma of 13 viremic macaques infected with SHIVSF162P3Nand 85 HIV-1-infected humans with known times of infection. We identified 5 macaques (38%) from 1 to 2 years postinfection (p.i.) with broadly neutralizing antibodies (bnAbs) against tier 2 HIV-1. In comparison, only 2 out of 42 (5%) human plasma samples collected in a similar time frame of 1 to 3 years p.i. exhibited comparable neutralizing breadths and potencies, with the number increasing to 7 out of 21 (30%) after 3 years p.i. Plasma mapping with monomeric gp120 identified only 2 out of 9 humans and 2 out of 4 macaques that contained gp120-reactive neutralizing antibodies, indicating distinct specificities in these plasma samples, with most of them recognizing the envelope trimer (including gp41) rather than the gp120 monomer. Indeed, a total of 20 gp120-directed monoclonal antibodies (MAbs) isolated from a human subject (AD358) and a Chinese rhesus macaque (GB40) displayed no or limited neutralizing activity against tier 2 strains. These isolated MAbs, mapped to the CD4-binding site, the V3 loop, the inner domain, and the C5 region of gp120, revealed genetic similarity between the human and macaque immunoglobulin genes used to encode some V3-directed MAbs. These results also support the use of envelope trimer probes for efficient isolation of HIV-1 bnAbs. HIV-1 vaccine research can benefit from understanding the development of broadly neutralizing antibodies (bnAbs) in rhesus macaques, commonly used to assess vaccine immunogenicity and efficacy. Here, we examined 85 HIV-1-infected humans and 13 SHIVSF162P3N-infected macaques for bnAbs and found that, similar to HIV-1-infected humans, bnAbs in SHIV-infected macaques are also rare, but their development might have been faster in some of the studied macaques. Plasma mapping with monomeric gp120 indicated that most bnAbs bind to the envelope trimer rather than the gp120 monomer. In support of this, none of the isolated gp120-reactive monoclonal antibodies (MAbs) displayed the neutralization breadth observed in the corresponding plasma. However, the MAb sequences revealed similarity between human and macaque genes used to encode some V3-directed MAbs. Our study sheds light on the timing and development of bnAbs in SHIV-infected macaques in comparison to HIV-1-infected humans and highlights the use of envelope trimer probes for efficient recovery of bnAbs. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Variation in hair δ13C and δ15N values in long-tailed macaques (Macaca fascicularis) from Singapore

USGS Publications Warehouse

Schillaci, Michael A.; Castellini, J. Margaret; Stricker, Craig A.; Jones-Engel, Lisa; Lee, Benjamin P.Y.-H.

2014-01-01

Much of the primatology literature on stable isotope ratios of carbon (δ13C) and nitrogen (δ15N) has focused on African and New World species, with comparatively little research published on Asian primates. Here we present hair δ13C and δ15N isotope values for a sample of 33 long-tailed macaques from Singapore. We evaluate the suggestion by a previous researcher that forest degradation and biodiversity loss in Singapore have led to a decline in macaque trophic level. The results of our analysis indicated significant spatial variability in δ13C but not δ15N. The range of variation in δ13C was consistent with a diet based on C3 resources, with one group exhibiting low values consistent with a closed canopy environment. Relative to other macaque species from Europe and Asia, the macaques from Singapore exhibited a low mean δ13C value but mid-range mean δ15N value. Previous research suggesting a decline in macaque trophic level is not supported by the results of our study.

Ability of herpes simplex virus vectors to boost immune responses to DNA vectors and to protect against challenge by simian immunodeficiency virus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaur, Amitinder; Sanford, Hannah B.; Garry, Deirdre

2007-01-20

The immunogenicity and protective capacity of replication-defective herpes simplex virus (HSV) vector-based vaccines were examined in rhesus macaques. Three macaques were inoculated with recombinant HSV vectors expressing Gag, Env, and a Tat-Rev-Nef fusion protein of simian immunodeficiency virus (SIV). Three other macaques were primed with recombinant DNA vectors expressing Gag, Env, and a Pol-Tat-Nef-Vif fusion protein prior to boosting with the HSV vectors. Robust anti-Gag and anti-Env cellular responses were detected in all six macaques. Following intravenous challenge with wild-type, cloned SIV239, peak and 12-week plasma viremia levels were significantly lower in vaccinated compared to control macaques. Plasma SIV RNAmore » in vaccinated macaques was inversely correlated with anti-Rev ELISPOT responses on the day of challenge (P value < 0.05), anti-Tat ELISPOT responses at 2 weeks post challenge (P value < 0.05) and peak neutralizing antibody titers pre-challenge (P value 0.06). These findings support continued study of recombinant herpesviruses as a vaccine approach for AIDS.« less

A slow progressor HIV-infected boy developing quadriplegia with evidence of Epstein-Barr virus associated smooth muscle tumour of the cervical spinal cord

PubMed Central

Wilaisakditipakorn, Tanaporn; Vilaisaktipakorn, Pitchamol; Bunupuradah, Torsak; Puthanakit, Thanyawee

2015-01-01

The authors report a case of slowly progressive HIV in an 11-year-old boy whose initial presenting AIDS-defining symptom was progressive quadriplegia with complete cord compression and pathological confirmation of Epstein-Barr virus associated smooth muscle tumour. Despite tumour removal, quadriplegia persisted as did ventilator dependence. PMID:26123466

Impaired glucose metabolism in subjects with the Williams-Beuren syndrome: A five-year follow-up cohort study

PubMed Central

Lunati, Maria Elena; Bedeschi, Maria Francesca; Resi, Veronica; Grancini, Valeria; Palmieri, Eva; Salera, Simona; Lalatta, Faustina; Pugliese, Giuseppe

2017-01-01

Objective The Williams-Beuren syndrome (WS) is associated with impaired glucose metabolism (IGM) early in adulthood. However, the pathophysiology of IGM remains poorly defined, due to the lack of longitudinal studies investigating the contribution of β-cell dysfunction and impaired insulin sensitivity. This study aimed at assessing incidence of IGM and the underlying mechanisms in WS adults. Methods This observational, longitudinal (5-year), cohort study enrolled thirty-one consecutive WS subjects attending a tertiary referral center. An oral glucose tolerance test (OGTT) was performed yearly and used to classify patients as normal or IGM, including impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and diabetes mellitus (DM), and to calculate surrogate measures of insulin secretion and/or sensitivity. Results IGM patients were 18 (58.1%, three DM) at baseline and 19 (61.3%, five DM) at end-of-follow-up. However, 13 individuals changed category of glucose homeostasis in both directions during follow-up (8 progressors, 5 regressors) and 18 did not (8 non-progressors, 10 non-regressors). New cases of IGM and DM were 11.1 and 2.53 per 100 persons-year, respectively, and were treated non-pharmacologically. In the whole cohort and, to a higher extent, in progressors, indices of early-phase insulin secretion and insulin sensitivity decreased significantly from baseline to end-of-follow-up, with concurrent reduction of the oral disposition index and insulin secretion-sensitivity index-2 (ISSI-2), compensating insulin secretion for the level of insulin resistance. No baseline measure independently predicted progression, which correlated with change from baseline in ISSI-2. Compared with patients with normal glucose homeostasis, IGT subjects had impaired insulin sensitivity, whereas insulin secretion was reduced only in those with IFG+IGT or DM. Conclusions IGM incidence is high in young adults with WS, suggesting the need of early screening and timed intervention. As in classical type 2 diabetes, impaired insulin sensitivity and β-cell dysfunction contribute, in this sequence, to progression to IGM and DM. PMID:29053727

Preservation affinity in consensus modules among stages of HIV-1 progression.

PubMed

Mosaddek Hossain, Sk Md; Ray, Sumanta; Mukhopadhyay, Anirban

2017-03-20

Analysis of gene expression data provides valuable insights into disease mechanism. Investigating relationship among co-expression modules of different stages is a meaningful tool to understand the way in which a disease progresses. Identifying topological preservation of modular structure also contributes to that understanding. HIV-1 disease provides a well-documented progression pattern through three stages of infection: acute, chronic and non-progressor. In this article, we have developed a novel framework to describe the relationship among the consensus (or shared) co-expression modules for each pair of HIV-1 infection stages. The consensus modules are identified to assess the preservation of network properties. We have investigated the preservation patterns of co-expression networks during HIV-1 disease progression through an eigengene-based approach. We discovered that the expression patterns of consensus modules have a strong preservation during the transitions of three infection stages. In particular, it is noticed that between acute and non-progressor stages the preservation is slightly more than the other pair of stages. Moreover, we have constructed eigengene networks for the identified consensus modules and observed the preservation structure among them. Some consensus modules are marked as preserved in two pairs of stages and are analyzed further to form a higher order meta-network consisting of a group of preserved modules. Additionally, we observed that module membership (MM) values of genes within a module are consistent with the preservation characteristics. The MM values of genes within a pair of preserved modules show strong correlation patterns across two infection stages. We have performed an extensive analysis to discover preservation pattern of co-expression network constructed from microarray gene expression data of three different HIV-1 progression stages. The preservation pattern is investigated through identification of consensus modules in each pair of infection stages. It is observed that the preservation of the expression pattern of consensus modules remains more prominent during the transition of infection from acute stage to non-progressor stage. Additionally, we observed that the module membership values of genes are coherent with preserved modules across the HIV-1 progression stages.

Randomised, controlled trial of avocado-soybean unsaponifiable (Piascledine) effect on structure modification in hip osteoarthritis: the ERADIAS study.

PubMed

Maheu, Emmanuel; Cadet, Christian; Marty, Marc; Moyse, Dominique; Kerloch, Isabelle; Coste, Philippe; Dougados, Maxime; Mazières, Bernard; Spector, Tim D; Halhol, Hafid; Grouin, Jean-Marie; Lequesne, Michel

2014-02-01

To assess the ability of avocado-soybean unsaponifiable-Expanscience (ASU-E) to slow radiographic progression in symptomatic hip osteoarthritis (OA). Prospective, randomised, double blind, parallel group, placebo controlled 3 year trial. Patients with symptomatic (painful ≥1 year, Lequesne Index between 3 and 10) hip OA (American College of Rheumatology criteria) and a minimum joint space width (JSW) of the target hip between 1 and 4 mm on a pelvic radiograph were randomly assigned to 300 mg/day ASU-E or placebo. Standing pelvis, target hip anteroposterior (AP) and oblique views were taken annually. The primary outcome was JSW change at year 3, measured at the narrowest point on pelvic or target hip AP view (manual measure using a 0.1 mm graduated magnifying glass). The full analysis dataset (FAS) included all patients having at least two successive radiographs. An analysis of covariance Mixed Model for Repeated Measurements with Missing at Random (for missing data) was performed to compare adjusted 3 year JSW changes (primary outcome) and the percentages of 'progressors' (JSW loss≥0.5 mm) between groups. 399 patients were randomised (345 kept in the FAS), aged 62 (35-84) years, 54% women, mean body mass index 27 (SD 4) kg/m(2), mean symptom duration 4 (SD 5) years, 0-100 normalised Lequesne Index 30 (SD 9) and global pain visual analogue scale 37 (SD 23) mm. Mean baseline JSW was 2.8 (0.9) mm. There was no significant difference on mean JSW loss (-0.638 mm vs -0.672 mm, p=0.72, in the ASU-E and placebo groups, respectively) but there were 20% less progressors in the ASU-E than in the placebo group (40% vs 50%, respectively, p=0.040). No difference was observed on clinical outcomes. Safety was excellent. 3 year treatment with ASU-E reduces the percentage of JSW progressors, indicating a potential structure modifying effect in hip OA to be confirmed, and the clinical relevance requires further assessment.

Social Tolerance in Wild Female Crested Macaques (Macaca nigra) in Tangkoko-Batuangus Nature Reserve, Sulawesi, Indonesia

PubMed Central

Duboscq, Julie; Micheletta, Jérôme; Agil, Muhammad; Hodges, Keith; Thierry, Bernard; Engelhardt, Antje

2013-01-01

In primates, females typically drive the evolution of the social system and present a wide diversity of social structures. To understand this diversity, it is necessary to document the consistency and/or flexibility of female social structures across and within species, contexts, and environments. Macaques (Macaca sp.) are an ideal taxon for such comparative study, showing both consistency and variation in their social relations. Their social styles, constituting robust sets of social traits, can be classified in four grades, from despotic to tolerant. However, tolerant species are still understudied, especially in the wild. To foster our understanding of tolerant societies and to assess the validity of the concept of social style, we studied female crested macaques, Macaca nigra, under entirely natural conditions. We assessed their degree of social tolerance by analyzing the frequency, intensity, and distribution of agonistic and affiliative behaviors, their dominance gradient, their bared-teeth display, and their level of conciliatory tendency. We also analyzed previously undocumented behavioral patterns in grade 4 macaques: reaction upon approach and distribution of affiliative behavior across partners. We compared the observed patterns to data from other populations of grade 4 macaques and from species of other grades. Overall, female crested macaques expressed a tolerant social style, with low intensity, frequently bidirectional, and reconciled conflicts. Dominance asymmetry was moderate, associated with an affiliative bared-teeth display. Females greatly tolerated one another in close proximity. The observed patterns matched the profile of other tolerant macaques and were outside the range of patterns of more despotic species. This study is the first comprehensive analysis of females’ social behavior in a tolerant macaque species under natural conditions and as such, contributes to a better understanding of macaque societies. It also highlights the relevance of the social style concept in the assessment of the degree of tolerance/despotism in social systems. Am. J. Primatol. 75:361-375, 2013. © 2013 Wiley Periodicals, Inc. PMID:23307343

Muscarinic acetylcholine receptors are expressed by most parvalbumin-immunoreactive neurons in area MT of the macaque.

PubMed

Disney, Anita A; Alasady, Hussein A; Reynolds, John H

2014-05-01

In the mammalian neocortex, cells that express parvalbumin (PV neurons) comprise a dominant class of inhibitory neuron that substantially overlaps with the fast/narrow-spiking physiological phenotype. Attention has pronounced effects on narrow-spiking neurons in the extrastriate cortex of macaques, and more consistently so than on their broad-spiking neighbors. Cortical neuromodulation by acetylcholine (ACh) is a candidate mechanism for aspects of attention and in the primary visual cortex (V1) of the macaque, receptors for ACh (AChRs) are strongly expressed by inhibitory neurons. In particular, most PV neurons in macaque V1 express m1 muscarinic AChRs and exogenously applied ACh can cause the release of γ-aminobutyric acid. In contrast, few PV neurons in rat V1 express m1 AChRs. While this could be a species difference, it has also been argued that macaque V1 is anatomically unique when compared with other cortical areas in macaques. The aim of this study was to better understand the extent to which V1 offers a suitable model circuit for cholinergic anatomy in the macaque occipital lobe, and to explore cholinergic modulation as a biological basis for the changes in circuit behavior seen with attention. We compared expression of m1 AChRs by PV neurons between area V1 and the middle temporal visual area (MT) in macaque monkeys using dual-immunofluorescence confocal microscopy. We find that, as in V1, most PV neurons in MT express m1 AChRs but, unlike in V1, it appears that so do most excitatory neurons. This provides support for V1 as a model of cholinergic modulation of inhibition in macaque visual cortex, but not of cholinergic modulation of visual cortical circuits in general. We also propose that ACh acting via m1 AChRs is a candidate underlying mechanism for the strong effects of attention on narrow-spiking neurons observed in behaving animals.

Social management of laboratory rhesus macaques housed in large groups using a network approach: A review.

PubMed

McCowan, Brenda; Beisner, Brianne; Hannibal, Darcy

2017-12-07

Biomedical facilities across the nation and worldwide aim to develop cost-effective methods for the reproductive management of macaque breeding groups, typically by housing macaques in large, multi-male multi-female social groups that provide monkey subjects for research as well as appropriate socialization for their psychological well-being. One of the most difficult problems in managing socially housed macaques is their propensity for deleterious aggression. From a management perspective, deleterious aggression (as opposed to less intense aggression that serves to regulate social relationships) is undoubtedly the most problematic behavior observed in group-housed macaques, which can readily escalate to the degree that it causes social instability, increases serious physical trauma leading to group dissolution, and reduces psychological well-being. Thus for both welfare and other management reasons, aggression among rhesus macaques at primate centers and facilities needs to be addressed with a more proactive approach.Management strategies need to be instituted that maximize social housing while also reducing problematic social aggression due to instability using efficacious methods for detection and prevention in the most cost effective manner. Herein we review a new proactive approach using social network analysis to assess and predict deleterious aggression in macaque groups. We discovered three major pathways leading to instability, such as unusually high rates and severity of trauma and social relocations.These pathways are linked either directly or indirectly to network structure in rhesus macaque societies. We define these pathways according to the key intrinsic and extrinsic variables (e.g., demographic, genetic or social factors) that influence network and behavioral measures of stability (see Fig. 1). They are: (1) presence of natal males, (2) matrilineal genetic fragmentation, and (3) the power structure and conflict policing behavior supported by this power structure. We discuss how these three major pathways leading to greater understanding and predictability of deleterious aggression in macaque social groups. Copyright © 2017. Published by Elsevier B.V.

Use of photogrammetry as a means to assess hybrids of rhesus (Macaca mulatta) and long-tailed (M. fascicularis) macaques.

PubMed

Jadejaroen, Janya; Hamada, Yuzuru; Kawamoto, Yoshi; Malaivijitnond, Suchinda

2015-01-01

Rhesus (Macaca mulatta) and long-tailed (M. fascicularis) macaques are the most commonly used non-human primate models for biomedical research, but it is difficult to identify these two species in the hybrid zone (15-20°N). In this work, we used morphological values obtained via photogrammetry to assess hybrids of rhesus and long-tailed macaques at Khao Khieow Open Zoo (KKZ; 13°21'N, 101°06'E), eastern Thailand. Long-tailed and rhesus macaques have species-specific tail lengths and contrasts of their yellowish pelages. The accuracy and precision of the relative tail length (%RTL) and the contrast of the yellow hue (Cb*) of the pelage, as obtained from photographs, were compared with the corresponding direct measurements (morphometrics). The photogrammetric and morphometric measurements of %RTL and Cb* were highly significantly correlated (r = 0.989 and 0.980, p < 0.001), and there were no significant differences between the two datasets (t test, p = 0.13 and 0.41; n = 42 and 17 for %RTL and Cb*, respectively). The reproducibilities of the %RTL and Cb* measurements (calculated in the photogrammetric case by taking photographs of the same macaques in two different environments) were significantly correlated between the datasets (r = 0.983 and 0.914, p < 0.001 and 0.005), and there were no significant differences between the datasets (t test, p = 0.539 and 0.344; n = 30 each for %RTL and Cb*, respectively). The %RTL and Cb* data were combined with data on the crown and cheek hair patterns and sex skin reddening of the macaques, and this combined data set was then analyzed by multiple correspondence analysis and agglomerative hierarchical cluster analysis, leading to the categorization of the rhesus macaques, long-tailed macaques, and hybrids at KKZ into five groups. Thus, photogrammetry can be utilized to identify macaque species or hybrids when species identification relies mainly on tail length and pelage color.

Functional evolution of new and expanded attention networks in humans

PubMed Central

Patel, Gaurav H.; Yang, Danica; Jamerson, Emery C.; Snyder, Lawrence H.; Corbetta, Maurizio; Ferrera, Vincent P.

2015-01-01

Macaques are often used as a model system for invasive investigations of the neural substrates of cognition. However, 25 million years of evolution separate humans and macaques from their last common ancestor, and this has likely substantially impacted the function of the cortical networks underlying cognitive processes, such as attention. We examined the homology of frontoparietal networks underlying attention by comparing functional MRI data from macaques and humans performing the same visual search task. Although there are broad similarities, we found fundamental differences between the species. First, humans have more dorsal attention network areas than macaques, indicating that in the course of evolution the human attention system has expanded compared with macaques. Second, potentially homologous areas in the dorsal attention network have markedly different biases toward representing the contralateral hemifield, indicating that the underlying neural architecture of these areas may differ in the most basic of properties, such as receptive field distribution. Third, despite clear evidence of the temporoparietal junction node of the ventral attention network in humans as elicited by this visual search task, we did not find functional evidence of a temporoparietal junction in macaques. None of these differences were the result of differences in training, experimental power, or anatomical variability between the two species. The results of this study indicate that macaque data should be applied to human models of cognition cautiously, and demonstrate how evolution may shape cortical networks. PMID:26170314

Functional evolution of new and expanded attention networks in humans.

PubMed

Patel, Gaurav H; Yang, Danica; Jamerson, Emery C; Snyder, Lawrence H; Corbetta, Maurizio; Ferrera, Vincent P

2015-07-28

Macaques are often used as a model system for invasive investigations of the neural substrates of cognition. However, 25 million years of evolution separate humans and macaques from their last common ancestor, and this has likely substantially impacted the function of the cortical networks underlying cognitive processes, such as attention. We examined the homology of frontoparietal networks underlying attention by comparing functional MRI data from macaques and humans performing the same visual search task. Although there are broad similarities, we found fundamental differences between the species. First, humans have more dorsal attention network areas than macaques, indicating that in the course of evolution the human attention system has expanded compared with macaques. Second, potentially homologous areas in the dorsal attention network have markedly different biases toward representing the contralateral hemifield, indicating that the underlying neural architecture of these areas may differ in the most basic of properties, such as receptive field distribution. Third, despite clear evidence of the temporoparietal junction node of the ventral attention network in humans as elicited by this visual search task, we did not find functional evidence of a temporoparietal junction in macaques. None of these differences were the result of differences in training, experimental power, or anatomical variability between the two species. The results of this study indicate that macaque data should be applied to human models of cognition cautiously, and demonstrate how evolution may shape cortical networks.

Interindividual Differences in Neonatal Imitation and the Development of Action Chains in Rhesus Macaques

ERIC Educational Resources Information Center

Ferrari, Pier Francesco; Paukner, Annika; Ruggiero, Angela; Darcey, Lisa; Unbehagen, Sarah; Suomi, Stephen J.

2009-01-01

The capacity to imitate facial gestures is highly variable in rhesus macaques and this variability may be related to differences in specific neurobehavioral patterns of development. This study evaluated the differential neonatal imitative response of 41 macaques in relation to the development of sensory, motor, and cognitive skills throughout the…

Rhesus Macaques Infected with Macrophage-Tropic Simian Immunodeficiency Virus (SIVmacR71/17E) Exhibit Extensive Focal Segmental and Global Glomerulosclerosis

PubMed Central

Stephens, Edward B.; Tian, Chunqiao; Li, Zhuang; Narayan, Opendra; Gattone, Vincent H.

1998-01-01

We previously showed that inoculation of rhesus macaques with molecularly cloned lymphocytetropic simian immunodeficiency virus (SIVmac239) results in SIV-associated nephropathy (SIVAN) and that the glomerulosclerotic lesions were associated with the selection of macrophagetropic (M-tropic) variants (V. H. Gattone et al., AIDS Res. Hum. Retroviruses 14:1163–1180, 1998). In the present study, seven rhesus macaques were inoculated with M-tropic SIVmacR71/17E, and the renal pathology was examined at necropsy. All SIVmacR71/17E-infected macaques developed AIDS, and most developed other systemic complications, including SIV-induced encephalitis and lentivirus interstitial pneumonia. There was no correlation between the length of infection (42 to 97 days), circulating CD4+ T-cell counts, and renal disease. Of the seven macaques inoculated with SIVmacR71/17E, five developed significant mesangial hyperplasia and expansion of matrix and four were clearly azotemic (serum urea nitrogen concentration of 40 to 112 mg/dl). These same five macaques developed focal segmental to global glomerulosclerotic lesions. Increased numbers of glomerular CD68+ cells (monocytes/macrophages) were found in glomeruli but not the tubulointerstitium of the macaques inoculated with SIVmacR71/17E. All macaques had glomerular deposits of immunoglobulin G (IgG), IgM, and tubuloreticular inclusions, and six of seven had IgA deposition. However, there was no correlation between the presence of circulating anti-SIVmac antibodies, immunoglobulin deposition, and glomerular disease. Tubulointerstitial infiltrates were mild, with little or no correlation to azotemia, while microcystic tubules were evident in those with glomerulosclerosis or azotemia. The four most severely affected macaques were positive for diffuse glomerular immunostaining for viral core p27 antigen, and there was intense staining in the glomeruli of the two macaques with the most severe glomerulosclerosis. Viral sequences were isolated from glomerular and tubulointerstitial fractions from macaques with severe glomerulosclerosis but only from the tubulointerstitial compartment of those that did not develop glomerulosclerosis. Interviral recombinant viruses generated with env sequences isolated from glomeruli confirmed the M-tropic nature of the virus found in the glomeruli. The correlation between the increased number of CD68+ cells (monocytes/macrophages) in the glomeruli, the localization of p27 antigen in the glomeruli, and the glomerular pathology confirms and extends our previous observations of an association between glomerular infection and infiltration by M-tropic virus and SIVAN. PMID:9765427

Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

PubMed Central

Myers, Amy J.; Jarvela, Jessica; Flynn, JoAnne; Rutledge, Tara; Bonfield, Tracey

2016-01-01

Immune cells of the distal airways serve as “first responders” of host immunity to the airborne pathogen Mycobacterium tuberculosis (Mtb). Mtb infection of cynomolgus macaques recapitulates the range of human outcomes from clinically silent latent tuberculosis infection (LTBI) to active tuberculosis of various degrees of severity. To further advance the application of this model to human studies, we compared profiles of bronchoalveolar lavage (BAL) cells of humans and cynomolgus macaques before and after Mtb infection. A simple gating strategy effectively defined BAL T-cell and phagocyte populations in both species. BAL from Mtb-naive humans and macaques showed similar differential cell counts. BAL T cells of macaques were composed of fewer CD4+cells but more CD8+ and CD4+CD8+ double-positive cells than were BAL T cells of humans. The most common mononuclear phagocyte population in BAL of both species displayed coexpression of HLA-DR, CD206, CD11b, and CD11c; however, multiple phagocyte subsets displaying only some of these markers were observed as well. Macaques with LTBI displayed a marked BAL lymphocytosis that was not observed in humans with LTBI. In macaques, the prevalence of specific mononuclear phagocyte subsets in baseline BAL correlated with ultimate outcomes of Mtb infection (i.e., LTBI versus active disease). Overall, these findings demonstrate the comparability of studies of pulmonary immunity to Mtb in humans and macaques. They also indicate a previously undescribed complexity of airway mononuclear phagocyte populations that suggests further lines of investigation relevant to understanding the mechanisms of both protection from and susceptibility to the development of active tuberculosis within the lung. PMID:27509488

Diversity and Molecular Phylogeny of Mitochondrial DNA of Rhesus Macaques (Macaca mulatta) in Bangladesh

PubMed Central

HASAN, M. KAMRUL; FEEROZ, M. MOSTAFA; JONES-ENGEL, LISA; ENGEL, GREGORY A.; KANTHASWAMY, SREE; SMITH, DAVID GLENN

2015-01-01

While studies of rhesus macaques (Macaca mulatta) in the eastern (e.g., China) and western (e.g., India) parts of their geographic range have revealed major genetic differences that warrant the recognition of two different subspecies, little is known about genetic characteristics of rhesus macaques in the transitional zone extending from eastern India and Bangladesh through the northern part of Indo-China, the probable original homeland of the species. We analyzed genetic variation of 762 base pairs of mitochondrial DNA from 86 fecal swab samples and 19 blood samples from 25 local populations of rhesus macaque in Bangladesh collected from January 2010 to August 2012. These sequences were compared with those of rhesus macaques from India, China, and Myanmar. Forty-six haplotypes defined by 200 (26%) polymorphic nucleotide sites were detected. Estimates of gene diversity, expected heterozygosity, and nucleotide diversity for the total population were 0.9599 ± 0.0097, 0.0193 ± 0.0582, and 0.0196 ± 0.0098, respectively. A mismatch distribution of paired nucleotide differences yielded a statistically significantly negative value of Tajima's D, reflecting a population that rapidly expanded after the terminal Pleistocene. Most haplotypes throughout regions of Bangladesh, including an isolated region in the southwestern area (Sundarbans), clustered with haplotypes assigned to the minor haplogroup Ind-2 from India reflecting an east to west dispersal of rhesus macaques to India. Haplotypes from the southeast region of Bangladesh formed a cluster with those from Myanmar, and represent the oldest rhesus macaque haplotypes of Bangladesh. These results are consistent with the hypothesis that rhesus macaques first entered Bangladesh from the southeast, probably from Indo-China, then dispersed westward throughout eastern and central India. PMID:24810278

Diversity and molecular phylogeny of mitochondrial DNA of rhesus macaques (Macaca mulatta) in Bangladesh.

PubMed

Hasan, M Kamrul; Feeroz, M Mostafa; Jones-Engel, Lisa; Engel, Gregory A; Kanthaswamy, Sree; Smith, David Glenn

2014-11-01

While studies of rhesus macaques (Macaca mulatta) in the eastern (e.g., China) and western (e.g., India) parts of their geographic range have revealed major genetic differences that warrant the recognition of two different subspecies, little is known about genetic characteristics of rhesus macaques in the transitional zone extending from eastern India and Bangladesh through the northern part of Indo-China, the probable original homeland of the species. We analyzed genetic variation of 762 base pairs of mitochondrial DNA from 86 fecal swab samples and 19 blood samples from 25 local populations of rhesus macaque in Bangladesh collected from January 2010 to August 2012. These sequences were compared with those of rhesus macaques from India, China, and Myanmar. Forty-six haplotypes defined by 200 (26%) polymorphic nucleotide sites were detected. Estimates of gene diversity, expected heterozygosity, and nucleotide diversity for the total population were 0.9599 ± 0.0097, 0.0193 ± 0.0582, and 0.0196 ± 0.0098, respectively. A mismatch distribution of paired nucleotide differences yielded a statistically significantly negative value of Tajima's D, reflecting a population that rapidly expanded after the terminal Pleistocene. Most haplotypes throughout regions of Bangladesh, including an isolated region in the southwestern area (Sundarbans), clustered with haplotypes assigned to the minor haplogroup Ind-2 from India reflecting an east to west dispersal of rhesus macaques to India. Haplotypes from the southeast region of Bangladesh formed a cluster with those from Myanmar, and represent the oldest rhesus macaque haplotypes of Bangladesh. These results are consistent with the hypothesis that rhesus macaques first entered Bangladesh from the southeast, probably from Indo-China, then dispersed westward throughout eastern and central India. © 2014 Wiley Periodicals, Inc.

Whole Mitochondrial Genomic and Y-Chromosomal Phylogenies of Burmese Long-Tailed Macaque (Macaca fascicularis aurea) Suggest Ancient Hybridization between fascicularis and sinica Species Groups.

PubMed

Matsudaira, Kazunari; Hamada, Yuzuru; Bunlungsup, Srichan; Ishida, Takafumi; San, Aye Mi; Malaivijitnond, Suchinda

2018-05-11

Macaca fascicularis aurea (Burmese long-tailed macaque) is 1 of the 10 subspecies of Macaca fascicularis. Despite having few morphological differences from other subspecies, a recent phylogeographic study showed that M. f. aurea is clearly distinct genetically from Macaca fascicularis fascicularis (common long-tailed macaque) and suggests that M. f. aurea experienced a disparate evolutionary pathway versus other subspecies. To construct a detailed evolutionary history of M. f. aurea and its relationships with other macaque species, we performed phylogenetic analyses and divergence time estimation of whole mitochondrial genomes (2 M. f. aurea, 8 M. f. fascicularis, and 16 animals of 12 macaque species) and 2871 bp of the Y chromosome (1 M. f. aurea, 2 M. f. fascicularis, and 5 animals of 5 macaque species) and haplotype network analysis of 758 bp of the Y chromosome (1 M. f. aurea, 2 M. f. fascicularis, and 21 animals of 19 macaque species). Whereas the Y chromosome of M. f. aurea clustered with those of the fascicularis species group in the phylogenetic and haplotype network analyses, its mtDNA clustered within the clade of the sinica species group. Based on this phylogenetic incongruence and the estimated divergence times, we propose that proto-M. f. aurea underwent hybridization with a population of the sinica species group between 2.5 and 0.95 MYA after divergence from the common ancestor of M. fascicularis. Hybridization and introgression might have been central in the evolution of M. f. aurea, similar to what occurred in the evolution of other macaque species and subspecies.

Topical tenofovir protects against vaginal simian HIV infection in macaques coinfected with Chlamydia trachomatis and Trichomonas vaginalis.

PubMed

Makarova, Natalia; Henning, Tara; Taylor, Andrew; Dinh, Chuong; Lipscomb, Jonathan; Aubert, Rachael; Hanson, Debra; Phillips, Christi; Papp, John; Mitchell, James; McNicholl, Janet; Garcia-Lerma, Gerardo J; Heneine, Walid; Kersh, Ellen; Dobard, Charles

2017-03-27

Chlamydia trachomatis and Trichomonas vaginalis, two prevalent sexually transmitted infections, are known to increase HIV risk in women and could potentially diminish preexposure prophylaxis efficacy, particularly for topical interventions that rely on local protection. We investigated in macaques whether coinfection with Chlamydia trachomatis/Trichomonas vaginalis reduces protection by vaginal tenofovir (TFV) gel. Vaginal TFV gel dosing previously shown to provide 100 or 74% protection when applied either 30 min or 3 days before simian HIV(SHIV) challenge was assessed in pigtailed macaques coinfected with Chlamydia trachomatis/Trichomonas vaginalis and challenged twice weekly with SHIV162p3 for up to 10 weeks (two menstrual cycles). Three groups of six macaques received either placebo or 1% TFV gel 30 min or 3 days before each SHIV challenge. We additionally assessed TFV and TFV diphosphate concentrations in plasma and vaginal tissues in Chlamydia trachomatis/Trichomonas vaginalis coinfected (n = 4) and uninfected (n = 4) macaques. Chlamydia trachomatis/Trichomonas vaginalis coinfections were maintained during the SHIV challenge period. All macaques that received placebo gel were SHIV infected after a median of seven challenges (one menstrual cycle). In contrast, no infections were observed in macaques treated with TFV gel 30 min before SHIV challenge (P < 0.001). Efficacy was reduced to 60% when TFV gel was applied 3 days before SHIV challenge (P = 0.07). Plasma TFV and TFV diphosphate concentrations in tissues and vaginal lymphocytes were significantly higher in Chlamydia trachomatis/Trichomonas vaginalis coinfected compared with Chlamydia trachomatis/Trichomonas vaginalis uninfected macaques. Our findings in this model suggest that Chlamydia trachomatis/Trichomonas vaginalis coinfection may have little or no impact on the efficacy of highly effective topical TFV modalities and highlight a significant modulation of TFV pharmacokinetics.

Mimetic Muscles in a Despotic Macaque (Macaca mulatta) Differ from Those in a Closely Related Tolerant Macaque (M. nigra).

PubMed

Burrows, Anne M; Waller, Bridget M; Micheletta, Jérôme

2016-10-01

Facial displays (or expressions) are a primary means of visual communication among conspecifics in many mammalian orders. Macaques are an ideal model among primates for investigating the co-evolution of facial musculature, facial displays, and social group size/behavior under the umbrella of "ecomorphology". While all macaque species share some social behaviors, dietary, and ecological parameters, they display a range of social dominance styles from despotic to tolerant. A previous study found a larger repertoire of facial displays in tolerant macaque species relative to despotic species. The present study was designed to further explore this finding by comparing the gross morphological features of mimetic muscles between the Sulawesi macaque (Macaca nigra), a tolerant species, and the rhesus macaque (M. mulatta), a despotic species. Five adult M. nigra heads were dissected and mimetic musculature was compared to those from M. mulatta. Results showed that there was general similarity in muscle presence/absence between the species as well as muscle form except for musculature around the external ear. M. mulatta had more musculature around the external ear than M. nigra. In addition, M. nigra lacked a zygomaticus minor while M. mulatta is reported to have one. These morphological differences match behavioral observations documenting a limited range of ear movements used by M. nigra during facial displays. Future studies focusing on a wider phylogenetic range of macaques with varying dominance styles may further elucidate the roles of phylogeny, ecology, and social variables in the evolution of mimetic muscles within Macaca Anat Rec, 299:1317-1324, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Cyto- and receptor architecture of area 32 in human and macaque brains.

PubMed

Palomero-Gallagher, Nicola; Zilles, Karl; Schleicher, Axel; Vogt, Brent A

2013-10-01

Human area 32 plays crucial roles in emotion and memory consolidation. It has subgenual (s32), pregenual (p32), dorsal, and midcingulate components. We seek to determine whether macaque area 32 has subgenual and pregenual subdivisions and the extent to which they are comparable to those in humans by means of NeuN immunohistochemistry and multireceptor analysis of laminar profiles. The macaque has areas s32 and p32. In s32, layer IIIa/b neurons are larger than those of layer IIIc. This relationship is reversed in p32. Layer Va is thicker and Vb thinner in s32. Area p32 contains higher kainate, benzodiazepine (BZ), and serotonin (5-HT)1A but lower N-methyl-D-aspartate (NMDA) and α2 receptor densities. Most differences were found in layers I, II, and VI. Together, these differences support the dual nature of macaque area 32. Comparative analysis of human and macaque s32 and p32 supports equivalences in cyto- and receptor architecture. Although there are differences in mean areal receptor densities, there are considerable similarities at the layer level. Laminar receptor distribution patterns in each area are comparable in the two species in layers III-Va for kainate, NMDA, γ-aminobutyric acid (GABA)B , BZ, and 5-HT1A receptors. Multivariate statistical analysis of laminar receptor densities revealed that human s32 is more similar to macaque s32 and p32 than to human p32. Thus, macaque 32 is more complex than hitherto known. Our data suggest a homologous neural architecture in anterior cingulate s32 and p32 in human and macaque brains. © 2013 Wiley Periodicals, Inc.

Three Divergent Subpopulations of the Malaria Parasite Plasmodium knowlesi

PubMed Central

Lin, Lee C.; Rovie-Ryan, Jeffrine J.; Kadir, Khamisah A.; Anderios, Fread; Hisam, Shamilah; Sharma, Reuben S.K.; Singh, Balbir; Conway, David J.

2017-01-01

Multilocus microsatellite genotyping of Plasmodium knowlesi isolates previously indicated 2 divergent parasite subpopulations in humans on the island of Borneo, each associated with a different macaque reservoir host species. Geographic divergence was also apparent, and independent sequence data have indicated particularly deep divergence between parasites from mainland Southeast Asia and Borneo. To resolve the overall population structure, multilocus microsatellite genotyping was conducted on a new sample of 182 P. knowlesi infections (obtained from 134 humans and 48 wild macaques) from diverse areas of Malaysia, first analyzed separately and then in combination with previous data. All analyses confirmed 2 divergent clusters of human cases in Malaysian Borneo, associated with long-tailed macaques and pig-tailed macaques, and a third cluster in humans and most macaques in peninsular Malaysia. High levels of pairwise divergence between each of these sympatric and allopatric subpopulations have implications for the epidemiology and control of this zoonotic species. PMID:28322705

Synanthropic Primates in Asia: Potential Sentinels for Environmental Toxins

PubMed Central

Engel, Gregory; O’Hara, Todd M.; Cardona-Marek, Tamara; Heidrich, John; Chalise, Mukesh K.; Kyes, Randall; Jones-Engel, Lisa

2010-01-01

Macaques are similar to humans both physiologically and behaviorally. In South and Southeast Asia they are also synanthropic, ecologically associated with humans. Synanthropy with humans raises the possibility that macaques come into contact with anthropogenic toxicants, such as lead and mercury, and might be appropriate sentinels for human exposures to certain toxic materials. We measured lead (Pb) and mercury (Hg) levels and characterized the stable isotopic compositions of δ15N and δ13C in hair from three groups of free-ranging macaques at the Swoyambhu temple in Kathmandhu, Nepal, an urban population that has abundant contact with humans. Hair lead levels were significantly higher among young macaques and differed among the three groups of macaques that were sampled. Hair Hg levels were low. No statistical association was found between stable isotopic compositions (δ15N and δ13C) and Pb and Hg levels. Our data did not find evidence that lead levels were associated with diet. We conclude that, in this population of macaques, behavioral and/or physiologic factors may play a significant role in determining exposure to lead. Chemical analysis of hair is a promising, noninvasive technique for determining exposure to toxic elements in free-ranging nonhuman primates. PMID:20033917

The high-affinity receptor for IgG, FcγRI, of humans and non-human primates.

PubMed

Chenoweth, Alicia M; Trist, Halina M; Tan, Peck-Szee; Wines, Bruce D; Hogarth, P Mark

2015-11-01

Non-human primate (NHP) models, especially involving macaques, are considered important models of human immunity and have been essential in preclinical testing for vaccines and therapeutics. Despite this, much less characterization of macaque Fc receptors has occurred compared to humans or mice. Much of the characterization of macaque Fc receptors so far has focused on the low-affinity Fc receptors, particularly FcγRIIIa. From these studies, it is clear that there are distinct differences between the human and macaque low-affinity receptors and their interaction with human IgG. Relatively little work has been performed on the high-affinity IgG receptor, FcγRI, especially in NHPs. This review will focus on what is currently known of how FcγRI interacts with IgG, from mutation studies and recent crystallographic studies of human FcγRI, and how amino acid sequence differences in the macaque FcγRI may affect this interaction. Additionally, this review will look at the functional consequences of differences in the amino acid sequences between humans and macaques. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Possible shift in macaque trophic level following a century of biodiversity loss in Singapore.

PubMed

Gibson, Luke

2011-07-01

Biodiversity loss in tropical forests is a major problem in conservation biology, and nowhere is this more dire than in Southeast Asia. Deforestation and the associated loss of species may trigger shifts in habitat and feeding preferences of persisting species. In this study, I compared the habitat use and diet of long-tailed macaque (Macaca fascicularis) populations in Singapore from two time periods: museum specimens originally collected between 1893 and 1944, and living macaques sampled in 2009. I collected hair and used stable carbon and nitrogen isotope analysis to identify temporal changes in dietary source and trophic position, respectively. δ(13)C ratios were virtually identical, suggesting that macaques foraged in similar habitats during both time periods. However, δ(15)N ratios decreased considerably over time, suggesting that macaques today feed at a lower trophic level than previously. This decline in trophic level may be because of the disappearance or decline of other species that compete with macaques for fruit. This study highlights the effect of biodiversity loss on persisting species in degraded habitats of Southeast Asia, and improves our understanding of how species will adapt to further human-driven changes in tropical forest habitats.

Enterically transmitted non-A, non-B hepatitis: serial passage of disease in cynomolgus macaques and tamarins and recovery of disease-associated 27- to 34-nm viruslike particles.

PubMed Central

Bradley, D W; Krawczynski, K; Cook, E H; McCaustland, K A; Humphrey, C D; Spelbring, J E; Myint, H; Maynard, J E

1987-01-01

An experimental model of enterically transmitted non-A, non-B hepatitis (ET-NANBH) was established in tamarins (Saguinus mystax mystax) and cynomolgus macaques (Macaca fascicularis). First-passage animals were inoculated with two different stool suspensions obtained from human patients with well-defined ET-NANBH that originated from Burma and Pakistan, where epidemics of ET-NANBH occur. Both inocula contained 27- ato 34-nm-diameter viruslike particles (VLPs) that were specifically aggregated by acute-phase ET-NANBH sera. ET-NANBH was subpassaged in both tamarins and cynomolgus macaques by using pools of stool suspensions from first-passage animals. One additional passage of disease in cynomolgus macaques resulted in a significantly shortened incubation period and increased severity of disease. VLPs similar to those found in the human inocula were observed in stool specimens of first-, second-, and third-passage cynomolgus macaques and in first- and second-passage tamarins. Our findings indicate that cynomolgus macaques are particularly suitable experimental models for studies of human ET-NANBH. The 27- to 34-nm VLPs found in infected human and primate stools appear to be etiologically linked to disease. Images PMID:3114746

A slow progressor HIV-infected boy developing quadriplegia with evidence of Epstein-Barr virus associated smooth muscle tumour of the cervical spinal cord.

PubMed

Wilaisakditipakorn, Tanaporn; Vilaisaktipakorn, Pitchamol; Bunupuradah, Torsak; Puthanakit, Thanyawee

2015-06-29

The authors report a case of slowly progressive HIV in an 11-year-old boy whose initial presenting AIDS-defining symptom was progressive quadriplegia with complete cord compression and pathological confirmation of Epstein-Barr virus associated smooth muscle tumour. Despite tumour removal, quadriplegia persisted as did ventilator dependence. 2015 BMJ Publishing Group Ltd.

Serum metabolomics of slow vs. rapid motor progression Parkinson's disease: a pilot study.

PubMed

Roede, James R; Uppal, Karan; Park, Youngja; Lee, Kichun; Tran, Vilinh; Walker, Douglas; Strobel, Frederick H; Rhodes, Shannon L; Ritz, Beate; Jones, Dean P

2013-01-01

Progression of Parkinson's disease (PD) is highly variable, indicating that differences between slow and rapid progression forms could provide valuable information for improved early detection and management. Unfortunately, this represents a complex problem due to the heterogeneous nature of humans in regards to demographic characteristics, genetics, diet, environmental exposures and health behaviors. In this pilot study, we employed high resolution mass spectrometry-based metabolic profiling to investigate the metabolic signatures of slow versus rapidly progressing PD present in human serum. Archival serum samples from PD patients obtained within 3 years of disease onset were analyzed via dual chromatography-high resolution mass spectrometry, with data extraction by xMSanalyzer and used to predict rapid or slow motor progression of these patients during follow-up. Statistical analyses, such as false discovery rate analysis and partial least squares discriminant analysis, yielded a list of statistically significant metabolic features and further investigation revealed potential biomarkers. In particular, N8-acetyl spermidine was found to be significantly elevated in the rapid progressors compared to both control subjects and slow progressors. Our exploratory data indicate that a fast motor progression disease phenotype can be distinguished early in disease using high resolution mass spectrometry-based metabolic profiling and that altered polyamine metabolism may be a predictive marker of rapidly progressing PD.

Cervical carotid and circle of willis arterial anatomy of macaque monkeys: a comparative anatomy study.

PubMed

Kumar, Nishant; Lee, John J; Perlmutter, Joel S; Derdeyn, Colin P

2009-07-01

Macaque monkeys are used in many research applications, including cerebrovascular investigations. However, detailed catalogs of the relevant vascular anatomy are scarce. We present our experience with macaque vessel patterns as determined by digital subtraction angiography of 34 different monkeys. We retrospectively analyzed digital subtraction angiograms obtained during experimental internal carotid artery (ICA) catheterization and subsequent injection of 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine. Results were catalogued according to vascular distribution and variants observed. Macaque monkeys have a bovine aortic arch. The carotid vessels generally bifurcate, but are occasionally observed to divide into three vessels. The external carotid gives rise primarily to two trunks: an occipital branch and a common vessel that subsequently gives off the lingual, facial, and superior thyroid arteries. The internal maxillary artery may be present as a terminal branch of the external carotid or as a branch of the occipital artery. The ICA is similar in course to that of the human. The anterior circle of Willis was intact in all monkeys in our study. Its primary difference from that of the human is the union of the bilateral anterior cerebral arteries as a single (azygous) median vessel. Macaque cervical carotid and circle of Willis arterial anatomy differs from humans in a couple of specific patterns. Knowledge of these differences and similarities between human and macaque anatomy is important in developing endovascular macaque models of human diseases, such as ischemic stroke.

Sustained release of the CCR5 inhibitors CMPD167 and maraviroc from vaginal rings in rhesus macaques.

PubMed

Malcolm, R Karl; Veazey, Ronald S; Geer, Leslie; Lowry, Deborah; Fetherston, Susan M; Murphy, Diarmaid J; Boyd, Peter; Major, Ian; Shattock, Robin J; Klasse, Per Johan; Doyle, Lara A; Rasmussen, Kelsi K; Goldman, Laurie; Ketas, Thomas J; Moore, John P

2012-05-01

Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 μg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ~10(6)-fold greater than the 50% inhibitory concentrations (IC(50)s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

PubMed Central

Veazey, Ronald S.; Geer, Leslie; Lowry, Deborah; Fetherston, Susan M.; Murphy, Diarmaid J.; Boyd, Peter; Major, Ian; Shattock, Robin J.; Klasse, Per Johan; Doyle, Lara A.; Rasmussen, Kelsi K.; Goldman, Laurie; Ketas, Thomas J.; Moore, John P.

2012-01-01

Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 μg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ∼106-fold greater than the 50% inhibitory concentrations (IC50s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle. PMID:22330914

Niche partitioning between sympatric rhesus macaques and Yunnan snub-nosed monkeys at Baimaxueshan Nature Reserve, China.

PubMed

Grueter, Cyril C; Li, Da-Yong; Feng, Shun-Kai; Ren, Bao-Ping

2010-10-01

Here we provide a preliminary assessment of dietary and habitat requirements of two sympatric primate taxa, a "simple-stomached" and "complex-stomached" species (Rhinopithecus bieti Colobinae vs. Macaca mulatta Cercopithecinae), as a basis for illuminating how the two coexist. Of ca. 22 plant food species consumed by the macaques, at least 16 were also eaten by the snub-nosed monkeys. Both species showed a preference for fruits. While the snub-nosed monkeys did not utilize any resources associated with human communities, rhesus macaques did occasionally raid agricultural crops. The mean elevation of the snub-nosed monkey group was 3,218 m, while the mean elevation of the macaque group was 2,995 m. Macaques were also spotted on meadows whereas snub-nosed monkeys evidently avoided these. For both species, mixed deciduous broadleaf/conifer forest was the most frequently used ecotype, but whereas evergreen broadleaf forest (Cyclobalanopsis community) accounted for only 3% of the location records of the snub-nosed monkeys, it accounted for 36% of the location records of the macaques. Groups of the two species usually kept a considerable spatial distance from one another (mean 2.4 km). One close encounter and confrontation between groups of the two species resulted in the macaque group moving away. Our findings suggest that the coexistence of the two taxa is facilitated via differential macrohabitat use and spatial avoidance. Although divergent habitat-use strategies may reflect interspecific competition, they may also merely reflect different physiological or ecological requirements.

Dietary adaptations of Assamese macaques (Macaca assamensis) in limestone forests in Southwest China.

PubMed

Huang, Zhonghao; Huang, Chengming; Tang, Chuangbin; Huang, Libin; Tang, Huaxing; Ma, Guangzhi; Zhou, Qihai

2015-02-01

Limestone hills are an unusual habitat for primates, prompting them to evolve specific behavioral adaptations to the component karst habitat. From September 2012 to August 2013, we collected data on the diet of one group of Assamese macaques living in limestone forests at Nonggang National Nature Reserve, Guangxi Province, China, using instantaneous scan sampling. Assamese macaques were primarily folivorous, young leaves accounting for 75.5% and mature leaves an additional 1.8% of their diet. In contrast, fruit accounted for only 20.1%. The young leaves of Bonia saxatilis, a shrubby, karst-endemic bamboo that is superabundant in limestone hills, comprised the bulk of the average monthly diet. Moreover, macaques consumed significantly more bamboo leaves during the season when the availability of fruit declined, suggesting that bamboo leaves are an important fallback food for Assamese macaques in limestone forests. In addition, diet composition varied seasonally. The monkeys consumed significantly more fruit and fewer young leaves in the fruit-rich season than in the fruit-lean season. Fruit consumption was positively correlated with fruit availability, indicating that fruit is a preferred food for Assamese macaques. Of seventy-eight food species, only nine contributed >0.5% of the annual diet, and together these nine foods accounted for 90.7% of the annual diet. Our results suggest that bamboo consumption represents a key factor in the Assamese macaque's dietary adaptation to limestone habitat. © 2014 Wiley Periodicals, Inc.

Temperament in rhesus, long-tailed, and pigtailed macaques varies by species and sex

PubMed Central

Sussman, Adrienne F.; Ha, James C.; Bentson, Kathy L.; Crockett, Carolyn M.

2012-01-01

Temperament differs among individuals both within and between species. Evidence suggests that differences in temperament of group members may parallel differences in social behavior among groups or between species. Here, we compared temperament between three closely related species of monkey - rhesus (Macaca mulatta), long-tailed (M. fascicularis), and pigtailed (M. nemestrina) macaques - using cage-front behavioral observations of individually housed monkeys at a National Primate Research Center. Frequencies of 12 behaviors in 899 subjects were analyzed using a PCA to identify temperament components. The analysis identified four components, which we interpreted as Sociability towards humans, Cautiousness, Aggressiveness, and Fearfulness. Species and sexes differed in their average scores on these components, even after controlling for differences in age and early-life experiences. Our results suggest that rhesus macaques are especially aggressive and unsociable towards humans, long-tailed macaques are more cautious and fearful, and pigtailed macaques are more sociable towards humans and less aggressive than the other species. Pigtailed males were notably more sociable than any other group. The differences observed are consistent with reported variation in these species’ social behaviors, as rhesus macaques generally engage in more social aggression and pigtailed macaques engage in more male-male affiliative behaviors. Differences in predation risks are among the socioecological factors that might make these species-typical behaviors adaptive. Our results suggest that adaptive species-level social differences may be encoded in individual-level temperaments, which are manifested even outside of a social context. PMID:23225368

Different macaque models of cognitive aging exhibit task-dependent behavioral disparities.

PubMed

Comrie, Alison E; Gray, Daniel T; Smith, Anne C; Barnes, Carol A

2018-05-15

Deficits in cognitive functions that rely on the integrity of the frontal and temporal lobes are characteristic of normative human aging. Due to similar aging phenotypes and homologous cortical organization between nonhuman primates and humans, several species of macaque monkeys are used as models to explore brain senescence. These macaque species are typically regarded as equivalent models of cognitive aging, yet no direct comparisons have been made to support this assumption. Here we used adult and aged rhesus and bonnet macaques (Macaca mulatta and Macaca radiata) to characterize the effect of age on acquisition and retention of information across delays in a battery of behavioral tasks that rely on prefrontal cortex and medial temporal lobe networks. The cognitive functions that were tested include visuospatial short-term memory, object recognition memory, and object-reward association memory. In general, bonnet macaques at all ages outperformed rhesus macaques on tasks thought to rely primarily on the prefrontal cortex, and were more resilient to age-related deficits in these behaviors. On the other hand, both species were comparably impaired by age on tasks thought to preferentially engage the medial temporal lobe. Together, these results suggest that rhesus and bonnet macaques are not equivalent models of cognitive aging and highlight the value of cross-species comparisons. These observations should enable improved design and interpretation of future experiments aimed at understanding changes in cognition across the lifespan. Copyright © 2018 Elsevier B.V. All rights reserved.

Cervical Carotid and Circle of Willis Arterial Anatomy of Macaque Monkeys: A Comparative Anatomy Study

PubMed Central

Kumar, Nishant; Lee, John J.; Perlmutter, Joel S.; Derdeyn, Colin P.

2009-01-01

Macaque monkeys are used in many research applications, including cerebrovascular investigations. However, detailed catalogs of the relevant vascular anatomy are scarce. We present our experience with macaque vessel patterns as determined by digital subtraction angiography of 34 different monkeys. METHODS AND MATERIALS: We retrospectively analyzed digital subtraction angiograms obtained during experimental internal carotid artery catheterization and subsequent injection of 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP). Results were catalogued according to vascular distribution and variants observed. RESULTS: Macaque monkeys have a bovine aortic arch. The carotid vessels generally bifurcate, but are occasionally observed to divide into three vessels. The external carotid gives rise primarily to two trunks: an occipital branch and a common vessel that subsequently gives off the lingual, facial, and superior thyroid arteries. The internal maxillary artery may be present as a terminal branch of the external carotid or as a branch of the occipital artery. The internal carotid artery is similar in course to that of the human. The anterior circle of Willis was intact in all monkeys in our study. Its primary difference from that of the human is the union of the bilateral anterior cerebral arteries as a single (azygous) median vessel. CONCLUSIONS: Macaque cervical carotid and circle of Willis arterial anatomy differs from humans in a couple of specific patterns. Knowledge of these differences and similarities between human and macaque anatomy is important in developing endovascular macaque models of human diseases, such as ischemic stroke. PMID:19434671

Color vision test for dichromatic and trichromatic macaque monkeys.

PubMed

Koida, Kowa; Yokoi, Isao; Okazawa, Gouki; Mikami, Akichika; Widayati, Kanthi Arum; Miyachi, Shigehiro; Komatsu, Hidehiko

2013-11-01

Dichromacy is a color vision defect in which one of the three cone photoreceptors is absent. Individuals with dichromacy are called dichromats (or sometimes "color-blind"), and their color discrimination performance has contributed significantly to our understanding of color vision. Macaque monkeys, which normally have trichromatic color vision that is nearly identical to humans, have been used extensively in neurophysiological studies of color vision. In the present study we employed two tests, a pseudoisochromatic color discrimination test and a monochromatic light detection test, to compare the color vision of genetically identified dichromatic macaques (Macaca fascicularis) with that of normal trichromatic macaques. In the color discrimination test, dichromats could not discriminate colors along the protanopic confusion line, though trichromats could. In the light detection test, the relative thresholds for longer wavelength light were higher in the dichromats than the trichromats, indicating dichromats to be less sensitive to longer wavelength light. Because the dichromatic macaque is very rare, the present study provides valuable new information on the color vision behavior of dichromatic macaques, which may be a useful animal model of human dichromacy. The behavioral tests used in the present study have been previously used to characterize the color behaviors of trichromatic as well as dichromatic new world monkeys. The present results show that comparative studies of color vision employing similar tests may be feasible to examine the difference in color behaviors between trichromatic and dichromatic individuals, although the genetic mechanisms of trichromacy/dichromacy is quite different between new world monkeys and macaques.

Admixture in Humans of Two Divergent Plasmodium knowlesi Populations Associated with Different Macaque Host Species

PubMed Central

Divis, Paul C. S.; Singh, Balbir; Anderios, Fread; Hisam, Shamilah; Matusop, Asmad; Kocken, Clemens H.; Assefa, Samuel A.; Duffy, Craig W.; Conway, David J.

2015-01-01

Human malaria parasite species were originally acquired from other primate hosts and subsequently became endemic, then spread throughout large parts of the world. A major zoonosis is now occurring with Plasmodium knowlesi from macaques in Southeast Asia, with a recent acceleration in numbers of reported cases particularly in Malaysia. To investigate the parasite population genetics, we developed sensitive and species-specific microsatellite genotyping protocols and applied these to analysis of samples from 10 sites covering a range of >1,600 km within which most cases have occurred. Genotypic analyses of 599 P. knowlesi infections (552 in humans and 47 in wild macaques) at 10 highly polymorphic loci provide radical new insights on the emergence. Parasites from sympatric long-tailed macaques (Macaca fascicularis) and pig-tailed macaques (M. nemestrina) were very highly differentiated (FST = 0.22, and K-means clustering confirmed two host-associated subpopulations). Approximately two thirds of human P. knowlesi infections were of the long-tailed macaque type (Cluster 1), and one third were of the pig-tailed-macaque type (Cluster 2), with relative proportions varying across the different sites. Among the samples from humans, there was significant indication of genetic isolation by geographical distance overall and within Cluster 1 alone. Across the different sites, the level of multi-locus linkage disequilibrium correlated with the degree of local admixture of the two different clusters. The widespread occurrence of both types of P. knowlesi in humans enhances the potential for parasite adaptation in this zoonotic system. PMID:26020959

Muscarinic acetylcholine receptors are expressed by most parvalbumin-immunoreactive neurons in area MT of the macaque

PubMed Central

Disney, Anita A; Alasady, Hussein A; Reynolds, John H

2014-01-01

Background In the mammalian neocortex, cells that express parvalbumin (PV neurons) comprise a dominant class of inhibitory neuron that substantially overlaps with the fast/narrow-spiking physiological phenotype. Attention has pronounced effects on narrow-spiking neurons in the extrastriate cortex of macaques, and more consistently so than on their broad-spiking neighbors. Cortical neuromodulation by acetylcholine (ACh) is a candidate mechanism for aspects of attention and in the primary visual cortex (V1) of the macaque, receptors for ACh (AChRs) are strongly expressed by inhibitory neurons. In particular, most PV neurons in macaque V1 express m1 muscarinic AChRs and exogenously applied ACh can cause the release of γ-aminobutyric acid. In contrast, few PV neurons in rat V1 express m1 AChRs. While this could be a species difference, it has also been argued that macaque V1 is anatomically unique when compared with other cortical areas in macaques. Aims The aim of this study was to better understand the extent to which V1 offers a suitable model circuit for cholinergic anatomy in the macaque occipital lobe, and to explore cholinergic modulation as a biological basis for the changes in circuit behavior seen with attention. Materials and methods We compared expression of m1 AChRs by PV neurons between area V1 and the middle temporal visual area (MT) in macaque monkeys using dual-immunofluorescence confocal microscopy. Results and conclusion We find that, as in V1, most PV neurons in MT express m1 AChRs but, unlike in V1, it appears that so do most excitatory neurons. This provides support for V1 as a model of cholinergic modulation of inhibition in macaque visual cortex, but not of cholinergic modulation of visual cortical circuits in general. We also propose that ACh acting via m1 AChRs is a candidate underlying mechanism for the strong effects of attention on narrow-spiking neurons observed in behaving animals. PMID:24944872

Pharmacokinetics and Preliminary Safety of Pod-Intravaginal Rings Delivering the Monoclonal Antibody VRC01-N for HIV Prophylaxis in a Macaque Model.

PubMed

Zhao, Chunxia; Gunawardana, Manjula; Villinger, Francois; Baum, Marc M; Remedios-Chan, Mariana; Moench, Thomas R; Zeitlin, Larry; Whaley, Kevin J; Bohorov, Ognian; Smith, Thomas J; Anderson, Deborah J; Moss, John A

2017-07-01

The broadly neutralizing antibody (bNAb) VRC01, capable of neutralizing 91% of known human immunodeficiency virus type 1 (HIV-1) isolates in vitro , is a promising candidate microbicide for preventing sexual HIV infection when administered topically to the vagina; however, accessibility to antibody-based prophylactic treatment by target populations in sub-Saharan Africa and other underdeveloped regions may be limited by the high cost of conventionally produced antibodies and the limited capacity to manufacture such antibodies. Intravaginal rings of the pod design (pod-IVRs) delivering Nicotiana -manufactured VRC01 (VRC01-N) over a range of release rates have been developed. The pharmacokinetics and preliminary safety of VRC01-N pod-IVRs were evaluated in a rhesus macaque model. The devices sustained VRC01-N release for up to 21 days at controlled rates, with mean steady-state VRC01-N levels in vaginal fluids in the range of 10 2 to 10 3 μg g -1 being correlated with in vitro release rates. No adverse safety indications were observed. These findings indicate that pod-IVRs are promising devices for the delivery of the candidate topical microbicide VRC01-N against HIV-1 infection and merit further preclinical evaluation. Copyright © 2017 American Society for Microbiology.

Comparison of rectal and infrared thermometry for obtaining body temperature in cynomolgus macaques (Macaca fascicularis).

PubMed

Sikoski, P; Banks, M L; Gould, R; Young, R W; Wallace, J M; Nader, M A

2007-12-01

It would be clinically advantageous to develop a method of body temperature evaluation in cynomolgus macaques (Macaca fascicularis) that did not require sedation, restraint, surgical manipulation, or expensive equipment. Body temperatures of 51 cynomolgus macaques were taken with rectal thermometry and non-contact infrared thermometry (NIFT) on the shoulder, face, abdomen, and axillary region. Body temperature measurements from NIFT were statistically different (P < 0.0001) from rectal thermometry. In addition, there was greater between- and within-subject variability in values using NIFT. There was no correlation between any sites of the NIFT and rectal thermometry. It was concluded that NIFT was not a valid alternative to rectal thermometry in cynomolgus macaques.

Occipital White Matter Tracts in Human and Macaque

PubMed Central

Takemura, Hiromasa; Pestilli, Franco; Weiner, Kevin S.; Landi, Sofia M.; Sliwa, Julia; Ye, Frank Q.; Barnett, Michael A.; Leopold, David A.; Freiwald, Winrich A.; Logothetis, Nikos K.; Wandell, Brian A.

2017-01-01

Abstract We compare several major white-matter tracts in human and macaque occipital lobe using diffusion magnetic resonance imaging. The comparison suggests similarities but also significant differences in the tracts. There are several apparently homologous tracts in the 2 species, including the vertical occipital fasciculus (VOF), optic radiation, forceps major, and inferior longitudinal fasciculus (ILF). There is one large human tract, the inferior fronto-occipital fasciculus, with no corresponding fasciculus in macaque. We could identify the macaque VOF (mVOF), which has been little studied. Its position is consistent with classical invasive anatomical studies by Wernicke. VOF homology is supported by similarity of the endpoints in V3A and ventral V4 across species. The mVOF fibers intertwine with the dorsal segment of the ILF, but the human VOF appears to be lateral to the ILF. These similarities and differences between the occipital lobe tracts will be useful in establishing which circuitry in the macaque can serve as an accurate model for human visual cortex. PMID:28369290

Codon-optimized filovirus DNA vaccines delivered by intramuscular electroporation protect cynomolgus macaques from lethal Ebola and Marburg virus challenges.

PubMed

Grant-Klein, Rebecca J; Altamura, Louis A; Badger, Catherine V; Bounds, Callie E; Van Deusen, Nicole M; Kwilas, Steven A; Vu, Hong A; Warfield, Kelly L; Hooper, Jay W; Hannaman, Drew; Dupuy, Lesley C; Schmaljohn, Connie S

2015-01-01

Cynomolgus macaques were vaccinated by intramuscular electroporation with DNA plasmids expressing codon-optimized glycoprotein (GP) genes of Ebola virus (EBOV) or Marburg virus (MARV) or a combination of codon-optimized GP DNA vaccines for EBOV, MARV, Sudan virus and Ravn virus. When measured by ELISA, the individual vaccines elicited slightly higher IgG responses to EBOV or MARV than did the combination vaccines. No significant differences in immune responses of macaques given the individual or combination vaccines were measured by pseudovirion neutralization or IFN-γ ELISpot assays. Both the MARV and mixed vaccines were able to protect macaques from lethal MARV challenge (5/6 vs. 6/6). In contrast, a greater proportion of macaques vaccinated with the EBOV vaccine survived lethal EBOV challenge in comparison to those that received the mixed vaccine (5/6 vs. 1/6). EBOV challenge survivors had significantly higher pre-challenge neutralizing antibody titers than those that succumbed.

Development of real-time PCR assays for the detection of Moraxella macacae associated with bloody nose syndrome in rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) macaques

PubMed Central

Whitehouse, Chris A.; Chase, Kitty; Embers, Monica E.; Kulesh, David A.; Ladner, Jason T.; Palacios, Gustavo F.; Minogue, Timothy D.

2016-01-01

Background Moraxella macacae is a recently described bacterial pathogen that causes epistaxis or so-called bloody nose syndrome in captive macaques. The aim of this study was to develop specific molecular diagnostic assays for M. macacae and to determine their performance characteristics. Methods We developed six real-time PCR assays on the Roche LightCycler. The accuracy, precision, selectivity, and limit of detection (LOD) were determined for each assay, in addition to further validation by testing nasal swabs from macaques presenting with epistaxis at the Tulane National Primate Research Center. Results All assays exhibited 100% specificity and were highly sensitive with an LOD of 10 fg for chromosomal assays and 1 fg for the plasmid assay. Testing of nasal swabs from 10 symptomatic macaques confirmed the presence of M. macacae in these animals. Conclusions We developed several accurate, sensitive, and species-specific real-time PCR assays for the detection of M. macacae in captive macaques. PMID:26365904

Specific Pathogen Free Macaque Colonies: A Review of Principles and Recent Advances for Viral Testing and Colony Management

PubMed Central

Yee, JoAnn L.; Vandeford, Thomas H.; Didier, Elizabeth S.; Gray, Stanton; Lewis, Anne; Roberts, Jeffrey; Taylor, Kerry; Bohm, Rudolf P.

2016-01-01

Specific Pathogen Free (SPF) macaques provide valuable animal models for biomedical research. In 1989 the National Center for Research Resources (now Office of Research Infrastructure Programs ORIP) of the National Institutes of Health initiated experimental research contracts to establish and maintain SPF colonies. The derivation and maintenance of SPF macaque colonies is a complex undertaking requiring knowledge of the biology of the agents for exclusion and normal physiology and behavior of macaques, application of the latest diagnostic technology, facilities management, and animal husbandry. This review provides information on the biology of the four viral agents targeted for exclusion in ORIP SPF macaque colonies, describes current state-of-the-art viral diagnostic algorithms, presents data from proficiency testing of diagnostic assays between laboratories at institutions participating in the ORIP SPF program, and outlines management strategies for maintaining the integrity of SPF colonies using results of diagnostic testing as a guide to decision making. PMID:26932456

Neisseria infection of rhesus macaques as a model to study colonization, transmission, persistence, and horizontal gene transfer.

PubMed

Weyand, Nathan J; Wertheimer, Anne M; Hobbs, Theodore R; Sisko, Jennifer L; Taku, Nyiawung A; Gregston, Lindsay D; Clary, Susan; Higashi, Dustin L; Biais, Nicolas; Brown, Lewis M; Planer, Shannon L; Legasse, Alfred W; Axthelm, Michael K; Wong, Scott W; So, Magdalene

2013-02-19

The strict tropism of many pathogens for man hampers the development of animal models that recapitulate important microbe-host interactions. We developed a rhesus macaque model for studying Neisseria-host interactions using Neisseria species indigenous to the animal. We report that Neisseria are common inhabitants of the rhesus macaque. Neisseria isolated from the rhesus macaque recolonize animals after laboratory passage, persist in the animals for at least 72 d, and are transmitted between animals. Neisseria are naturally competent and acquire genetic markers from each other in vivo, in the absence of selection, within 44 d after colonization. Neisseria macacae encodes orthologs of known or presumed virulence factors of human-adapted Neisseria, as well as current or candidate vaccine antigens. We conclude that the rhesus macaque model will allow studies of the molecular mechanisms of Neisseria colonization, transmission, persistence, and horizontal gene transfer. The model can potentially be developed further for preclinical testing of vaccine candidates.

Neisseria infection of rhesus macaques as a model to study colonization, transmission, persistence, and horizontal gene transfer

PubMed Central

Weyand, Nathan J.; Wertheimer, Anne M.; Hobbs, Theodore R.; Sisko, Jennifer L.; Taku, Nyiawung A.; Gregston, Lindsay D.; Clary, Susan; Higashi, Dustin L.; Biais, Nicolas; Brown, Lewis M.; Planer, Shannon L.; Legasse, Alfred W.; Axthelm, Michael K.; Wong, Scott W.; So, Magdalene

2013-01-01

The strict tropism of many pathogens for man hampers the development of animal models that recapitulate important microbe–host interactions. We developed a rhesus macaque model for studying Neisseria–host interactions using Neisseria species indigenous to the animal. We report that Neisseria are common inhabitants of the rhesus macaque. Neisseria isolated from the rhesus macaque recolonize animals after laboratory passage, persist in the animals for at least 72 d, and are transmitted between animals. Neisseria are naturally competent and acquire genetic markers from each other in vivo, in the absence of selection, within 44 d after colonization. Neisseria macacae encodes orthologs of known or presumed virulence factors of human-adapted Neisseria, as well as current or candidate vaccine antigens. We conclude that the rhesus macaque model will allow studies of the molecular mechanisms of Neisseria colonization, transmission, persistence, and horizontal gene transfer. The model can potentially be developed further for preclinical testing of vaccine candidates. PMID:23382234

Heterospecific SNP diversity in humans and rhesus macaque (Macaca mulatta)

PubMed Central

Ng, Jillian; Trask, Jessica Satkoski; Smith, David Glenn; Kanthaswamy, Sree

2018-01-01

Background Conservation of single nucleotide polymorphisms (SNPs) between human and other primates (i.e., heterospecific SNPs) in candidate genes can be used to assess the utility of those organisms as models for human biomedical research. Methods 59,691 heterospecific SNPs in 22 rhesus macaques and 20 humans were analyzed for human trait associations and 4,207 heterospecific SNPs biallelic in both taxa were compared for genetic variation. Results Variation comparisons at the 4,207 SNPs showed that humans were more genetically diverse than rhesus macaques with observed and expected heterozygosities of 0.337 and 0.323 versus 0.119 and 0.102, and minor allele frequencies of 0.239 and 0.063, respectively. 431 of the 59,691 heterospecific SNPs are reportedly associated with human-specific traits. Conclusion While comparisons between human and rhesus macaque genomes are plausible, functional studies of heterospecific SNPs are necessary to determine whether rhesus macaque alleles are associated with the same phenotypes as their corresponding human alleles. PMID:25963897

Hematologic abnormalities associated with Simian Immunodeficieny Virus (SIV) Infection mimic those in HIV infection

PubMed Central

Gill, Amy F.; Ahsan, Muhammad H.; Lackner, Andrew A.; Veazey, Ronald S.

2012-01-01

Studies of hematologic abnormalities in HIV infected patients are confounded by a multitude of factors. A retrospective data analysis of SIV infected Rhesus macaques (RM) of Indian origin was performed to determine the prevalence of hematologic abnormalities free of these confounds. Hematologic data from rhesus macaques inoculated with SIV and without antiviral therapy were examined pre-inoculation, and throughout infection and the development of AIDS. Anemia, thrombocytopenia, lymphopenia, eosinophilia, and neutropenia all increased in prevalence with SIV infection. Significant increases in prevalence for both neutropenia and neutrophilia were also detected in SIV-infected macaques. SIV-infected macaques also had lower lymphocyte counts and increased prevalence of lymphopenia compared to non-infected subjects. The prevalence of eosinophilia was significantly increased during SIV infection. Concordance of hematologic abnormalities during SIV infection of macaques with similar changes in HIV infection of humans suggest that, like in HIV infection, hematologic abnormalities are major complications of SIV infection. PMID:22620272

A Chinese rhesus macaque (Macaca mulatta) model for vaginal Lactobacillus colonization and live microbicide development

PubMed Central

Yu, Rosa R.; Cheng, Andrew T.; Lagenaur, Laurel A.; Huang, Wenjun; Weiss, Deborah E.; Treece, Jim; Sanders-Beer, Brigitte E.; Hamer, Dean H.; Lee, Peter P.; Xu, Qiang; Liu, Yang

2015-01-01

Background We sought to establish a nonhuman primate model of vaginal Lactobacillus colonization suitable for evaluating live microbial microbicide candidates. Methods Vaginal and rectal microflora in Chinese rhesus macaques (Macaca mulatta) were analyzed, with cultivable bacteria identified by 16S rRNA gene sequencing. Live lactobacilli were intravaginally administered to evaluate bacterial colonization. Results Chinese rhesus macaques harbored abundant vaginal Lactobacillus, with Lactobacillus johnsonii as the predominant species. Like humans, most examined macaques harbored only one vaginal Lactobacillus species. Vaginal and rectal Lactobacillus isolates from the same animal exhibited different genetic and biochemical profiles. Vaginal Lactobacillus was cleared by a vaginal suppository of azithromycin, and endogenous L. johnsonii was subsequently restored by intravaginal inoculation. Importantly, prolonged colonization of a human vaginal Lactobacillus jensenii was established in these animals. Conclusions The Chinese rhesus macaque harbors vaginal Lactobacillus and is a potentially useful model to support the pre-clinical evaluation of Lactobacillus-based topical microbicides. PMID:19367737

Comparative Proteomics of Human and Macaque Milk Reveals Species-Specific Nutrition during Postnatal Development.

PubMed

Beck, Kristen L; Weber, Darren; Phinney, Brett S; Smilowitz, Jennifer T; Hinde, Katie; Lönnerdal, Bo; Korf, Ian; Lemay, Danielle G

2015-05-01

Milk has been well established as the optimal nutrition source for infants, yet there is still much to be understood about its molecular composition. Therefore, our objective was to develop and compare comprehensive milk proteomes for human and rhesus macaques to highlight differences in neonatal nutrition. We developed a milk proteomics technique that overcomes previous technical barriers including pervasive post-translational modifications and limited sample volume. We identified 1606 and 518 proteins in human and macaque milk, respectively. During analysis of detected protein orthologs, we identified 88 differentially abundant proteins. Of these, 93% exhibited increased abundance in human milk relative to macaque and include lactoferrin, polymeric immunoglobulin receptor, alpha-1 antichymotrypsin, vitamin D-binding protein, and haptocorrin. Furthermore, proteins more abundant in human milk compared with macaque are associated with development of the gastrointestinal tract, the immune system, and the brain. Overall, our novel proteomics method reveals the first comprehensive macaque milk proteome and 524 newly identified human milk proteins. The differentially abundant proteins observed are consistent with the perspective that human infants, compared with nonhuman primates, are born at a slightly earlier stage of somatic development and require additional support through higher quantities of specific proteins to nurture human infant maturation.

A preliminary study on activity budget, daily travel distance and feeding behaviour of long-tailed macaques and spectacled dusky leaf monkey in Bangi campus of Universiti Kebangsaan Malaysia, Selangor

NASA Astrophysics Data System (ADS)

Ruslin, Farhani; Yaakop, Salmah; Zain, Badrul Munir Md.

2014-09-01

The activity budget, ranging behaviour and feeding behaviour of a multimale-multifemale group of long-tailed macaques (Macaca fascicularis) and a multimale-multifemale group of spectacled dusky leaf monkey (Trachypithecus obscurus) were studied. A total of 145 hours and 143 hours have been spent to observe the group of long-tailed macaque and spectacled dusky leaf monkey that ranged the same habitat adjacent to the campus areas. The researchers examined the activity budgets, daily travel length and feeding activity of both species and distinguished how the sympatric species used the same forested habitat. Preliminary study found that the long-tailed macaques spent longer time feeding, moving than resting and other activities. On the other hand, the dusky leaf monkey spent much time in feeding and resting than moving. The differences of daily pattern between these two groups are significant. Macaques have higher daily mean of path length compared to the dusky leaf monkey and spent much time moving compare to the leaf monkey group. The spectacled dusky leaf monkey group also has fully utilized the forested areas where else the long-tailed macaques adopted foraging to the adjacent residential colleges.

Rotational displacement skills in rhesus macaques (Macaca mulatta).

PubMed

Hughes, Kelly D; Santos, Laurie R

2012-11-01

Rotational displacement tasks, in which participants must track an object at a hiding location within an array while the array rotates, exhibit a puzzling developmental pattern in humans. Human children take an unusually long time to master this task and tend to solve rotational problems through the use of nongeometric features or landmarks as opposed to other kinds of spatial cues. We investigated whether these developmental characteristics are unique to humans by testing rotational displacement skills in a monkey species, the rhesus macaque (Macaca mulatta), using a looking-time method. Monkeys first saw food hidden in two differently colored boxes within an array. The array was then rotated 180° and the boxes reopened to reveal the food in an expected or unexpected location. Our first two experiments explored the developmental time-course of performance on this rotational displacement task. We found that adult macaques looked longer at the unexpected event, but such performance was not mirrored in younger-aged macaques. In a third study, we systematically varied featural information and visible access to the array to investigate which strategies adult macaques used in solving rotational displacements. Our results show that adult macaques need both sets of information to solve the task. Taken together, these results suggest both similarities and differences in mechanisms by which human and nonhuman primates develop this spatial skill.

Evolutionary interrogation of human biology in well-annotated genomic framework of rhesus macaque.

PubMed

Zhang, Shi-Jian; Liu, Chu-Jun; Yu, Peng; Zhong, Xiaoming; Chen, Jia-Yu; Yang, Xinzhuang; Peng, Jiguang; Yan, Shouyu; Wang, Chenqu; Zhu, Xiaotong; Xiong, Jingwei; Zhang, Yong E; Tan, Bertrand Chin-Ming; Li, Chuan-Yun

2014-05-01

With genome sequence and composition highly analogous to human, rhesus macaque represents a unique reference for evolutionary studies of human biology. Here, we developed a comprehensive genomic framework of rhesus macaque, the RhesusBase2, for evolutionary interrogation of human genes and the associated regulations. A total of 1,667 next-generation sequencing (NGS) data sets were processed, integrated, and evaluated, generating 51.2 million new functional annotation records. With extensive NGS annotations, RhesusBase2 refined the fine-scale structures in 30% of the macaque Ensembl transcripts, reporting an accurate, up-to-date set of macaque gene models. On the basis of these annotations and accurate macaque gene models, we further developed an NGS-oriented Molecular Evolution Gateway to access and visualize macaque annotations in reference to human orthologous genes and associated regulations (www.rhesusbase.org/molEvo). We highlighted the application of this well-annotated genomic framework in generating hypothetical link of human-biased regulations to human-specific traits, by using mechanistic characterization of the DIEXF gene as an example that provides novel clues to the understanding of digestive system reduction in human evolution. On a global scale, we also identified a catalog of 9,295 human-biased regulatory events, which may represent novel elements that have a substantial impact on shaping human transcriptome and possibly underpin recent human phenotypic evolution. Taken together, we provide an NGS data-driven, information-rich framework that will broadly benefit genomics research in general and serves as an important resource for in-depth evolutionary studies of human biology.

Vaccination against H9N2 avian influenza virus reduces bronchus-associated lymphoid tissue formation in cynomolgus macaques after intranasal virus challenge infection.

PubMed

Nakayama, Misako; Ozaki, Hiroichi; Itoh, Yasushi; Soda, Kosuke; Ishigaki, Hirohito; Okamatsu, Masatoshi; Sakoda, Yoshihiro; Park, Chun-Ho; Tsuchiya, Hideaki; Kida, Hiroshi; Ogasawara, Kazumasa

2016-12-01

H9N2 avian influenza virus causes sporadic human infection. Since humans do not possess acquired immunity specific to this virus, we examined the pathogenicity of an H9N2 virus isolated from a human and then analyzed protective effects of a vaccine in cynomolgus macaques. After intranasal challenge with A/Hong Kong/1073/1999 (H9N2) (HK1073) isolated from a human patient, viruses were isolated from nasal and tracheal swabs in unvaccinated macaques with mild fever and body weight loss. A formalin-inactivated H9N2 whole particle vaccine derived from our virus library was subcutaneously inoculated to macaques. Vaccination induced viral antigen-specific IgG and neutralization activity in sera. After intranasal challenge with H9N2, the virus was detected only the day after inoculation in the vaccinated macaques. Without vaccination, many bronchus-associated lymphoid tissues (BALTs) were formed in the lungs after infection, whereas the numbers of BALTs were smaller and the cytokine responses were weaker in the vaccinated macaques than those in the unvaccinated macaques. These findings indicate that the H9N2 avian influenza virus HK1073 is pathogenic in primates but seems to cause milder symptoms than does H7N9 influenza virus as found in our previous studies and that a formalin-inactivated H9N2 whole particle vaccine induces protective immunity against H9N2 virus. © 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

Brief communication: Hip joint mobility in free-ranging rhesus macaques

PubMed Central

Hammond, Ashley S.; Johnson, Victoria P.; Higham, James P.

2016-01-01

Objectives We aimed to test for differences in hip joint range of motion (ROM) between captive and free-ranging rhesus macaques (Macaca mulatta), particularly for hip joint abduction, which previous studies of captive macaques have found to be lower than predicted. Materials and Methods Hip ROM was assessed following standard joint measurement methodology in anesthetized adult free-ranging rhesus macaques (n=39) from Cayo Santiago, and compared to published ROM data from captive rhesus macaques (n=16) (Hammond 2014a, American Journal of Physical Anthropology). Significant differences between populations were detected using one-way analysis of variance (p<0.05). Results In a sample of pooled sexes and ages, free-ranging macaques are capable of increased hip abduction, flexion, and internal rotation compared to captive individuals. These differences in joint excursion resulted in free-ranging individuals having significantly increased ROM for hip adduction-abduction, rotation, flexion-extension, and the distance spanned by the knee during hip abduction. When looking at data for a smaller sample of age-matched males, fewer ROM differences are significant, but free-ranging males have significantly increased hip abduction, internal rotation, range of flexion-extension, and distance spanned by the knee during hip abduction compared to captive males of similar age. Discussion Our results suggest that a spatially restrictive environment results in decreased hip mobility in cage-confined animals and ultimately limits the potential limb postures in captive macaques. These results have implications for selection of animal samples in model validation studies, as well as laboratory animal husbandry practices. PMID:27731892

Left Ventricular Hypertrophy in Rhesus Macaques (Macaca mulatta) at the California National Primate Research Center (1992-2014).

PubMed

Reader, J Rachel; Canfield, Don R; Lane, Jennifer F; Kanthaswamy, Sreetharan; Ardeshir, Amir; Allen, A Mark; Tarara, Ross P

2016-04-01

Necropsy records and associated clinical histories from the rhesus macaque colony at the California National Primate Research Center were reviewed to identify mortality related to cardiac abnormalities involving left ventricular hypertrophy (LVH). Over a 21-y period, 162 cases (female, 90; male, 72) of idiopathic LVH were identified. Macaques presented to necropsy with prominent concentric hypertrophy of the left ventricle associated with striking reduction of the ventricular lumen. Among all LVH cases, 74 macaques (female, 39; male, 35), mostly young adults, presented for spontaneous (sudden) death; more than 50% of these 74 cases were associated with a recent history of sedation or intraspecific aggression. The risk of sudden death in the 6- to 9-y-old age group was significantly higher in male macaques. Subtle histologic cardiac lesions included karyomegaly and increased cardiac myocyte diameter. Pedigree analyses based on rhesus macaque LVH probands suggested a strong genetic predisposition for the condition. In humans, hypertrophic cardiomyopathy (HCM) is defined by the presence of unexplained left ventricular hypertrophy, associated with diverse clinical outcomes ranging from asymptomatic disease to sudden death. Although the overall risk of disease complications such as sudden death, end-stage heart failure, and stroke is low (1% to 2%) in patients with HCM, the absolute risk can vary dramatically. Prima facie comparison of HCM and LVH suggest that further study may allow the development of spontaneously occurring LVH in rhesus macaques as a useful model of HCM, to better understand the pathogenesis of this remarkably heterogeneous disease.

Park Rangers’ Behaviors and Their Effects on Tourists and Tibetan Macaques (Macaca thibetana) at Mt. Huangshan, China

PubMed Central

Usui, Rie; Sheeran, Lori K.; Li, Jin-hua; Sun, Lixing; Wang, Xi; Pritchard, Alexander J.; DuVall-Lash, Alexander S.; Wagner, R. Steve

2014-01-01

Simple Summary Conflict between macaques and humans is a commonly reported problem in Asian tourism. However, without understanding how macaques are managed, the establishment of an effective management design is impracticable. This study explored how monkeys were managed and tourists were regulated at the Valley of the Wild Monkeys in Mt. Huangshan, Anhui Province, China, through a field observation. Two teams of park rangers alternated monthly and managed a group of macaques. The results suggested that undesired tourists’ interactions with monkeys were not regularly intervened by park rangers, and park rangers established dominance over the monkeys by using physical threats to manage them. Abstract Previous studies have reported the negative impacts of tourism on nonhuman primates (NHPs) and tourists and advocated the improvement of tourism management, yet what constitutes good quality management remains unclear. We explored whether rates of macaque aggression and self-directed behaviors (SDBs) differed under the supervision of two park ranger teams at the Valley of the Wild Monkeys (VWM) in Mt. Huangshan, Anhui Province, China. The two ranger teams provisioned and managed a group of macaques on an alternating monthly basis. Monkey, tourist and ranger behaviors were collected from August 16–September 30, 2012. Macaque aggression and SDB rates did not differ significantly under the management of the two teams. Overall, there was little intervention in tourist-macaque interactions by park rangers, and even when rangers discouraged tourists’ undesirable behaviors, tourist interactions with monkeys persisted. Furthermore, only one or sometimes two park rangers managed monkeys and tourists, and rangers established dominance over the monkeys to control them. In order to effectively manage tourists and monkeys by a single park ranger, we recommend that rangers: (1) prohibit tourists from feeding; (2) move around the viewing platform more frequently; and (3) limit the number of tourists each visiting session. PMID:26480324

Is Diet Flexibility an Adaptive Life Trait for Relictual and Peri-Urban Populations of the Endangered Primate Macaca sylvanus?

PubMed Central

Maibeche, Yasmina; Moali, Aissa; Yahi, Nassima; Menard, Nelly

2015-01-01

Habitat loss, fragmentation and urban expansion may drive some species to marginal habitats while others succeed in exploiting urban areas. Species that show dietary flexibility are more able to take advantage of human activities to supplement their diet with anthropogenically abundant and accessible resources. The Barbary macaque (Macaca sylvanus) is an endangered species due to the loss of its habitat, and human pressure. The population of Gouraya National Park (Algeria) lives in a relictual habitat that constitutes about 0.6% of the species range. In addition, this population is a unique case where urban expansion favours contact zones between Barbary macaque habitats and a big city (Bejaia). We quantified the dietary composition of Gouraya macaques over an annual cycle with the objective to understand how diet flexibility of this species may help it adapt to a relictual habitat or cope with urban expansion. We recorded the phenology of plant species every month. This study shows that Gouraya macaques, compared to those living in other forest types of the distribution area, are under lower seasonal constraints. They consume a greater amount of fruit and seeds that are available throughout much of the year, and a lesser amount of costly to find and extract subterranean foods. Therefore the Gouraya relictual habitat appears as a favourable environment compared to other major habitats of that species. This study also shows that colonizing peri-urban zones increases the availability and species richness of diet resources for Barbary macaques as they consume more human foods and exotic plants than in farther sites. Adult males eat more human foods than adult females and immatures do. The exploitation of high-energy anthropogenic food could favour macaque population growth and expansion towards the city center associated with human/macaque conflicts. We recommend applying management actions to restore macaques back to their natural habitat. PMID:25714476

Spontaneous Urinary Bladder Leiomyoma in a Rhesus Macaque (Macaca mulatta).

PubMed

Scott, Kathleen E; Frydman, Galit; Fox, James G; Bakthavatchalu, Vasudevan

2018-06-01

Here we report the case of a urinary bladder leiomyoma in a rhesus macaque. The animal was clinically normal and had a lipoma localized to the stifle. Endovesicular leiomyomas are the most common form of urinary bladder leiomyoma in humans. In contrast, this macaque's tumor exhibited extravesicular localization in the bladder. Urinary bladder leiomyomas account for less than 0.5% of all bladder tumors in humans, with only 250 cases reported in total.

Smallpox DNA Vaccine Protects Nonhuman Primates Against Lethal Monkeypox

DTIC Science & Technology

2004-05-01

skin, the vaccine itself can pose a serious health risk. Here, we demonstrate that rhesus macaques vaccinated with a DNA vaccine consisting of four...administered to the skin, the vaccine itself can pose a serious health risk. Here, we demonstrate that rhesus macaques vaccinated with a DNA vaccine consisting...vaccine to protect rhesus macaques from severe monkeypox. MATERIALS AND METHODS Viruses and cells. The VACV Connaught vaccine strain (derived from the New

Isolation and sequence analysis of a novel rhesus macaque foamy virus isolate with a serotype-1-like env.

PubMed

Ensser, Armin; Großkopf, Anna K; Mätz-Rensing, Kerstin; Roos, Christian; Hahn, Alexander S

2018-06-02

SFVmmu-DPZ9524 represents the third completely sequenced rhesus macaque simian foamy virus (SFV) isolate, alongside SFVmmu_K3T with a similar SFV-1-type env, and R289HybAGM with a SFV-2-like env. Sequence analysis demonstrates that, in gag and pol, SFVmmu-DPZ9524 is more closely related to R289HybAGM than to SFVmmu_K3T, which, outside of env, is more similar to a Japanese macaque isolate than to the other two rhesus macaque isolates SFVmmu-DPZ9524 and R289HybAGM. Further, we identify bel as another recombinant locus in R289HybAGM, confirming that recombination contributes to sequence diversity in SFV.

Supplementation of Reduced Gluten Barley Diet with Oral Prolyl Endopeptidase Effectively Abrogates Enteropathy-Associated Changes in Gluten-Sensitive Macaques.

PubMed

Sestak, Karol; Thwin, Hazel; Dufour, Jason; Liu, David X; Alvarez, Xavier; Laine, David; Clarke, Adam; Doyle, Anthony; Aye, Pyone P; Blanchard, James; Moehs, Charles P

2016-06-28

Celiac disease (CD) is an autoimmune disorder that affects approximately three million people in the United States. Furthermore, non-celiac gluten sensitivity (NCGS) affects an estimated additional 6% of the population, e.g., 20 million in the U.S. The only effective treatment of CD and NCGS requires complete removal of gluten sources from the diet. While required adherence to a gluten-free diet (GFD) is extremely difficult to accomplish, efforts to develop additional supportive treatments are needed. To facilitate these efforts, we developed a gluten-sensitive (GS) rhesus macaque model to study the effects of novel therapies. Recently reported results from phase one of this project suggest that partial improvement-but not remission-of gluten-induced disease can be accomplished by 100-fold reduction of dietary gluten, i.e., 200 ppm-by replacement of conventional dietary sources of gluten with a mutant, reduced gluten (RG) barley (lys3a)-derived source. The main focus of this (phase two) study was to determine if the inflammatory effects of the residual gluten in lys3a mutant barley grain could be further reduced by oral supplementation with a prolylendopeptidase (PE). Results reveal that PE supplementation of RG barley diet induces more complete immunological, histopathological and clinical remission than RG barley diet alone. The combined effects of RG barley diet and PE supplementation resulted in a further decrease of inflammatory mediators IFN-γ and TNF secretion by peripheral lymphocytes, as well as decreased plasma anti-gliadin and anti-intestinal tissue transglutaminase (TG2) antibodies, diminished active caspase production in small intestinal mucosa, and eliminated clinical diarrhea-all comparable with a gluten-free diet induced remission. In summary, the beneficial results of a combined RG barley and PE administration in GS macaques may warrant the investigation of similar synergistic approaches.

Supplementation of Reduced Gluten Barley Diet with Oral Prolyl Endopeptidase Effectively Abrogates Enteropathy-Associated Changes in Gluten-Sensitive Macaques

PubMed Central

Sestak, Karol; Thwin, Hazel; Dufour, Jason; Liu, David X.; Alvarez, Xavier; Laine, David; Clarke, Adam; Doyle, Anthony; Aye, Pyone P.; Blanchard, James; Moehs, Charles P.

2016-01-01

Celiac disease (CD) is an autoimmune disorder that affects approximately three million people in the United States. Furthermore, non-celiac gluten sensitivity (NCGS) affects an estimated additional 6% of the population, e.g., 20 million in the U.S. The only effective treatment of CD and NCGS requires complete removal of gluten sources from the diet. While required adherence to a gluten-free diet (GFD) is extremely difficult to accomplish, efforts to develop additional supportive treatments are needed. To facilitate these efforts, we developed a gluten-sensitive (GS) rhesus macaque model to study the effects of novel therapies. Recently reported results from phase one of this project suggest that partial improvement—but not remission—of gluten-induced disease can be accomplished by 100-fold reduction of dietary gluten, i.e., 200 ppm—by replacement of conventional dietary sources of gluten with a mutant, reduced gluten (RG) barley (lys3a)-derived source. The main focus of this (phase two) study was to determine if the inflammatory effects of the residual gluten in lys3a mutant barley grain could be further reduced by oral supplementation with a prolylendopeptidase (PE). Results reveal that PE supplementation of RG barley diet induces more complete immunological, histopathological and clinical remission than RG barley diet alone. The combined effects of RG barley diet and PE supplementation resulted in a further decrease of inflammatory mediators IFN-γ and TNF secretion by peripheral lymphocytes, as well as decreased plasma anti-gliadin and anti-intestinal tissue transglutaminase (TG2) antibodies, diminished active caspase production in small intestinal mucosa, and eliminated clinical diarrhea—all comparable with a gluten-free diet induced remission. In summary, the beneficial results of a combined RG barley and PE administration in GS macaques may warrant the investigation of similar synergistic approaches. PMID:27367722

Longevity of rAAV vector and plasmid DNA in blood after intramuscular injection in nonhuman primates: implications for gene doping.

PubMed

Ni, W; Le Guiner, C; Gernoux, G; Penaud-Budloo, M; Moullier, P; Snyder, R O

2011-07-01

Legitimate uses of gene transfer technology can benefit from sensitive detection methods to determine vector biodistribution in pre-clinical studies and in human clinical trials, and similar methods can detect illegitimate gene transfer to provide sports-governing bodies with the ability to maintain fairness. Real-time PCR assays were developed to detect a performance-enhancing transgene (erythropoietin, EPO) and backbone sequences in the presence of endogenous cellular sequences. In addition to developing real-time PCR assays, the steps involved in DNA extraction, storage and transport were investigated. By real-time PCR, the vector transgene is distinguishable from the genomic DNA sequence because of the absence of introns, and the vector backbone can be identified by heterologous gene expression control elements. After performance of the assays was optimized, cynomolgus macaques received a single dose by intramuscular (IM) injection of plasmid DNA, a recombinant adeno-associated viral vector serotype 1 (rAAV1) or a rAAV8 vector expressing cynomolgus macaque EPO. Macaques received a high plasmid dose intended to achieve a significant, but not life-threatening, increase in hematocrit. rAAV vectors were used at low doses to achieve a small increase in hematocrit and to determine the limit of sensitivity for detecting rAAV sequences by single-step PCR. DNA extracted from white blood cells (WBCs) was tested to determine whether WBCs can be collaterally transfected by plasmid or transduced by rAAV vectors in this context, and can be used as a surrogate marker for gene doping. We demonstrate that IM injection of a conventional plasmid and rAAV vectors results in the presence of DNA that can be detected at high levels in blood before rapid elimination, and that rAAV genomes can persist for several months in WBCs.

An intravaginal ring that releases three antiviral agents and a contraceptive blocks SHIV-RT infection, reduces HSV-2 shedding, and suppresses hormonal cycling in rhesus macaques.

PubMed

Derby, Nina; Aravantinou, Meropi; Kenney, Jessica; Ugaonkar, Shweta R; Wesenberg, Asa; Wilk, Jolanta; Kizima, Larisa; Rodriguez, Aixa; Zhang, Shimin; Mizenina, Olga; Levendosky, Keith; Cooney, Michael L; Seidor, Samantha; Gettie, Agegnehu; Grasperge, Brooke; Blanchard, James; Piatak, Michael; Lifson, Jeffrey D; Fernández-Romero, José; Zydowsky, Thomas M; Robbiani, Melissa

2017-12-01

Women globally need access to multipurpose prevention technologies (MPTs) that prevent human immunodeficiency virus (HIV), sexually transmitted infections that increase HIV acquisition/transmission risk, and unintended pregnancy. Seeking an MPT with activity against HIV, herpes simplex virus-2 (HSV-2), and human papillomavirus (HPV), we developed a prototype intravaginal ring (IVR), the MZCL IVR, which released the antiviral agents MIV-150, zinc acetate, and carrageenan (MZC for short) and the contraceptive levonorgestrel (LNG). Previously, we showed that an MZC gel has potent activity against immunodeficiency viruses, HSV-2, and HPV and that the MZCL (MZC with LNG) IVR releases all four components in macaques in vivo at levels associated with efficacy. Vaginal fluid from treated macaques has in vitro activity against HIV, HSV-2, and HPV. Herein, we assessed the ability of the MZCL IVR to protect macaques against repeated co-challenge with HSV-2 and SHIV-RT (simian immunodeficiency virus [SIV] containing the reverse transcriptase gene from HIV) and prevent hormonal cycling. We evaluated in vivo drug release in co-challenged macaques by measuring drug levels in blood and vaginal fluid and residual drug levels in used IVRs. The MZCL IVR significantly prevented SHIV-RT infection, reduced HSV-2 vaginal shedding, and prevented cycling. No non-nucleoside HIV reverse transcriptase inhibitor (NNRTI)-resistant SHIV was detected in macaques that became infected after continuous exposure to MZC from the IVR. Macaques wearing the MZCL IVR also had carrageenan levels in vaginal fluid expected to protect from HPV (extrapolated from mice) and LNG levels in blood associated with contraceptive efficacy. The MZCL IVR is a promising MPT candidate that warrants further development.

Expression of Kv3.1b potassium channel is widespread in macaque motor cortex pyramidal cells: A histological comparison between rat and macaque

PubMed Central

Soares, David; Goldrick, Isabelle; Lemon, Roger N.; Kraskov, Alexander; Greensmith, Linda

2017-01-01

Abstract There are substantial differences across species in the organization and function of the motor pathways. These differences extend to basic electrophysiological properties. Thus, in rat motor cortex, pyramidal cells have long duration action potentials, while in the macaque, some pyramidal neurons exhibit short duration “thin” spikes. These differences may be related to the expression of the fast potassium channel Kv3.1b, which in rat interneurons is associated with generation of thin spikes. Rat pyramidal cells typically lack these channels, while there are reports that they are present in macaque pyramids. Here we made a systematic, quantitative comparison of the Kv3.1b expression in sections from macaque and rat motor cortex, using two different antibodies (NeuroMab, Millipore). As our standard reference, we examined, in the same sections, Kv3.1b staining in parvalbumin‐positive interneurons, which show strong Kv3.1b immunoreactivity. In macaque motor cortex, a large sample of pyramidal neurons were nearly all found to express Kv3.1b in their soma membranes. These labeled neurons were identified as pyramidal based either by expression of SMI32 (a pyramidal marker), or by their shape and size, and lack of expression of parvalbumin (a marker for some classes of interneuron). Large (Betz cells), medium, and small pyramidal neurons all expressed Kv3.1b. In rat motor cortex, SMI32‐postive pyramidal neurons expressing Kv3.1b were very rare and weakly stained. Thus, there is a marked species difference in the immunoreactivity of Kv3.1b in pyramidal neurons, and this may be one of the factors explaining the pronounced electrophysiological differences between rat and macaque pyramidal neurons. PMID:28213922

Phylogeny and History of the Lost SIV from Crab-Eating Macaques: SIVmfa.

PubMed

McCarthy, Kevin R; Johnson, Welkin E; Kirmaier, Andrea

2016-01-01

In the 20th century, thirteen distinct human immunodeficiency viruses emerged following independent cross-species transmission events involving simian immunodeficiency viruses (SIV) from African primates. In the late 1900s, pathogenic SIV strains also emerged in the United Sates among captive Asian macaque species following their unintentional infection with SIV from African sooty mangabeys (SIVsmm). Since their discovery in the 1980s, SIVs from rhesus macaques (SIVmac) and pig-tailed macaques (SIVmne) have become invaluable models for studying HIV pathogenesis, vaccine design and the emergence of viruses. SIV isolates from captive crab-eating macaques (SIVmfa) were initially described but lost prior to any detailed molecular and genetic characterization. In order to infer the origins of the lost SIVmfa lineage, we located archived material and colony records, recovered its genomic sequence by PCR, and assessed its phylogenetic relationship to other SIV strains. We conclude that SIVmfa is the product of two cross-species transmission events. The first was the established transmission of SIVsmm to rhesus macaques, which occurred at the California National Primate Research Center in the late 1960s and the virus later emerged as SIVmac. In a second event, SIVmac was transmitted to crab-eating macaques, likely at the Laboratory for Experimental Medicine and Surgery in Primates in the early 1970s, and it was later spread to the New England Primate Research Center colony in 1973 and eventually isolated in 1986. Our analysis suggests that SIVmac had already emerged by the early 1970s and had begun to diverge into distinct lineages. Furthermore, our findings suggest that pathogenic SIV strains may have been more widely distributed than previously appreciated, raising the possibility that additional isolates may await discovery.

Effective spatial scales for evaluating environmental determinants of population density in Yakushima macaques.

PubMed

Agetsuma, Naoki; Koda, Ryosuke; Tsujino, Riyou; Agetsuma-Yanagihara, Yoshimi

2015-02-01

Population densities of wildlife species tend to be correlated with resource productivity of habitats. However, wildlife density has been greatly modified by increasing human influences. For effective conservation, we must first identify the significant factors that affect wildlife density, and then determine the extent of the areas in which the factors should be managed. Here, we propose a protocol that accomplishes these two tasks. The main threats to wildlife are thought to be habitat alteration and hunting, with increases in alien carnivores being a concern that has arisen recently. Here, we examined the effect of these anthropogenic disturbances, as well as natural factors, on the local density of Yakushima macaques (Macaca fuscata yakui). We surveyed macaque densities at 30 sites across their habitat using data from 403 automatic cameras. We quantified the effect of natural vegetation (broad-leaved forest, mixed coniferous/broad-leaved forest, etc.), altered vegetation (forestry area and agricultural land), hunting pressure, and density of feral domestic dogs (Canis familiaris). The effect of each vegetation type was analyzed at numerous spatial scales (between 150 and 3,600-m radii from the camera locations) to determine the best scale for explaining macaque density (effective spatial scale). A model-selection procedure (generalized linear mixed model) was used to detect significant factors affecting macaque density. We detected that the most effective spatial scale was 400 m in radius, a scale that corresponded to group range size of the macaques. At this scale, the amount of broad-leaved forest was selected as a positive factor, whereas mixed forest and forestry area were selected as negative factors for macaque density. This study demonstrated the importance of the simultaneous evaluation of all possible factors of wildlife population density at the appropriate spatial scale. © 2014 Wiley Periodicals, Inc.

Laboratory rhesus macaque social housing and social changes: Implications for research.

PubMed

Hannibal, Darcy L; Bliss-Moreau, Eliza; Vandeleest, Jessica; McCowan, Brenda; Capitanio, John

2017-01-01

Macaque species, specifically rhesus (Macaca mulatta), are the most common nonhuman primates (NHPs) used in biomedical research due to their suitability as a model of high priority diseases (e.g., HIV, obesity, cognitive aging), cost effective breeding and housing compared to most other NHPs, and close evolutionary relationship to humans. With this close evolutionary relationship, however, is a shared adaptation for a socially stimulating environment, without which both their welfare and suitability as a research model are compromised. While outdoor social group housing provides the best approximation of a social environment that matches the macaque behavioral biology in the wild, this is not always possible at all facilities, where animals may be housed indoors in small groups, in pairs, or alone. Further, animals may experience many housing changes in their lifetime depending on project needs, changes in social status, management needs, or health concerns. Here, we review the evidence for the physiological and health effects of social housing changes and the potential impacts on research outcomes for studies using macaques, particularly rhesus. We situate our review in the context of increasing regulatory pressure for research facilities to both house NHPs socially and mitigate trauma from social aggression. To meet these regulatory requirements and further refine the macaque model for research, significant advances must be made in our understanding and management of rhesus macaque social housing, particularly pair-housing since it is the most common social housing configuration for macaques while on research projects. Because most NHPs are adapted for sociality, a social context is likely important for improving repeatability, reproducibility, and external validity of primate biomedical research. Am. J. Primatol. 79:e22528, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir

PubMed Central

Avalos, Claudia R.; Abreu, Celina M.; Queen, Suzanne E.; Li, Ming; Price, Sarah; Shirk, Erin N.; Engle, Elizabeth L.; Forsyth, Ellen; Bullock, Brandon T.; Mac Gabhann, Feilim; Wietgrefe, Stephen W.; Haase, Ashley T.; Zink, M. Christine; Mankowski, Joseph L.; Clements, Janice E.

2017-01-01

ABSTRACT A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are reported in HIV-infected individuals on ART. Biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (CSF) of HIV-infected individuals demonstrate continued effects of HIV in brain and suggest that the central nervous system (CNS) may serve as a viral reservoir. Using a simian immunodeficiency virus (SIV)/macaque model for HIV encephalitis and AIDS, we evaluated whether infected cells persist in brain despite ART. Eight SIV-infected pig-tailed macaques were virally suppressed with ART, and plasma and CSF viremia levels were analyzed longitudinally. To assess whether virus persisted in brain macrophages (BrMΦ) in these macaques, we used a macrophage quantitative viral outgrowth assay (MΦ-QVOA), PCR, and in situ hybridization (ISH) to measure the frequency of infected cells and the levels of viral RNA and DNA in brain. Viral RNA in brain tissue of suppressed macaques was undetectable, although viral DNA was detected in all animals. The MΦ-QVOA demonstrated that the majority of suppressed animals contained latently infected BrMΦ. We also showed that virus produced in the MΦ-QVOAs was replication competent, suggesting that latently infected BrMΦ are capable of reestablishing productive infection upon treatment interruption. This report provides the first confirmation of the presence of replication-competent SIV in BrMΦ of ART-suppressed macaques and suggests that the highly debated issue of viral latency in macrophages, at least in brain, has been addressed in SIV-infected macaques treated with ART. PMID:28811349

Mixed-complexity artificial grammar learning in humans and macaque monkeys: evaluating learning strategies.

PubMed

Wilson, Benjamin; Smith, Kenny; Petkov, Christopher I

2015-03-01

Artificial grammars (AG) can be used to generate rule-based sequences of stimuli. Some of these can be used to investigate sequence-processing computations in non-human animals that might be related to, but not unique to, human language. Previous AG learning studies in non-human animals have used different AGs to separately test for specific sequence-processing abilities. However, given that natural language and certain animal communication systems (in particular, song) have multiple levels of complexity, mixed-complexity AGs are needed to simultaneously evaluate sensitivity to the different features of the AG. Here, we tested humans and Rhesus macaques using a mixed-complexity auditory AG, containing both adjacent (local) and non-adjacent (longer-distance) relationships. Following exposure to exemplary sequences generated by the AG, humans and macaques were individually tested with sequences that were either consistent with the AG or violated specific adjacent or non-adjacent relationships. We observed a considerable level of cross-species correspondence in the sensitivity of both humans and macaques to the adjacent AG relationships and to the statistical properties of the sequences. We found no significant sensitivity to the non-adjacent AG relationships in the macaques. A subset of humans was sensitive to this non-adjacent relationship, revealing interesting between- and within-species differences in AG learning strategies. The results suggest that humans and macaques are largely comparably sensitive to the adjacent AG relationships and their statistical properties. However, in the presence of multiple cues to grammaticality, the non-adjacent relationships are less salient to the macaques and many of the humans. © 2015 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Concentrations of dapivirine in the rhesus macaque and rabbit following once daily intravaginal administration of a gel formulation of [14C]dapivirine for 7 days.

PubMed

Nuttall, Jeremy P; Thake, Daryl C; Lewis, Mark G; Ferkany, John W; Romano, Joseph W; Mitchnick, Mark A

2008-03-01

Dapivirine is a nonnucleoside reverse transcriptase inhibitor being developed as a topical microbicide for the prevention of human immunodeficiency virus infection. The distribution of radioactivity and drug in plasma and in vaginal, cervical, and draining lymph node tissues was investigated after daily application of a vaginal gel formulation of [14C]dapivirine to rhesus macaques. This was preceded by a preliminary study with rabbits. Following the intravaginal administration of [14C]dapivirine ( approximately 0.1 mg/ml [15 microCi/ml]) to rabbits (0.5 ml/day) and macaques (1 ml/day) for 7 days, the dapivirine levels associated with vaginal and cervical tissue samples 1 h after the final dose were high (quantities of microg/g of tissue) and remained detectable at 24 h (mean, >or=2.5 ng/g in rabbits) and 48 h (mean, >80 ng/g in macaques). Radioactivity levels were low in the plasma and very low or unquantifiable in the draining lymph nodes of the macaques. Microautoradiography identified drug-related material (DRM) on the surfaces of the vaginal and cervical tissues of the rabbits and macaques. Although DRM was primarily associated with the outermost layer of shedding cells in rabbits, two animals showed some evidence of small quantities in the mucosal epithelium of the cervix. In macaques, DRM was seen within the keratinized layer of the vaginal epithelium and and was found to extend into the superficial cellular layers, and in at least one animal it appeared to be present in the deepest (germinal) layer of the epithelium and in submucosal tissues. The persistence of biologically significant concentrations of dapivirine in vaginal and cervical tissues for >24 h supports the development of dapivirine as a microbicide for once daily application.

Laboratory Rhesus Macaque Social Housing and Social Changes: Implications for Research

PubMed Central

Hannibal, Darcy L; Bliss-Moreau, Eliza; Vandeleest, Jessica; McCowan, Brenda; Capitanio, John

2017-01-01

Macaque species, specifically rhesus (Macaca mulatta), are the most common nonhuman primates (NHPs) used in biomedical research due to their suitability as a model of high priority diseases (e.g., HIV, obesity, cognitive aging), cost effective breeding and housing compared to most other NHPs, and close evolutionary relationship to humans. With this close evolutionary relationship, however, is a shared adaptation for a socially stimulating environment, without which both their welfare and suitability as a research model are compromised. While outdoor social group housing provides the best approximation of a social environment that matches the macaque behavioral biology in the wild, this is not always possible at all facilities, where animals may be housed indoors in small groups, in pairs, or alone. Further, animals may experience many housing changes in their lifetime depending on project needs, changes in social status, management needs, or health concerns. Here we review the evidence for the physiological and health effects of social housing changes and the potential impacts on research outcomes for studies using macaques, particularly rhesus. We situate our review in the context of increasing regulatory pressure for research facilities to both house NHPs socially and mitigate trauma from social aggression. To meet these regulatory requirements and further refine the macaque model for research, significant advances must be made in our understanding and management of rhesus macaque social housing, particularly pair-housing since it is the most common social housing configuration for macaques while on research projects. Because most NHPs are adapted for sociality, a social context is likely important for improving repeatability, reproducibility, and external validity of primate biomedical research. PMID:26848542

Distribution of Vesicular Glutamate Transporter 2 (VGluT2) in the Primary Visual Cortex of the Macaque and Human

PubMed Central

Garcia-Marin, Virginia; Ahmed, Tunazzina H.; Afzal, Yasmeen C.; Hawken, Michael J.

2014-01-01

The majority of thalamic terminals in V1 arise from lateral geniculate nucleus (LGN) afferents. Thalamic afferent terminals are preferentially labeled by an isoform of the vesicular glutamate transporter, VGluT2. The goal of our study was to determine the distribution of VGluT2-ir puncta in macaque and human visual cortex. First, we investigated the distribution of VGluT2-ir puncta in all layers of macaque monkey primary visual cortex (V1), and found a very close correspondence between the known distribution of LGN afferents from previous studies and the distribution of VGluT2-immunoreactive (-ir) puncta. There was also a close correspondence between cytochrome oxidase density and VGluT2-ir puncta distribution. After validating the correspondence in macaque, we made a comparative study in human V1. In many aspects, the distribution of VGluT2-ir puncta in human was qualitatively similar to that of the macaque: high densities in layer 4C, patches of VGluT2-ir puncta in the supragranular layer (2/3), lower but clear distribution in layers 1 and 6, and very few puncta in layers 5 and 4B. However, there were also important differences between macaques and humans. In layer 4A of human, there was a sparse distribution of VGluT2-ir puncta, whereas in macaque, there was a dense distribution with the characteristic honeycomb organization. The results suggest important changes in the pattern of cortical VGluT2 immunostaining that may be related to evolutionary differences in the cortical organization of LGN afferents between Old World monkeys and humans. PMID:22684983

Impact of menstruation on select hematology and clinical chemistry variables in cynomolgus macaques.

PubMed

Perigard, Christopher J; Parrula, M Cecilia M; Larkin, Matthew H; Gleason, Carol R

2016-06-01

In preclinical studies with cynomolgus macaques, it is common to have one or more females presenting with menses. Published literature indicates that the blood lost during menses causes decreases in red blood cell mass variables (RBC, HGB, and HCT), which would be a confounding factor in the interpretation of drug-related effects on clinical pathology data, but no scientific data have been published to support this claim. This investigation was conducted to determine if the amount of blood lost during menses in cynomolgus macaques has an effect on routine hematology and serum chemistry variables. Ten female cynomolgus macaques (Macaca fascicularis), 5 to 6.5 years old, were observed daily during approximately 3 months (97 days) for the presence of menses. Hematology and serum chemistry variables were evaluated twice weekly. The results indicated that menstruation affects the erythrogram including RBC, HGB, HCT, MCHC, MCV, reticulocyte count, RDW, the leukogram including neutrophil, lymphocyte, and monocyte counts, and chemistry variables, including GGT activity, and the concentrations of total proteins, albumin, globulins, and calcium. The magnitude of the effect of menstruation on susceptible variables is dependent on the duration of the menstrual phase. Macaques with menstrual phases lasting ≥ 7 days are more likely to develop changes in variables related to chronic blood loss. In preclinical toxicology studies with cynomolgus macaques, interpretation of changes in several commonly evaluated hematology and serum chemistry variables requires adequate clinical observation and documentation concerning presence and duration of menses. There is a concern that macaques with long menstrual cycles can develop iron deficiency anemia due to chronic menstrual blood loss. © 2016 American Society for Veterinary Clinical Pathology.

Evolutionary Distance of Amino Acid Sequence Orthologs across Macaque Subspecies: Identifying Candidate Genes for SIV Resistance in Chinese Rhesus Macaques

PubMed Central

Ross, Cody T.; Roodgar, Morteza; Smith, David Glenn

2015-01-01

We use the Reciprocal Smallest Distance (RSD) algorithm to identify amino acid sequence orthologs in the Chinese and Indian rhesus macaque draft sequences and estimate the evolutionary distance between such orthologs. We then use GOanna to map gene function annotations and human gene identifiers to the rhesus macaque amino acid sequences. We conclude methodologically by cross-tabulating a list of amino acid orthologs with large divergence scores with a list of genes known to be involved in SIV or HIV pathogenesis. We find that many of the amino acid sequences with large evolutionary divergence scores, as calculated by the RSD algorithm, have been shown to be related to HIV pathogenesis in previous laboratory studies. Four of the strongest candidate genes for SIVmac resistance in Chinese rhesus macaques identified in this study are CDK9, CXCL12, TRIM21, and TRIM32. Additionally, ANKRD30A, CTSZ, GORASP2, GTF2H1, IL13RA1, MUC16, NMDAR1, Notch1, NT5M, PDCD5, RAD50, and TM9SF2 were identified as possible candidates, among others. We failed to find many laboratory experiments contrasting the effects of Indian and Chinese orthologs at these sites on SIVmac pathogenesis, but future comparative studies might hold fertile ground for research into the biological mechanisms underlying innate resistance to SIVmac in Chinese rhesus macaques. PMID:25884674

Using Hematology Data from Malaria Vaccine Research Trials in Humans and Rhesus Macaques (Macaca mulatta) To Guide Volume Limits for Blood Withdrawal.

PubMed

Hegge, Sara R; Hickey, Bradley W; Mcgrath, Shannon M; Stewart, V Ann

2016-12-01

Guidelines on safe volume limits for blood collection from research participants in both humans and laboratory animals vary widely between institutions. The main adverse event that may be encountered in large blood volume withdrawal is iron-deficiency anemia. Monitoring various parameters in a standard blood panel may help to prevent this outcome. To this end, we analyzed the Hgb and MCV values from 43 humans and 46 macaques in malaria vaccine research trials. Although the percentage of blood volume removed was greater for macaques than humans, macaques demonstrated an overall increase of MCV over time, indicating the ability to respond appropriately to frequent volume withdrawals. In contrast, humans showed a consistent declining trend in MCV. These declines in human MCV and Hgb were significant from the beginning to end of the study despite withdrawals that were smaller than recommended volume limits. Limiting the volume withdrawn to no more than 12.5% seemed to be sufficient for macaques, and at 14% or more individual animals tended to fail to respond appropriately to large-volume blood loss, as demonstrated by a decrease in MCV. The overall positive erythropoietic response seen in macaques was likely due to the controlled, iron-fortified diet they received. The lack of erythropoietic response in the human subjects may warrant iron supplementation or reconsideration of current blood volume withdrawal guidelines.

The mucosal expression pattern of interferon-ε in rhesus macaques.

PubMed

Demers, Andrew; Kang, Guobin; Ma, Fungrui; Lu, Wuxun; Yuan, Zhe; Li, Yue; Lewis, Mark; Kraiselburd, Edmundo N; Montaner, Luis; Li, Qingsheng

2014-12-01

Type I IFNs play an important role in innate and adaptive immunity against viral infections. A novel type I IFN, namely IFN-ε, which can protect against vaginal transmission of HSV2 and Chlamydia muridarum bacterial infection, has been described in mice and humans. Nevertheless, the principle cell type and the expression pattern of IFN-ε in tissues remain uncertain. In addition, the expression of IFN-ε in Indian rhesus macaques (Macaca mulatta) has not been reported. Here, we analyzed IFN-ε expression in multiple mucosal sites of uninfected or SIV-infected Indian rhesus macaques using IHCS. We report for the first time the detection of IFN-ε expression in situ in the lung, foreskin, vaginal, cervical, and small and large intestinal mucosae of rhesus macaques. We found that the expression of IFN-ε was exclusive to the epithelial cells in all of the aforementioned mucosal tissues. Furthermore, the macaque IFN-ε sequence in this study revealed that macaque IFN-ε is highly conserved among human and other nonhuman primates. Lastly, SIV rectal infection did not significantly alter the expression of IFN-ε in rectal mucosae. Together, these findings indicate that IFN-ε may function as the first line of defense against the invasion of mucosal pathogens. Further studies should be conducted to examine IFN-ε protection against gastrointestinal as well as respiratory infections. © 2014 Society for Leukocyte Biology.

The mucosal expression pattern of interferon-ε in rhesus macaques

PubMed Central

Demers, Andrew; Kang, Guobin; Ma, Fungrui; Lu, Wuxun; Yuan, Zhe; Li, Yue; Lewis, Mark; Kraiselburd, Edmundo N.; Montaner, Luis; Li, Qingsheng

2014-01-01

Type I IFNs play an important role in innate and adaptive immunity against viral infections. A novel type I IFN, namely IFN-ε, which can protect against vaginal transmission of HSV2 and Chlamydia muridarum bacterial infection, has been described in mice and humans. Nevertheless, the principle cell type and the expression pattern of IFN-ε in tissues remain uncertain. In addition, the expression of IFN-ε in Indian rhesus macaques (Macaca mulatta) has not been reported. Here, we analyzed IFN-ε expression in multiple mucosal sites of uninfected or SIV-infected Indian rhesus macaques using IHCS. We report for the first time the detection of IFN-ε expression in situ in the lung, foreskin, vaginal, cervical, and small and large intestinal mucosae of rhesus macaques. We found that the expression of IFN-ε was exclusive to the epithelial cells in all of the aforementioned mucosal tissues. Furthermore, the macaque IFN-ε sequence in this study revealed that macaque IFN-ε is highly conserved among human and other nonhuman primates. Lastly, SIV rectal infection did not significantly alter the expression of IFN-ε in rectal mucosae. Together, these findings indicate that IFN-ε may function as the first line of defense against the invasion of mucosal pathogens. Further studies should be conducted to examine IFN-ε protection against gastrointestinal as well as respiratory infections. PMID:25139290

Rotational Displacement Skills in Rhesus Macaques (Macaca mulatta)

PubMed Central

Hughes, Kelly D.; Santos, Laurie R.

2016-01-01

Rotational displacement tasks, in which participants must track an object at a hiding location within an array while the array rotates, exhibit a puzzling developmental pattern in humans. Human children take an unusually long time to master this task and tend to solve rotational problems through the use of nongeometric features or landmarks as opposed to other kinds of spatial cues. We investigated whether these developmental characteristics are unique to humans by testing rotational displacement skills in a monkey species, the rhesus macaque (Macaca mulatta), using a looking-time method. Monkeys first saw food hidden in two differently colored boxes within an array. The array was then rotated 180° and the boxes reopened to reveal the food in an expected or unexpected location. Our first two experiments explored the developmental time-course of performance on this rotational displacement task. We found that adult macaques looked longer at the unexpected event, but such performance was not mirrored in younger-aged macaques. In a third study, we systematically varied featural information and visible access to the array to investigate which strategies adult macaques used in solving rotational displacements. Our results show that adult macaques need both sets of information to solve the task. Taken together, these results suggest both similarities and differences in mechanisms by which human and nonhuman primates develop this spatial skill. PMID:22866770

Identification of Entamoeba polecki with Unique 18S rRNA Gene Sequences from Celebes Crested Macaques and Pigs in Tangkoko Nature Reserve, North Sulawesi, Indonesia.

PubMed

Tuda, Josef; Feng, Meng; Imada, Mihoko; Kobayashi, Seiki; Cheng, Xunjia; Tachibana, Hiroshi

2016-09-01

Unique species of macaques are distributed across Sulawesi Island, Indonesia, and the details of Entamoeba infections in these macaques are unknown. A total of 77 stool samples from Celebes crested macaques (Macaca nigra) and 14 stool samples from pigs were collected in Tangkoko Nature Reserve, North Sulawesi, and the prevalence of Entamoeba infection was examined by PCR. Entamoeba polecki was detected in 97% of the macaques and all of the pigs, but no other Entamoeba species were found. The nucleotide sequence of the 18S rRNA gene in E. polecki from M. nigra was unique and showed highest similarity with E. polecki subtype (ST) 4. This is the first case of identification of E. polecki ST4 from wild nonhuman primates. The sequence of the 18S rRNA gene in E. polecki from pigs was also unique and showed highest similarity with E. polecki ST1. These results suggest that the diversity of the 18S rRNA gene in E. polecki is associated with differences in host species and geographic localization, and that there has been no transmission of E. polecki between macaques and pigs in the study area. © 2016 The Author(s) Journal of Eukaryotic Microbiology © 2016 International Society of Protistologists.

Longitudinal Changes in Insulin Resistance, Beta-Cell Function and Glucose Regulation Status in Prediabetes.

PubMed

Kim, Chul-Hee; Kim, Hong-Kyu; Kim, Eun-Hee; Bae, Sung-Jin; Choe, Jaewon; Park, Joong-Yeol

2018-01-01

The changes in insulin resistance and insulin secretion and their association with changes in glucose regulation status in Asians with prediabetes remain uncertain. We included Korean adults (aged 20-79 years) with prediabetes who underwent routine medical check-ups at a mean interval of 5 years. Prediabetes was defined as fasting plasma glucose (FPG) 5.6-6.9mmol/l or HbA1c 5.7-6.4% (39-46mmol/mol). Insulin resistance (HOMA-IR) and beta-cell function (HOMA-%B) indices were assessed by homeostasis model assessment. Incident diabetes was defined as FPG ≥ 7.0mmol/l, HbA1c ≥ 6.5% (48mmol/mol), or initiation of antidiabetic medications. Among the 7,208 participants with prediabetes, 4,410 (61.2%) remained as prediabetes (control group), 2,123 (29.5%) reverted to normal glucose regulation (regressors), and 675 (9.4%) progressed to type 2 diabetes (progressors) after 5 years. Compared with the control group, the progressors had higher baseline HOMA-IR (2.48 ± 1.45 versus 2.06 ± 1.20, P < 0.001), but similar baseline HOMA-%B (74.6 ± 47.6 versus 73.1 ± 41.4, P=0.68). By contrast, the regressors had lower baseline HOMA-IR (1.98 ± 1.14 versus 2.06 ± 1.20, P = 0.035) but higher baseline HOMA-%B (77.4 ± 43.1 versus 73.1 ± 41.4, P = 0.001). After 5 years, the progressors showed a 31% increase in HOMA-IR (2.48 ± 1.45 versus 3.24 ± 2.10, P < 0.001) and 15% decrease in HOMA-%B (74.6 ± 47.6 versus 63.8 ± 40.4, P < 0.001), whereas the regressors showed 29% decrease in HOMA-IR (1.98 ± 1.14 versus 1.41 ± 0.78, P < 0.001) and 4% increase in HOMA-%B (77.4 ± 43.1 versus 80.2 ± 47.9, P = 0.010). Although increase in insulin resistance and decrease in beta-cell function both contributed to the progression to type 2 diabetes from prediabetes, longitudinal change in insulin resistance was the predominant factor in Koreans. Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Tracking early decline in cognitive function in older individuals at risk for Alzheimer disease dementia: the Alzheimer's Disease Cooperative Study Cognitive Function Instrument.

PubMed

Amariglio, Rebecca E; Donohue, Michael C; Marshall, Gad A; Rentz, Dorene M; Salmon, David P; Ferris, Steven H; Karantzoulis, Stella; Aisen, Paul S; Sperling, Reisa A

2015-04-01

Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. Longitudinal study from February 2002 through February 2007 at participating Alzheimer's Disease Cooperative Study sites. Individuals were followed up annually for 48 months after the baseline visit. The study included 468 healthy older individuals (Clinical Dementia Rating scale [CDR] global scores of 0, above cutoff on the modified Mini-Mental State Examination and Free and Cued Selective Reminding Test) (mean [SD] age, 79.4 [3.6] years; age range, 75.0-93.8 years). All study participants and their study partners completed the self and partner CFIs annually. Individuals also underwent concurrent annual neuropsychological assessment and APOE genotyping. The CFI scores between clinical progressors (CDR score, ≥0.5) and nonprogressors (CDR score, 0) and between APOE ε4 carriers and noncarriers were compared. Correlations of change between the CFI scores and neuropsychological performance were assessed longitudinally. At 48 months, group differences between clinical progressors and non-progressors were significant for self (2.13, SE=0.45, P<.001), partner (5.08, SE=0.59, P<.001), and self plus partner (7.04, SE=0.83, P<.001) CFI total scores. At month 48, APOE ε4 carriers had greater progression than noncarriers on the partner (1.10, SE=0.44, P<.012) and self plus partner (1.56, SE=0.63, P<.014) CFI scores. Both self and partner CFI change were associated with longitudinal cognitive decline (self, ρ=0.32, 95% CI, 0.13 to 0.46; partner, ρ=0.56, 95% CI, 0.42 to 0.68), although findings suggest self-report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment. Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, but informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease.

Infection of Mice, Ferrets, and Rhesus Macaques with a Clinical Mumps Virus Isolate

PubMed Central

Xu, Pei; Huang, Zhixiang; Gao, Xiudan; Michel, Frank J.; Hirsch, Gwen; Hogan, Robert J.; Sakamoto, Kaori; Ho, Wenzhe; Wu, Jianguo

2013-01-01

In recent years, many mumps outbreaks have occurred in vaccinated populations worldwide. The reasons for these outbreaks are not clear. Animal models are needed to investigate the causes of outbreaks and to understand the pathogenesis of mumps virus (MuV). In this study, we have examined the infection of three animal models with an isolate of mumps virus from a recent outbreak (MuV-IA). We have found that while both ferrets and mice generated humoral and cellular immune responses to MuV-IA infection, no obvious signs of illness were observed in these animals; rhesus macaques were the most susceptible to MuV-IA infection. Infection of rhesus macaques via both intranasal and intratracheal routes with MuV-IA led to the typical clinical signs of mumps 2 weeks to 4 weeks postinfection. However, none of the infected macaques showed any fever or neurologic signs during the experimental period. Mumps viral antigen was detected in parotid glands by immunohistochemistry (IHC). Rhesus macaques represent the best animal model for the study of mumps virus pathogenesis. PMID:23678169

Pathogenic infection of Rhesus macaques by an evolving SIV-HIV derived from CCR5-using envelope genes of acute HIV-1 infections

PubMed Central

Asmal, Mohammed; Lane, Sophie; Tian, Meijuan; Nickle, Gabrielle; Venner, Colin; Dirk, Brennan; Dikeakos, Jimmy; Luedemann, Corinne; Mach, Linh; Balachandran, Harikrishnan; Buzby, Adam; Rao, Srinivas; Letvin, Norman; Gao, Yong; Arts, Eric J.

2016-01-01

For studies on vaccines and therapies for HIV disease, SIV-HIV chimeric viruses harboring the HIV-1 env gene (SHIVenv) remain the best virus in non-human primate models. However, there are still very few SHIVenv viruses that can cause AIDS in non-CD8-depleted animals. In the present study, a recently created CCR5-using SHIVenv_B3 virus with env gene derived from acute/early HIV-1 infections (AHI) successfully established pathogenic infection in macaques. Through a series of investigations on the evolution, mutational profile, and phenotype of the virus and the resultant humoral immune response in infected rhesus macaques, we found that the E32K mutation in the Env C1 domain was associated with macaque pathogenesis, and that the electrostatic interactions in Env may favor E32K at the gp120 N terminus and “lock” the binding to heptad repeat 1 of gp41 in the trimer and produce a SHIVenv with increased fitness and pathogenesis during macaque infections. PMID:27723488

New-Onset Diabetes Mellitus After Transplantation in a Cynomolgus Macaque (Macaca fasicularis).

PubMed

Matthews, Kristin A; Tonsho, Makoto; Madsen, Joren C

2015-08-01

A 5.5-y-old intact male cynomolgus macaque (Macaca fasicularis) presented with inappetence and weight loss 57 d after heterotopic heart and thymus transplantation while receiving an immunosuppressant regimen consisting of tacrolimus, mycophenolate mofetil, and methylprednisolone to prevent graft rejection. A serum chemistry panel, a glycated hemoglobin test, and urinalysis performed at presentation revealed elevated blood glucose and glycated hemoglobin (HbA1c) levels (727 mg/dL and 10.1%, respectively), glucosuria, and ketonuria. Diabetes mellitus was diagnosed, and insulin therapy was initiated immediately. The macaque was weaned off the immunosuppressive therapy as his clinical condition improved and stabilized. Approximately 74 d after discontinuation of the immunosuppressants, the blood glucose normalized, and the insulin therapy was stopped. The animal's blood glucose and HbA1c values have remained within normal limits since this time. We suspect that our macaque experienced new-onset diabetes mellitus after transplantation, a condition that is commonly observed in human transplant patients but not well described in NHP. To our knowledge, this report represents the first documented case of new-onset diabetes mellitus after transplantation in a cynomolgus macaque.

Resource depletion through primate stone technology

PubMed Central

Tan, Amanda; Haslam, Michael; Kulik, Lars; Proffitt, Tomos; Malaivijitnond, Suchinda; Gumert, Michael

2017-01-01

Tool use has allowed humans to become one of the most successful species. However, tool-assisted foraging has also pushed many of our prey species to extinction or endangerment, a technology-driven process thought to be uniquely human. Here, we demonstrate that tool-assisted foraging on shellfish by long-tailed macaques (Macaca fascicularis) in Khao Sam Roi Yot National Park, Thailand, reduces prey size and prey abundance, with more pronounced effects where the macaque population size is larger. We compared availability, sizes and maturation stages of shellfish between two adjacent islands inhabited by different-sized macaque populations and demonstrate potential effects on the prey reproductive biology. We provide evidence that once technological macaques reach a large enough group size, they enter a feedback loop – driving shellfish prey size down with attendant changes in the tool sizes used by the monkeys. If this pattern continues, prey populations could be reduced to a point where tool-assisted foraging is no longer beneficial to the macaques, which in return may lessen or extinguish the remarkable foraging technology employed by these primates. PMID:28884681

Mapping visual cortex in monkeys and humans using surface-based atlases

NASA Technical Reports Server (NTRS)

Van Essen, D. C.; Lewis, J. W.; Drury, H. A.; Hadjikhani, N.; Tootell, R. B.; Bakircioglu, M.; Miller, M. I.

2001-01-01

We have used surface-based atlases of the cerebral cortex to analyze the functional organization of visual cortex in humans and macaque monkeys. The macaque atlas contains multiple partitioning schemes for visual cortex, including a probabilistic atlas of visual areas derived from a recent architectonic study, plus summary schemes that reflect a combination of physiological and anatomical evidence. The human atlas includes a probabilistic map of eight topographically organized visual areas recently mapped using functional MRI. To facilitate comparisons between species, we used surface-based warping to bring functional and geographic landmarks on the macaque map into register with corresponding landmarks on the human map. The results suggest that extrastriate visual cortex outside the known topographically organized areas is dramatically expanded in human compared to macaque cortex, particularly in the parietal lobe.

Plasma Metabolomics Biosignature According to HIV Stage of Infection, Pace of Disease Progression, Viremia Level and Immunological Response to Treatment.

PubMed

Scarpellini, Bruno; Zanoni, Michelle; Sucupira, Maria Cecilia Araripe; Truong, Hong-Ha M; Janini, Luiz Mario Ramos; Segurado, Ismael Dale Cotrin; Diaz, Ricardo Sobhie

2016-01-01

We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non-responders (INR), before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment. Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. β-oxidation and sphingosine-1-phosphate-phosphatase-1 activity were down-regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl-coenzyme A dehydrogenase deficiency [MADD]) was detected. Blood-based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease.

[Prevalence study of the genetic markers associated with slow progression of human inmunodefiency virus type 1 in the Galician population (Northwest of Spain)].

PubMed

Rodríguez-Da Silva, Alfredo; Miralles, Celia; Ocampo, Antonio; Valverde, Diana

2017-02-01

The deletion in the CCR5 gene (CCR5Δ32), the HLA-B*27:05, and polymorphisms rs2395029 and rs9264942 have been associated with slower progression of HIV-1. An analysis was performed on 408 patients on follow-up. The analysis of viral load, CD4+ Tlymphocytes and other clinical variables since the diagnosis of the infection were collected. The prevalence of the genetic markers rs9264942, CCR5wt/Δ32, rs2395029, HLA-B*27:05 was 17.9%, 11.5%, 7.6%, and 6.4%, respectively. Of all the patients, 354 were classified as progressors and 46 as long-term non-progressors (LTNPs). Except for the HLA-B*27:05 allele, other genetic markers were associated with slower progression: CCR5wt/Δ32 (P=.011) and SNPs rs2395029 and rs9264942 (P<.0001), as well as their association (P<.0001). The prevalence of the HLA-B*57:01 allele was higher than described nationally. No association could be found between the HLA-B*27:05 allele and the presence of slower disease progression. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Impact of accelerated progression to AIDS on public health monitoring of late HIV diagnosis.

PubMed

Sabharwal, Charulata J; Sepkowitz, Kent; Mehta, Reshma; Shepard, Colin; Bodach, Sara; Torian, Lucia; Begier, Elizabeth M

2011-03-01

Some patients develop AIDS within a year of HIV infection ("accelerated progression"). Classifying such cases as late HIV diagnosis may lead to inaccurate evaluation of HIV testing efforts. We sought to determine this group's contribution to overall late diagnosis rates. To identify cases of accelerated progression (development of AIDS within 12 months of a negative HIV test), we reviewed published HIV seroconverter cohort studies and used New York City's (NYC) HIV/AIDS surveillance registry. From the literature review, three seroconverter cohort studies revealed that 1.0-3.6% of participants had accelerated progression to AIDS. Applying this frequency estimate to the number of new infections in NYC (4762) for 2006 calculated by the Centers for Diseases Control and Prevention's incidence formula, we estimated that 3.6-13.0% of 1317 NYC HIV cases who are diagnosed with AIDS within 12 months of HIV diagnosis are accelerated progressors, not persons HIV infected for many years who did not test and present with AIDS (i.e., delayed diagnosis). In addition, our analysis of the 2006 NYC surveillance registry confirmed the occurrence of accelerated progression in a population-based setting; 67 accelerated progressors were reported and 9 (13%) could be confirmed through follow-up medical record review. With increased HIV testing initiatives, the irreducible proportion of AIDS cases with accelerated progression must be considered when interpreting late diagnosis data.

Expression of decoy receptor 3 in kidneys is associated with allograft survival after kidney transplant rejection.

PubMed

Weng, Shuo-Chun; Shu, Kuo-Hsiung; Wu, Ming-Ju; Wen, Mei-Chin; Hsieh, Shie-Liang; Chen, Nien-Jung; Tarng, Der-Cherng

2015-09-03

Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation.

Development of a liposome microbicide formulation for vaginal delivery of octylglycerol for HIV prevention

PubMed Central

Wang, Lin; Sassi, Alexandra Beumer; Patton, Dorothy; Isaacs, Charles; Moncla, B. J.; Gupta, Phalguni; Rohan, Lisa Cencia

2015-01-01

The feasibility of using a liposome drug delivery system to formulate octylglycerol (OG) as a vaginal microbicide product was explored. A liposome formulation was developed containing 1% OG and phosphatidyl choline in a ratio that demonstrated in vitro activity against Neisseria gonorrhoeae, HSV-1, HSV-2 and HIV-1 while sparing the innate vaginal flora, Lactobacillus. Two conventional gel formulations were prepared for comparison. The OG liposome formulation with the appropriate OG/lipid ratio and dosing level had greater efficacy than either conventional gel formulation and maintained this efficacy for at least 2 months. No toxicity was observed for the liposome formulation in ex vivo testing in a human ectocervical tissue model or in vivo testing in the macaque safety model. Furthermore, minimal toxicity was observed to lactobacilli in vitro or in vivo safety testing. The OG liposome formulation offers a promising microbicide product with efficacy against HSV, HIV and N. gonorrhoeae. PMID:22149387

Directed shift of vaginal microbiota induced by vaginal application of sucrose gel in rhesus macaques.

PubMed

Hu, Kai-tao; Zheng, Jin-xin; Yu, Zhi-jian; Chen, Zhong; Cheng, Hang; Pan, Wei-guang; Yang, Wei-zhi; Wang, Hong-yan; Deng, Qi-wen; Zeng, Zhong-ming

2015-04-01

Sucrose gel was used to treat bacterial vaginosis in a phase III clinical trial. However, the changes of vaginal flora after treatment were only examined by Nugent score in that clinical trial, While the vaginal microbiota of rhesus macaques is characterized by anaerobic, Gram-negative bacteria, few lactobacilli, and pH levels above 4.6, similar to the microbiota of patients with bacterial vaginosis. This study is aimed to investigate the change of the vaginal microbiota of rehsus macaques after topical use of sucrose gel to reveal more precisely the bacterial population shift after the topical application of sucrose gel. Sixteen rhesus macaques were treated with 0.5 g sucrose gel vaginally and three with 0.5 g of placebo gel. Vaginal swabs were collected daily following treatment. Vaginal pH levels and Nugent scores were recorded. The composition of the vaginal micotbiota was tested by V3∼V4 16S rDNA metagenomic sequencing. Dynamic changes in the Lactobacillus genus were analyzed by qPCR. The vaginal microbiota of rhesus macaques are dominated by anaerobic Gram-negative bacteria, with few lactobacilli and high pH levels above 4.6. After five days' treatment with topical sucrose gel, the component percentage of Lactobacillus in vaginal microbiota increased from 1.31% to 81.59%, while the component percentage of Porphyromonas decreased from 18.60% to 0.43%, Sneathia decreased from 15.09% to 0.89%, Mobiluncus decreased from 8.23% to 0.12%, etc.. The average vaginal pH values of 16 rhesus macaques of the sucrose gel group decreased from 5.4 to 3.89. There were no significant changes in microbiota and vaginal pH observed in the placebo group. Rhesus macaques can be used as animal models of bacterial vaginosis to develop drugs and test treatment efficacy. Furthermore, the topical application of sucrose gel induced the shifting of vaginal flora of rhesus macaques from a BV kind of flora to a lactobacilli-dominating flora. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Dengue, Japanese encephalitis and Chikungunya virus antibody prevalence among captive monkey (Macaca nemestrina) colonies of Northern Thailand.

PubMed

Nakgoi, Khajornpong; Nitatpattana, Narong; Wajjwalku, Worawidh; Pongsopawijit, Pornsawan; Kaewchot, Supakarn; Yoksan, Sutee; Siripolwat, Voravit; Souris, Marc; Gonzalez, Jean-Paul

2014-01-01

The potential of macaque Macaca nemestrina leonina in Thailand to be infected by endemic arboviruses was assessed. The prevalence of antibodies of three arboviruses actively circulating in Thailand was determined by Plaque Reduction Neutralization assay procedures using samples from captive colonies in Northern Thailand. Out of 38 macaques, 9 (24%) presented reacting antibodies against dengue virus, 5 (13%) against Japanese encephalitis virus, and 4 (10%) against Chikungunya virus. Our results indicate that the northern pig-tailed macaque in Thailand can be infected by these arboviruses, inferring therefore that their virus specific vectors have bitten them. Given that, northern pig-tailed macaque represents an abundant population, living in close range to human or in peridomestic setting, they could play a role as potential reservoir host for arboviruses circulating in Thailand. © 2013 Wiley Periodicals, Inc.

Survey of prevalence of overweight body condition in laboratory-housed cynomolgus macaques (Macaca fascicularis).

PubMed

Bauer, Sharon A; Leslie, Ken E; Pearl, David L; Fournier, Jocelyn; Turner, Patricia V

2010-07-01

Excessive weight gain has been reported to occur in captive cynomolgus macaques with little to no change in diet. Overweight body condition can result in development of hyperglycemia and type 2 diabetes and should be avoided. The purpose of this survey was to assess the prevalence of overweight cynomolgus macaques in North American research facilities, including breeding colonies and short-term and long-term facilities, and to describe current methods used to assess body condition. The survey consisted of 51 questions covering animal population demographics, body weight and body condition scoring, feeding, and behavior. Voluntary participants included veterinarians and animal care managers. Respondents from 13 facilities completed the survey, and information was collected on 17,500 cynomolgus macaques. The majority of surveyed facilities housed juvenile and young adult macaques. The reported prevalence of overweight (greater than 10% of ideal body weight) animals ranged between 0% and 20% and reportedly was more frequent in animals younger than 10 y. Most facilities had weight reduction strategies in place. Despite these programs, a significant proportion of animals were reported as being overweight. The results of this survey demonstrate that most North American facilities housing cynomolgus macaques recognize the importance of tracking body condition regularly. However, implementing effective weight reduction programs may be difficult in captive housing environments. Because of the potential for adverse health effects, facilities should have a means of regularly tracking body weight as well as an action plan for managing overweight animals.

Sequencing the transcriptome of milk production: milk trumps mammary tissue.

PubMed

Lemay, Danielle G; Hovey, Russell C; Hartono, Stella R; Hinde, Katie; Smilowitz, Jennifer T; Ventimiglia, Frank; Schmidt, Kimberli A; Lee, Joyce W S; Islas-Trejo, Alma; Silva, Pedro Ivo; Korf, Ian; Medrano, Juan F; Barry, Peter A; German, J Bruce

2013-12-12

Studies of normal human mammary gland development and function have mostly relied on cell culture, limited surgical specimens, and rodent models. Although RNA extracted from human milk has been used to assay the mammary transcriptome non-invasively, this assay has not been adequately validated in primates. Thus, the objectives of the current study were to assess the suitability of lactating rhesus macaques as a model for lactating humans and to determine whether RNA extracted from milk fractions is representative of RNA extracted from mammary tissue for the purpose of studying the transcriptome of milk-producing cells. We confirmed that macaque milk contains cytoplasmic crescents and that ample high-quality RNA can be obtained for sequencing. Using RNA sequencing, RNA extracted from macaque milk fat and milk cell fractions more accurately represented RNA from mammary epithelial cells (cells that produce milk) than did RNA from whole mammary tissue. Mammary epithelium-specific transcripts were more abundant in macaque milk fat, whereas adipose or stroma-specific transcripts were more abundant in mammary tissue. Functional analyses confirmed the validity of milk as a source of RNA from milk-producing mammary epithelial cells. RNA extracted from the milk fat during lactation accurately portrayed the RNA profile of milk-producing mammary epithelial cells in a non-human primate. However, this sample type clearly requires protocols that minimize RNA degradation. Overall, we validated the use of RNA extracted from human and macaque milk and provided evidence to support the use of lactating macaques as a model for human lactation.

Δ9-Tetrahydrocannabinol (Δ9-THC) Promotes Neuroimmune-Modulatory MicroRNA Profile in Striatum of Simian Immunodeficiency Virus (SIV)-Infected Macaques.

PubMed

Simon, Liz; Song, Keijing; Vande Stouwe, Curtis; Hollenbach, Andrew; Amedee, Angela; Mohan, Mahesh; Winsauer, Peter; Molina, Patricia

2016-03-01

Cannabinoid administration before and after simian immunodeficiency virus (SIV)-inoculation ameliorated disease progression and decreased inflammation in male rhesus macaques. Δ9-tetrahydrocannabinol (Δ9-THC) did not increase viral load in brain tissue or produce additive neuropsychological impairment in SIV-infected macaques. To determine if the neuroimmunomodulation of Δ9-THC involved differential microRNA (miR) expression, miR expression in the striatum of uninfected macaques receiving vehicle (VEH) or Δ9-THC (THC) and SIV-infected macaques administered either vehicle (VEH/SIV) or Δ9-THC (THC/SIV) was profiled using next generation deep sequencing. Among the 24 miRs that were differentially expressed among the four groups, 16 miRs were modulated by THC in the presence of SIV. These 16 miRs were classified into four categories and the biological processes enriched by the target genes determined. Our results indicate that Δ9-THC modulates miRs that regulate mRNAs of proteins involved in 1) neurotrophin signaling, 2) MAPK signaling, and 3) cell cycle and immune response thus promoting an overall neuroprotective environment in the striatum of SIV-infected macaques. This is also reflected by increased Brain Derived Neurotrophic Factor (BDNF) and decreased proinflammatory cytokine expression compared to the VEH/SIV group. Whether Δ9-THC-mediated modulation of epigenetic mechanisms provides neuroprotection in other regions of the brain and during chronic SIV-infection remains to be determined.

Pharmacokinetics of Cefovecin in Cynomolgus Macaques (Macaca fascicularis), Olive Baboons (Papio anubis), and Rhesus Macaques (Macaca mulatto)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raabe, Brigitte M.; Lovaglio, Jamie A.; Grover, GScott

Cefovecin sodium is a long-acting, third-generation, cephalosporin antibiotic approved for the treatment of skin infections in dogs and cats. The pharmacokinetic properties of cefovecin were evaluated in cynomolgus macaques (Macaca fascicularis), olive baboons (Papio anubis), and rhesus macaques (Macaca mulatto) by using a single-dose (8 mg/kg SC) dosing regimen. Plasma cefovecin concentrations were determined by using ultra-performance liquid chromatography with tandem mass spectrometry, and a noncompartmental model was used to determine pharmacokinetic parameters. The half-life of cefovecin was 4.95 {+-} 1.47 h in cynomolgus macaques, 9.17 {+-} 1.84 h in olive baboons, and 8.40 {+-} 2.53 h in rhesus macaques.more » These values are considerably lower than the half-lives previously published for dogs (133 h) and cats (166 h). The extended half-life of cefovecin in dogs and cats is speculated to be due to active reabsorption of drug in the kidney tubules because plasma clearance is well below the normal glomerular filtration rate. In nonhuman primates, renal clearance rates approximated plasma clearance rates, suggesting that active renal reabsorption of cefovecin does not occur in these species. The pharmacokinetic properties of cefovecin in nonhuman primates are vastly different from the pharmacokinetic properties in dogs and cats, precluding its use as a long-acting antibiotic in nonhuman primates. This study highlights the importance of performing pharmacokinetic studies prior to extralabel drug usage.« less

Performing monkeys of Bangladesh: characterizing their source and genetic variation.

PubMed

Hasan, M Kamrul; Feeroz, M Mostafa; Jones-Engel, Lisa; Engel, Gregory A; Akhtar, Sharmin; Kanthaswamy, Sree; Smith, David Glenn

2016-04-01

The acquisition and training of monkeys to perform is a centuries-old tradition in South Asia, resulting in a large number of rhesus macaques kept in captivity for this purpose. The performing monkeys are reportedly collected from free-ranging populations, and may escape from their owners or may be released into other populations. In order to determine whether this tradition involving the acquisition and movement of animals has influenced the population structure of free-ranging rhesus macaques in Bangladesh, we first characterized the source of these monkeys. Biological samples from 65 performing macaques collected between January 2010 and August 2013 were analyzed for genetic variation using 716 base pairs of mitochondrial DNA. Performing monkey sequences were compared with those of free-ranging rhesus macaque populations in Bangladesh, India and Myanmar. Forty-five haplotypes with 116 (16 %) polymorphic nucleotide sites were detected among the performing monkeys. As for the free-ranging rhesus population, most of the substitutions (89 %) were transitions, and no indels (insertion/deletion) were observed. The estimate of the mean number of pair-wise differences for the performing monkey population was 10.1264 ± 4.686, compared to 14.076 ± 6.363 for the free-ranging population. Fifteen free-ranging rhesus macaque populations were identified as the source of performing monkeys in Bangladesh; several of these populations were from areas where active provisioning has resulted in a large number of macaques. The collection of performing monkeys from India was also evident.

Binding of Complement Factor H (FH) Decreases Protective Anti-FH Binding Protein Antibody Responses of Infant Rhesus Macaques Immunized With a Meningococcal Serogroup B Vaccine

PubMed Central

Granoff, Dan M.; Costa, Isabella; Konar, Monica; Giuntini, Serena; Van Rompay, Koen K. A.; Beernink, Peter T.

2015-01-01

Background. The meningococcal vaccine antigen, factor H (FH)–binding protein (FHbp), binds human complement FH. In human FH transgenic mice, binding decreased protective antibody responses. Methods. To investigate the effect of primate FH binding, we immunized rhesus macaques with a 4-component serogroup B vaccine (4CMenB). Serum FH in 6 animals bound strongly to FHbp (FHbp-FHhigh) and, in 6 animals, bound weakly to FHbp (FHbp-FHlow). Results. There were no significant differences between the respective serum bactericidal responses of the 2 groups against meningococcal strains susceptible to antibody to the NadA or PorA vaccine antigens. In contrast, anti-FHbp bactericidal titers were 2-fold lower in FHbp-FHhigh macaques against a strain with an exact FHbp match to the vaccine (P = .08) and were ≥4-fold lower against 4 mutants with other FHbp sequence variants (P ≤ .005, compared with FHbp-FHlow macaques). Unexpectedly, postimmunization sera from all 12 macaques enhanced FH binding to meningococci. In contrast, serum anti-FHbp antibodies elicited by 4CMenB in mice whose mouse FH did not bind to the vaccine antigen inhibited FH binding. Conclusions. Binding of FH to FHbp decreases protective anti-FHbp antibody responses of macaques to 4CMenB. Even low levels of FH binding skew the antibody repertoire to FHbp epitopes outside of the FH-binding site, which enhance FH binding. PMID:25676468

Performing monkeys of Bangladesh: characterizing their source and genetic variation

PubMed Central

Hasan, M Kamrul; Feeroz, M Mostafa; Jones-Engel, Lisa; Engel, Gregory A; Akhtar, Sharmin; Kanthaswamy, Sree; Smith, David Glenn

2016-01-01

The acquisition and training of monkeys to perform is a century's old tradition in South Asia, resulting in a large number of rhesus macaques kept in captivity for this purpose. The performing monkeys are reportedly collected from free-ranging populations and may escape from their owners or be released into other populations. In order to determine whether this tradition, that involves the acquisition and movement of animals, has influenced the population structure of free-ranging rhesus macaques in Bangladesh we first characterized the source of these monkeys. Biological samples from 65 performing macaques, collected between January 2010 and August 2013 were analyzed for genetic variation using 716 base pairs of mitochondrial DNA. Performing monkey sequences were compared with those of free-ranging rhesus macaque populations in Bangladesh, India and Myanmar. Forty-five haplotypes with 116 (16%) polymorphic nucleotide sites were detected among the performing monkeys. As for the free-ranging rhesus population, most of the substitutions (89%) were transitions and no indels (insertion/deletion) were observed. The estimate of the mean number of pair-wise difference for the performing monkey population was 10.1264 ± 4.686, compared to 14.076 ± 6.363 for the free-ranging population. Fifteen free-ranging rhesus macaque populations were identified as the source of performing monkeys in Bangladesh; several of these populations were from areas where active provisioning has resulted in a large number of macaques. Collection of performing monkeys from India was also evident. PMID:26758818

Areas V1 and V2 show microsaccade-related 3-4-Hz covariation in gamma power and frequency.

PubMed

Lowet, E; Roberts, M J; Bosman, C A; Fries, P; De Weerd, P

2016-05-01

Neuronal gamma-band synchronization (25-80 Hz) in visual cortex appears sustained and stable during prolonged visual stimulation when investigated with conventional averages across trials. However, recent studies in macaque visual cortex have used single-trial analyses to show that both power and frequency of gamma oscillations exhibit substantial moment-by-moment variation. This has raised the question of whether these apparently random variations might limit the functional role of gamma-band synchronization for neural processing. Here, we studied the moment-by-moment variation in gamma oscillation power and frequency, as well as inter-areal gamma synchronization, by simultaneously recording local field potentials in V1 and V2 of two macaque monkeys. We additionally analyzed electrocorticographic V1 data from a third monkey. Our analyses confirm that gamma-band synchronization is not stationary and sustained but undergoes moment-by-moment variations in power and frequency. However, those variations are neither random and nor a possible obstacle to neural communication. Instead, the gamma power and frequency variations are highly structured, shared between areas and shaped by a microsaccade-related 3-4-Hz theta rhythm. Our findings provide experimental support for the suggestion that cross-frequency coupling might structure and facilitate the information flow between brain regions. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Experience-based human perception of facial expressions in Barbary macaques (Macaca sylvanus).

PubMed

Maréchal, Laëtitia; Levy, Xandria; Meints, Kerstin; Majolo, Bonaventura

2017-01-01

Facial expressions convey key cues of human emotions, and may also be important for interspecies interactions. The universality hypothesis suggests that six basic emotions (anger, disgust, fear, happiness, sadness, and surprise) should be expressed by similar facial expressions in close phylogenetic species such as humans and nonhuman primates. However, some facial expressions have been shown to differ in meaning between humans and nonhuman primates like macaques. This ambiguity in signalling emotion can lead to an increased risk of aggression and injuries for both humans and animals. This raises serious concerns for activities such as wildlife tourism where humans closely interact with wild animals. Understanding what factors (i.e., experience and type of emotion) affect ability to recognise emotional state of nonhuman primates, based on their facial expressions, can enable us to test the validity of the universality hypothesis, as well as reduce the risk of aggression and potential injuries in wildlife tourism. The present study investigated whether different levels of experience of Barbary macaques, Macaca sylvanus , affect the ability to correctly assess different facial expressions related to aggressive, distressed, friendly or neutral states, using an online questionnaire. Participants' level of experience was defined as either: (1) naïve: never worked with nonhuman primates and never or rarely encountered live Barbary macaques; (2) exposed: shown pictures of the different Barbary macaques' facial expressions along with the description and the corresponding emotion prior to undertaking the questionnaire; (3) expert: worked with Barbary macaques for at least two months. Experience with Barbary macaques was associated with better performance in judging their emotional state. Simple exposure to pictures of macaques' facial expressions improved the ability of inexperienced participants to better discriminate neutral and distressed faces, and a trend was found for aggressive faces. However, these participants, even when previously exposed to pictures, had difficulties in recognising aggressive, distressed and friendly faces above chance level. These results do not support the universality hypothesis as exposed and naïve participants had difficulties in correctly identifying aggressive, distressed and friendly faces. Exposure to facial expressions improved their correct recognition. In addition, the findings suggest that providing simple exposure to 2D pictures (for example, information signs explaining animals' facial signalling in zoos or animal parks) is not a sufficient educational tool to reduce tourists' misinterpretations of macaque emotion. Additional measures, such as keeping a safe distance between tourists and wild animals, as well as reinforcing learning via videos or supervised visits led by expert guides, could reduce such issues and improve both animal welfare and tourist experience.

Aerosol exposure to Zaire ebolavirus in three nonhuman primate species: differences in disease course and clinical pathology.

PubMed

Reed, Douglas S; Lackemeyer, Matthew G; Garza, Nicole L; Sullivan, Lawrence J; Nichols, Donald K

2011-10-01

There is little known concerning the disease caused by Zaire ebolavirus (ZEBOV) when inhaled, the likely route of exposure in a biological attack. Cynomolgus macaques, rhesus macaques, and African green monkeys were exposed to aerosolized ZEBOV to determine which species might be the most relevant model of the human disease. A petechial rash was noted on cynomolgus and rhesus macaques after fever onset but not on African green monkeys. Fever duration was shortest in rhesus macaques (62.7 ± 16.3 h) and longest in cynomolgus macaques (82.7 ± 22.3h) and African green monkeys (88.4 ± 16.7h). Virus was first detectable in the blood 3 days after challenge; the level of viremia was comparable among all three species. Hematological changes were noted in all three species, including decreases in lymphocyte and platelet counts. Increased blood coagulation times were most pronounced in African green monkeys. Clinical signs and time to death in all three species were comparable to what has been reported previously for each species after parenteral inoculation with ZEBOV. These data will be useful in selection of an animal model for efficacy studies. Published by Elsevier Masson SAS.

Methemoglobin and sulfhemoglobin formation due to benzocaine and lidocaine in macaques

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martin, D.G.; Woodard, C.L.; Gold, M.B.

1993-05-13

Benzocaine (BNZ) and lidocaine (LC) are commonly used topical (spray) anesthetics approved for use in humans. BNZ has structural similarities to methemoglobin (MHb) forming drugs that are current candidates for cyanide prophylaxis, while LC has been reported to increase MHb in man. We therefore, compared MHb and sulfhemoglobin (SHb) production in three groups of Macaques (Macaca mulata, Chinese rhesus and Indian rhesus, and Macaca nemistrina, Pig-tailed Macaques) after exposure to BNZ and LC. Formation of SHb, unlike MHb, is not thought to be reversible and is considered to be toxic. MHb and SHb levels were measured periodically on a CO-Oximeter.more » All rhesus (n=8) were dosed intratrachealy/intranasaly with 56 mg and 280 mg BNZ and with 40 mg of LC in a randomized cross-over design. Pig-tailed macaques (n=6) were dosed with BNZ intranasaly 56 mg and with 40 mg of LC. Since no differences in the peak MHb or time to peak (mean +/- SD) were observed among the three macaque subspecies, the data were pooled. LC did not cause MHb or SHb formation above baseline in any monkey.« less

Indoleamine 2,3-dioxygenase is differentially expressed by different white blood cell populations of rhesus macaques (Macaca mulatta).

PubMed

Lei, N; Wang, Y; Zhang, W-J; Duan, J-Z; Yang, G-B

2013-08-01

Indoleamine 2,3-dioxygenase (IDO) is involved in immune processes such as transplant and fetal rejection, autoimmunity, cancer, and infection; however, its expression in rhesus macaques has not been fully addressed. Indoleamine 2,3-dioxygenase mRNA and protein in the white blood cells (WBCs) of Chinese rhesus macaques were examined by RT-PCR, western blotting, real-time RT-PCR, and flow cytometry. Both IDO protein and mRNA could be readily detected in WBCs or peripheral blood mononuclear cells (PBMCs) of normal rhesus macaques. IDO+ cell frequency was the highest among CD14(+) mononuclear cells, followed by CD56(+) cells and DCs. No difference in the frequency of IDO+ cells between CD4(+) and CD8(+) T cells; however, Th17 cells have higher frequency of IDO+ cells than Th1 cells, with Th2 cells the lowest. Toll-like receptor (TLR) stimulation significantly increased IDO protein level in CD14(+) , CD56(+) , CD1c(+) , CD11c(+) , and CD123(+) myeloid cells. Rhesus macaques express IDO differentially in their leukocyte subsets and are suitable for IDO-related pathophysiological studies. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Characteristics of Herpes Simplex Virus Type 1 Infection in Rhesus Macaques and the Associated Pathological Features.

PubMed

Fan, Shengtao; Cai, Hongzhi; Xu, Xingli; Feng, Min; Wang, Lichun; Liao, Yun; Zhang, Ying; He, Zhanlong; Yang, Fengmei; Yu, Wenhai; Wang, Jingjing; Zhou, Jumin; Li, Qihan

2017-01-30

As one of the major pathogens for human herpetic diseases, herpes simplex virus type 1 (HSV1) causes herpes labialis, genital herpes and herpetic encephalitis. Our aim here was to investigate the infectious process of HSV1 in rhesus macaques and the pathological features induced during this infection. Clinical symptoms that manifested in the rhesus macaque during HSV1 infection included vesicular lesions and their pathological features. Viral distribution in the nervous tissues and associated pathologic changes indicated the typical systematic pathological processes associated with viral distribution of HSV1.Interestingly, vesicular lesions recurred in oral skin or in mucosa associated with virus shedding in macaques within four to five months post-infection,and viral latency-associated transcript (LAT) mRNA was found in the trigeminal ganglia (TG)on day 365 post-infection. Neutralization testing and enzyme-linked immunospot (ELISpot) detection of specific T cell responses confirmed the specific immunity induced by HSV1 infection. Thus, rhesus macaques could serve as an infectious model for HSV1 due to their typical clinical symptoms and the pathological recurrence associated with viral latency in nervous tissues.

Ebola Virus Localization in the Macaque Reproductive Tract during Acute Ebola Virus Disease.

PubMed

Perry, Donna L; Huzella, Louis M; Bernbaum, John G; Holbrook, Michael R; Jahrling, Peter B; Hagen, Katie R; Schnell, Matthias J; Johnson, Reed F

2018-03-01

Sexual transmission of Ebola virus (EBOV) has been demonstrated more than a year after recovery from the acute phase of Ebola virus disease (EVD). The mechanisms underlying EBOV persistence and sexual transmission are not currently understood. Using the acute macaque model of EVD, we hypothesized EBOV would infect the reproductive tissues and sought to localize the infection in these tissues using immunohistochemistry and transmission electron microscopy. In four female and eight male macaques that succumbed to EVD between 6 and 9 days after EBOV challenge, we demonstrate widespread EBOV infection of the interstitial tissues and endothelium in the ovary, uterus, testis, seminal vesicle, epididymis, and prostate gland, with minimal associated tissue immune response or organ pathology. Given the widespread involvement of EBOV in the reproductive tracts of both male and female macaques, it is reasonable to surmise that our understanding of the mechanisms underlying sexual transmission of EVD and persistence of EBOV in immune-privileged sites would be facilitated by the development of a nonhuman primate model in which the macaques survived past the acute stage into convalescence. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Personality of Wild Male Crested Macaques (Macaca nigra)

PubMed Central

Neumann, Christof; Agil, Muhammad; Widdig, Anja; Engelhardt, Antje

2013-01-01

Animal personalities, i.e. consistent differences in behavior across time and/or context, have received increased attention of behavioral biologists over the last years. Recent research shows that personalities represent traits on which natural and sexual selection work and which can have substantial fitness consequences. The aim of this study is to establish the personality structure of crested macaque (Macaca nigra) males as foundation for future studies on its adaptive value. We collected behavioral data through focal animal sampling and additionally conducted two sets of playback experiments. Results of a factor analysis on the behavioral data revealed a four factor structure with components we labeled Anxiety, Sociability, Connectedness and Aggressiveness. Results from the experiments revealed an additional and independent Boldness factor but the absence of Neophilia. Overall, this structure resembles other macaque and animal species with the exception of Connectedness, which might be a consequence of the species' tolerant social style. Our results thus not only form the basis for future studies on the adaptive value of personality in crested macaques but also contribute an important data point for investigating the evolution of personality structure from a comparative perspective by refining, for example, which personality factors characterized the last common ancestor of hominids and macaques. PMID:23940517

Protection of macaques from vaginal SHIV challenge by an orally delivered CCR5 inhibitor.

PubMed

Veazey, Ronald S; Springer, Martin S; Marx, Preston A; Dufour, Jason; Klasse, Per Johan; Moore, John P

2005-12-01

Pre-exposure oral prophylaxis with antiviral drugs is a potential method for preventing transmission of human immunodeficiency virus type 1 (HIV-1). We show that oral delivery of CMPD167, a small molecule that binds to the CCR5 coreceptor, for 10-14 d can protect a substantial proportion of macaques from vaginal infection with a CCR5-using virus (SHIV-162P3). The macaques that became infected despite receiving CMPD167 had reduced plasma viremia levels during the earliest stages of infection.

Complete Genome Sequence of Pig-Tailed Macaque Rhadinovirus 2 and Its Evolutionary Relationship with Rhesus Macaque Rhadinovirus and Human Herpesvirus 8/Kaposi's Sarcoma-Associated Herpesvirus

PubMed Central

Bruce, A. Gregory; Thouless, Margaret E.; Haines, Anthony S.; Pallen, Mark J.; Grundhoff, Adam

2015-01-01

ABSTRACT Two rhadinovirus lineages have been identified in Old World primates. The rhadinovirus 1 (RV1) lineage consists of human herpesvirus 8, Kaposi's sarcoma-associated herpesvirus (KSHV), and closely related rhadinoviruses of chimpanzees, gorillas, macaques and other Old World primates. The RV2 rhadinovirus lineage is distinct and consists of closely related viruses from the same Old World primate species. Rhesus macaque rhadinovirus (RRV) is the RV2 prototype, and two RRV isolates, 26-95 and 17577, were sequenced. We determined that the pig-tailed macaque RV2 rhadinovirus, MneRV2, is highly associated with lymphomas in macaques with simian AIDS. To further study the role of rhadinoviruses in the development of lymphoma, we sequenced the complete genome of MneRV2 and identified 87 protein coding genes and 17 candidate microRNAs (miRNAs). A strong genome colinearity and sequence homology were observed between MneRV2 and RRV26-95, although the open reading frame (ORF) encoding the KSHV ORFK15 homolog was disrupted in RRV26-95. Comparison with MneRV2 revealed several genomic anomalies in RRV17577 that were not present in other rhadinovirus genomes, including an N-terminal duplication in ORF4 and a recombinative exchange of more distantly related homologs of the ORF22/ORF47 interacting glycoprotein genes. The comparison with MneRV2 has revealed novel genes and important conservation of protein coding domains and transcription initiation, termination, and splicing signals, which have added to our knowledge of RV2 rhadinovirus genetics. Further comparisons with KSHV and other RV1 rhadinoviruses will provide important avenues for dissecting the biology, evolution, and pathology of these closely related tumor-inducing viruses in humans and other Old World primates. IMPORTANCE This work provides the sequence characterization of MneRV2, the pig-tailed macaque homolog of rhesus rhadinovirus (RRV). MneRV2 and RRV belong to the rhadinovirus 2 (RV2) rhadinovirus lineage of Old World primates and are distinct but related to Kaposi's sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi's sarcoma. Pig-tailed macaques provide important models of human disease, and our previous studies have indicated that MneRV2 plays a causal role in AIDS-related lymphomas in macaques. Delineation of the MneRV2 sequence has allowed a detailed characterization of the genome structure, and evolutionary comparisons with RRV and KSHV have identified conserved promoters, splice junctions, and novel genes. This comparison provides insight into RV2 rhadinovirus biology and sets the groundwork for more intensive next-generation (Next-Gen) transcript and genetic analysis of this class of tumor-inducing herpesvirus. This study supports the use of MneRV2 in pig-tailed macaques as an important model for studying rhadinovirus biology, transmission and pathology. PMID:25609822

Expression of Kv3.1b potassium channel is widespread in macaque motor cortex pyramidal cells: A histological comparison between rat and macaque.

PubMed

Soares, David; Goldrick, Isabelle; Lemon, Roger N; Kraskov, Alexander; Greensmith, Linda; Kalmar, Bernadett

2017-06-15

There are substantial differences across species in the organization and function of the motor pathways. These differences extend to basic electrophysiological properties. Thus, in rat motor cortex, pyramidal cells have long duration action potentials, while in the macaque, some pyramidal neurons exhibit short duration "thin" spikes. These differences may be related to the expression of the fast potassium channel Kv3.1b, which in rat interneurons is associated with generation of thin spikes. Rat pyramidal cells typically lack these channels, while there are reports that they are present in macaque pyramids. Here we made a systematic, quantitative comparison of the Kv3.1b expression in sections from macaque and rat motor cortex, using two different antibodies (NeuroMab, Millipore). As our standard reference, we examined, in the same sections, Kv3.1b staining in parvalbumin-positive interneurons, which show strong Kv3.1b immunoreactivity. In macaque motor cortex, a large sample of pyramidal neurons were nearly all found to express Kv3.1b in their soma membranes. These labeled neurons were identified as pyramidal based either by expression of SMI32 (a pyramidal marker), or by their shape and size, and lack of expression of parvalbumin (a marker for some classes of interneuron). Large (Betz cells), medium, and small pyramidal neurons all expressed Kv3.1b. In rat motor cortex, SMI32-postive pyramidal neurons expressing Kv3.1b were very rare and weakly stained. Thus, there is a marked species difference in the immunoreactivity of Kv3.1b in pyramidal neurons, and this may be one of the factors explaining the pronounced electrophysiological differences between rat and macaque pyramidal neurons. © 2017 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

Robust vaginal colonization of macaques with a novel vaginally disintegrating tablet containing a live biotherapeutic product to prevent HIV infection in women.

PubMed

Lagenaur, Laurel A; Swedek, Iwona; Lee, Peter P; Parks, Thomas P

2015-01-01

MucoCept is a biotherapeutic for prevention of HIV-1 infection in women and contains a human, vaginal Lactobacillus jensenii that has been genetically enhanced to express the HIV-1 entry inhibitor, modified cyanovirin-N (mCV-N). The objective of this study was to develop a solid vaginal dosage form that supports sustained vaginal colonization of the MucoCept Lactobacillus at levels previously shown, with freshly prepared cultures, to protect macaques from SHIV infection and to test this formulation in a macaque vaginal colonization model. Vaginally disintegrating tablets were prepared by lyophilizing the formulated bacteria in tablet-shaped molds, then packaging in foil pouches with desiccant. Disintegration time, potency and stability of the tablets were assessed. For colonization, non-synchronized macaques were dosed vaginally with either one tablet or five tablets delivered over five days. Vaginal samples were obtained at three, 14, and 21 days post-dosing and cultured to determine Lactobacillus colonization levels. To confirm identity of the MucoCept Lactobacillus strain, genomic DNA was extracted from samples on days 14 and 21 and a strain-specific PCR was performed. Supernatants from bacteria were tested for the presence of the mCV-N protein by Western blot. The tablets were easy to handle, disintegrated within two minutes, potent (5.7x1011 CFU/g), and stable at 4°C and 25°C. Vaginal administration of the tablets to macaques resulted in colonization of the MucoCept Lactobacillus in 66% of macaques at 14 days post-dosing and 83% after 21 days. There was no significant difference in colonization levels for the one or five tablet dosing regimens (p=0.88 Day 14, p=0.99 Day 21). Strain-specific PCR confirmed the presence of the bacteria even in culture-negative macaques. Finally, the presence of mCV-N protein was confirmed by Western blot analysis using a specific anti-mCV-N antibody.

Robust Vaginal Colonization of Macaques with a Novel Vaginally Disintegrating Tablet Containing a Live Biotherapeutic Product to Prevent HIV Infection in Women

PubMed Central

Lagenaur, Laurel A.; Swedek, Iwona; Lee, Peter P.; Parks, Thomas P.

2015-01-01

MucoCept is a biotherapeutic for prevention of HIV-1 infection in women and contains a human, vaginal Lactobacillus jensenii that has been genetically enhanced to express the HIV-1 entry inhibitor, modified cyanovirin-N (mCV-N). The objective of this study was to develop a solid vaginal dosage form that supports sustained vaginal colonization of the MucoCept Lactobacillus at levels previously shown, with freshly prepared cultures, to protect macaques from SHIV infection and to test this formulation in a macaque vaginal colonization model. Vaginally disintegrating tablets were prepared by lyophilizing the formulated bacteria in tablet-shaped molds, then packaging in foil pouches with desiccant. Disintegration time, potency and stability of the tablets were assessed. For colonization, non-synchronized macaques were dosed vaginally with either one tablet or five tablets delivered over five days. Vaginal samples were obtained at three, 14, and 21 days post-dosing and cultured to determine Lactobacillus colonization levels. To confirm identity of the MucoCept Lactobacillus strain, genomic DNA was extracted from samples on days 14 and 21 and a strain-specific PCR was performed. Supernatants from bacteria were tested for the presence of the mCV-N protein by Western blot. The tablets were easy to handle, disintegrated within two minutes, potent (5.7x1011 CFU/g), and stable at 4°C and 25°C. Vaginal administration of the tablets to macaques resulted in colonization of the MucoCept Lactobacillus in 66% of macaques at 14 days post-dosing and 83% after 21 days. There was no significant difference in colonization levels for the one or five tablet dosing regimens (p=0.88 Day 14, p=0.99 Day 21). Strain-specific PCR confirmed the presence of the bacteria even in culture-negative macaques. Finally, the presence of mCV-N protein was confirmed by Western blot analysis using a specific anti-mCV-N antibody. PMID:25875100

Effect of complement Factor H on anti-FHbp serum bactericidal antibody responses of infant rhesus macaques boosted with a licensed meningococcal serogroup B vaccine.

PubMed

Giuntini, Serena; Beernink, Peter T; Granoff, Dan M

2015-12-16

FHbp is a major serogroup B meningococcal vaccine antigen. Binding of complement Factor H (FH) to FHbp is specific for human and some non-human primate FH. In previous studies, FH binding to FHbp vaccines impaired protective anti-FHbp antibody responses. In this study we investigated anti-FHbp antibody responses to a third dose of a licensed serogroup B vaccine (MenB-4C) in infant macaques vaccinated in a previous study with MenB-4C. Six macaques with high binding of FH to FHbp (FH(high)), and six with FH(low) baseline phenotypes, were immunized three months after dose 2. After dose 2, macaques with the FH(low) baseline phenotype had serum anti-FHbp antibodies that enhanced FH binding to FHbp (functionally converting them to a FH(high) phenotype). In this group, activation of the classical complement pathway (C4b deposition) by serum anti-FHbp antibody, and anti-FHbp serum bactericidal titers were lower after dose 3 than after dose 2 (p<0.02). In macaques with the FH(high) baseline phenotype, the respective anti-FHbp C4b deposition and bactericidal titers were similar after doses 2 and 3. Two macaques developed serum anti-FH autoantibodies after dose 2, which were not detected after dose 3. In conclusion, in macaques with the FH(low) baseline phenotype whose post-dose 2 serum anti-FHbp antibodies had converted them to FH(high), the anti-FHbp antibody repertoire to dose 3 was skewed to less protective epitopes than after dose 2. Mutant FHbp vaccines that eliminate FH binding may avoid eliciting anti-FHbp antibodies that enhance FH binding, and confer greater protection with less risk of inducing anti-FH autoantibodies than FHbp vaccines that bind FH. Copyright © 2015 Elsevier Ltd. All rights reserved.

Concentrations of Dapivirine in the Rhesus Macaque and Rabbit following Once Daily Intravaginal Administration of a Gel Formulation of [14C]Dapivirine for 7 Days▿

PubMed Central

Nuttall, Jeremy P.; Thake, Daryl C.; Lewis, Mark G.; Ferkany, John W.; Romano, Joseph W.; Mitchnick, Mark A.

2008-01-01

Dapivirine is a nonnucleoside reverse transcriptase inhibitor being developed as a topical microbicide for the prevention of human immunodeficiency virus infection. The distribution of radioactivity and drug in plasma and in vaginal, cervical, and draining lymph node tissues was investigated after daily application of a vaginal gel formulation of [14C]dapivirine to rhesus macaques. This was preceded by a preliminary study with rabbits. Following the intravaginal administration of [14C]dapivirine (∼0.1 mg/ml [15 μCi/ml]) to rabbits (0.5 ml/day) and macaques (1 ml/day) for 7 days, the dapivirine levels associated with vaginal and cervical tissue samples 1 h after the final dose were high (quantities of μg/g of tissue) and remained detectable at 24 h (mean, ≥2.5 ng/g in rabbits) and 48 h (mean, >80 ng/g in macaques). Radioactivity levels were low in the plasma and very low or unquantifiable in the draining lymph nodes of the macaques. Microautoradiography identified drug-related material (DRM) on the surfaces of the vaginal and cervical tissues of the rabbits and macaques. Although DRM was primarily associated with the outermost layer of shedding cells in rabbits, two animals showed some evidence of small quantities in the mucosal epithelium of the cervix. In macaques, DRM was seen within the keratinized layer of the vaginal epithelium and and was found to extend into the superficial cellular layers, and in at least one animal it appeared to be present in the deepest (germinal) layer of the epithelium and in submucosal tissues. The persistence of biologically significant concentrations of dapivirine in vaginal and cervical tissues for >24 h supports the development of dapivirine as a microbicide for once daily application. PMID:18086845

Real-time monitoring of cardiovascular function in rhesus macaques infected with Zaire ebolavirus.

PubMed

Kortepeter, Mark G; Lawler, James V; Honko, Anna; Bray, Mike; Johnson, Joshua C; Purcell, Bret K; Olinger, Gene G; Rivard, Robert; Hepburn, Matthew J; Hensley, Lisa E

2011-11-01

Nine rhesus macaques were implanted with multisensor telemetry devices and internal jugular vein catheters before being infected with Zaire ebolavirus. All animals developed viremia, fever, a hemorrhagic rash, and typical changes of Ebola hemorrhagic fever in clinical laboratory tests. Three macaques unexpectedly survived this usually lethal disease, making it possible to compare physiological parameters in lethally challenged animals and survivors. After the onset of fever, lethal illness was characterized by a decline in mean arterial blood pressure, an increase in pulse and respiratory rate, lactic acidosis, and renal failure. Survivors showed less pronounced change in these parameters. Four macaques were randomized to receive supplemental volumes of intravenous normal saline when they became hypotensive. Although those animals had less severe renal compromise, no apparent survival benefit was observed. This is the first report of continuous physiologic monitoring in filovirus-infected nonhuman primates and the first to attempt cardiovascular support with intravenous fluids.

Exceptional Evolutionary Divergence of Human Muscle and Brain Metabolomes Parallels Human Cognitive and Physical Uniqueness

PubMed Central

Bozek, Katarzyna; Wei, Yuning; Yan, Zheng; Liu, Xiling; Xiong, Jieyi; Sugimoto, Masahiro; Tomita, Masaru; Pääbo, Svante; Pieszek, Raik; Sherwood, Chet C.; Hof, Patrick R.; Ely, John J.; Steinhauser, Dirk; Willmitzer, Lothar; Bangsbo, Jens; Hansson, Ola; Call, Josep; Giavalisco, Patrick; Khaitovich, Philipp

2014-01-01

Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized by superior cognition, their muscular performance might be markedly inferior to that of chimpanzees and macaque monkeys. PMID:24866127

Allometry and Interspecific Differences in the Facial Cranium of Two Closely Related Macaque Species

PubMed Central

Ito, Tsuyoshi; Nishimura, Takeshi; Takai, Masanaru

2011-01-01

Interpreting evolutionary history of macaque monkeys from fossil evidence is difficult, because their evolutionary fluctuations in body size might have removed or formed important morphological features differently in each lineage. We employed geometric morphometrics to explore allometric trajectories of craniofacial shape in two closely related species, Macaca fascicularis and M. fuscata. These two species exhibit a single shared allometric trajectory in superoinferior deflection of the anterior face, indicating that the differences in this feature can be explained by size variation. In contrast, two parallel trajectories are demonstrated in craniofacial protrusion, indicating that even if they are comparable in size, M. fuscata has a higher and shorter face than M. fascicularis. The degree of facial protrusion is most likely a critical feature for phyletic evaluation in the fascicularis group. Such analyses in various macaques would help to resolve controversies regarding phyletic interpretations of fossil macaques. PMID:22567301

Food resources, distribution and seasonal variations in ranging in lion-tailed macaques, Macaca silenus in the Western Ghats, India.

PubMed

Erinjery, Joseph J; Kavana, T S; Singh, Mewa

2015-01-01

The distribution and availability of food was examined to see how it influenced ranging patterns and sleeping site selection in a group of lion-tailed macaques. The home range and core area were 130.48 ha (95% kernel) and 26.68 ha (50% kernel) respectively. The lion-tailed macaques had a longer day range, had a greater number of sleeping sites and used more core areas in the summer as compared to the monsoon and the post-monsoon seasons. The ranging patterns and sleeping site use were influenced by the major food resources used in a particular season. The ranging was mainly influenced by Artocarpus heterophyllus in monsoon, Cullenia exarillata and Toona ciliata in post- monsoon, and Artocarpus heterophyllus and Ficus amplissima in summer. The distribution of these four plant species is, therefore, critical to ranging, and thus to conservation of the lion-tailed macaque.

Virus-specific T cell responses in macaques acutely infected with SHIV(sf162p3).

PubMed

Pahar, Bapi; Wang, Xiaolei; Dufour, Jason; Lackner, Andrew A; Veazey, Ronald S

2007-06-20

CD4(+) T helper and CD8(+) cytotoxic T lymphocyte responses are believed to play an important role in the control of primary HIV and SIV infection. However, the role of these cells in macaques acutely infected with SHIV(sf162p3) has not been well characterized. In this study, ten adult rhesus macaques were intravaginally infected with SHIV(sf162p3), and antigen-specific cytokine responses to SHIV-Tat, Nef, Gag and Env peptide pools were examined through 70 days post inoculation (p.i.) using ELISPOT and/or cytokine flow cytometry (CFC). Peak plasma viral replication occurred between 14 and 21 days p.i. followed by low to undetectable plasma viremia by 70 days of infection in most macaques. Although some animals had strong virus-specific cellular immune responses, many had weak or minimal responses that did not correlate with the post peak decline in plasma viremia.

Virus-specific T cell responses in macaques acutely infected with SHIVsf162p3

PubMed Central

Pahar, Bapi; Wang, Xiaolei; Dufour, Jason; Lackner, Andrew A.; Veazey, Ronald S.

2007-01-01

CD4+ T helper and CD8+ cytotoxic T lymphocyte responses are believed to play an important role in the control of primary HIV and SIV infection. However, the role of these cells in macaques acutely infected with SHIVsf162p3 has not been well characterized. In this study, ten adult rhesus macaques were intravaginally infected with SHIVsf162p3, and antigen specific cytokine responses to SHIV-Tat, Nef, Gag and Env peptide pools were examined through 70 days post inoculation (p.i.) using ELISPOT and/or cytokine flow cytometry (CFC). Peak plasma viral replication occurred between 14 and 21 days p.i., followed by low to undetectable plasma viremia by 70 days of infection in most macaques. Although some animals had strong virus-specific cellular immune responses, many had weak or minimal responses that did not correlate with the post peak decline in plasma viremia. PMID:17307212

Chronic Administration of Δ9-Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

PubMed Central

Chandra, Lawrance C.; Kumar, Vinay; Torben, Workineh; Stouwe, Curtis Vande; Winsauer, Peter; Amedee, Angela; Molina, Patricia E.

2014-01-01

ABSTRACT Recreational and medical use of cannabis among human immunodeficiency virus (HIV)-infected individuals has increased in recent years. In simian immunodeficiency virus (SIV)-infected macaques, chronic administration of Δ9-tetrahydrocannabinol (Δ9-THC) inhibited viral replication and intestinal inflammation and slowed disease progression. Persistent gastrointestinal disease/inflammation has been proposed to facilitate microbial translocation and systemic immune activation and promote disease progression. Cannabinoids including Δ9-THC attenuated intestinal inflammation in mouse colitis models and SIV-infected rhesus macaques. To determine if the anti-inflammatory effects of Δ9-THC involved differential microRNA (miRNA) modulation, we profiled miRNA expression at 14, 30, and 60 days postinfection (days p.i.) in the intestine of uninfected macaques receiving Δ9-THC (n = 3) and SIV-infected macaques administered either vehicle (VEH/SIV; n = 4) or THC (THC/SIV; n = 4). Chronic Δ9-THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days p.i. At 60 days p.i., ∼28% of miRNAs showed decreased expression in the VEH/SIV group compared to none showing decrease in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149, and miR-187, previously been shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator, was confirmed as a direct miR-99b target. A significant increase in NOX4+ crypt epithelial cells was detected in VEH/SIV macaques compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage. These results support a role for differential miRNA induction in THC-mediated suppression of intestinal inflammation. Whether similar miRNA modulation occurs in other tissues requires further investigation. IMPORTANCE Gastrointestinal (GI) tract disease/inflammation is a hallmark of HIV/SIV infection. Previously, we showed that chronic treatment of SIV-infected macaques with Δ9-tetrahydrocannabinol (Δ9-THC) increased survival and decreased viral replication and infection-induced gastrointestinal inflammation. Here, we show that chronic THC administration to SIV-infected macaques induced an anti-inflammatory microRNA expression profile in the intestine at 60 days p.i. These included several miRNAs bioinformatically predicted to directly target CXCL12, a chemokine known to regulate lymphocyte and macrophage trafficking into the intestine. Specifically, miR-99b was significantly upregulated in THC-treated SIV-infected macaques and confirmed to directly target NADPH oxidase 4 (NOX4), a reactive oxygen species generator known to damage intestinal epithelial cells. Elevated miR-99b expression was associated with a significantly decreased number of NOX4+ epithelial cells in the intestines of THC-treated SIV-infected macaques. Overall, our results show that selective upregulation of anti-inflammatory miRNA expression contributes to THC-mediated suppression of gastrointestinal inflammation and maintenance of intestinal homeostasis. PMID:25378491

Sequencing the transcriptome of milk production: milk trumps mammary tissue

PubMed Central

2013-01-01

Background Studies of normal human mammary gland development and function have mostly relied on cell culture, limited surgical specimens, and rodent models. Although RNA extracted from human milk has been used to assay the mammary transcriptome non-invasively, this assay has not been adequately validated in primates. Thus, the objectives of the current study were to assess the suitability of lactating rhesus macaques as a model for lactating humans and to determine whether RNA extracted from milk fractions is representative of RNA extracted from mammary tissue for the purpose of studying the transcriptome of milk-producing cells. Results We confirmed that macaque milk contains cytoplasmic crescents and that ample high-quality RNA can be obtained for sequencing. Using RNA sequencing, RNA extracted from macaque milk fat and milk cell fractions more accurately represented RNA from mammary epithelial cells (cells that produce milk) than did RNA from whole mammary tissue. Mammary epithelium-specific transcripts were more abundant in macaque milk fat, whereas adipose or stroma-specific transcripts were more abundant in mammary tissue. Functional analyses confirmed the validity of milk as a source of RNA from milk-producing mammary epithelial cells. Conclusions RNA extracted from the milk fat during lactation accurately portrayed the RNA profile of milk-producing mammary epithelial cells in a non-human primate. However, this sample type clearly requires protocols that minimize RNA degradation. Overall, we validated the use of RNA extracted from human and macaque milk and provided evidence to support the use of lactating macaques as a model for human lactation. PMID:24330573

Quantitative and qualitative iNKT repertoire associations with disease susceptibility and outcome in macaque tuberculosis infection.

PubMed

Chancellor, Andrew; White, Andrew; Tocheva, Anna S; Fenn, Joe R; Dennis, Mike; Tezera, Liku; Singhania, Akul; Elliott, Tim; Tebruegge, Marc; Elkington, Paul; Gadola, Stephan; Sharpe, Sally; Mansour, Salah

2017-07-01

Correlates of immune protection that reliably predict vaccine efficacy against Mycobacterium tuberculosis (Mtb) infection are urgently needed. Invariant NKT cells (iNKTs) are CD1d-dependent innate T cells that augment host antimicrobial immunity through production of cytokines, including interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We determined peripheral blood iNKT numbers, their proliferative responses and iNKT subset proportions after in vitro antigen expansion by α-galactosylceramide (αGC) in a large cohort of mycobacteria-naïve non-human primates, and macaques from Bacillus Calmette-Guerin (BCG) vaccine and Mtb challenge studies. Animals studied included four genetically distinct groups of macaques within cynomolgus and rhesus species that differ in their susceptibility to Mtb infection. We demonstrate significant differences in ex vivo iNKT frequency between groups, which trends towards an association with susceptibility to Mtb, but no significant difference in overall iNKT proliferative responses. Susceptible animals exhibited a skewed CD4 + /CD8 + iNKT subset ratio in comparison to more Mtb-resistant groups. Correlation of iNKT subsets post BCG vaccination with clinical disease manifestations following Mtb challenge in the Chinese cynomolgus and Indian rhesus macaques identified a consistent trend linking increased CD8 + iNKTs with favourable disease outcome. Finally, a similar iNKT profile was conferred by BCG vaccination in rhesus macaques. Our study provides the first detailed characterisation of iNKT cells in macaque tuberculosis infection, suggesting that iNKT repertoire differences may impact on disease outcome, which warrants further investigation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficient generation of monoclonal antibodies from single rhesus macaque antibody secreting cells.

PubMed

Meng, Weixu; Li, Leike; Xiong, Wei; Fan, Xuejun; Deng, Hui; Bett, Andrew J; Chen, Zhifeng; Tang, Aimin; Cox, Kara S; Joyce, Joseph G; Freed, Daniel C; Thoryk, Elizabeth; Fu, Tong-Ming; Casimiro, Danilo R; Zhang, Ningyan; A Vora, Kalpit; An, Zhiqiang

2015-01-01

Nonhuman primates (NHPs) are used as a preclinical model for vaccine development, and the antibody profiles to experimental vaccines in NHPs can provide critical information for both vaccine design and translation to clinical efficacy. However, an efficient protocol for generating monoclonal antibodies from single antibody secreting cells of NHPs is currently lacking. In this study we established a robust protocol for cloning immunoglobulin (IG) variable domain genes from single rhesus macaque (Macaca mulatta) antibody secreting cells. A sorting strategy was developed using a panel of molecular markers (CD3, CD19, CD20, surface IgG, intracellular IgG, CD27, Ki67 and CD38) to identify the kinetics of B cell response after vaccination. Specific primers for the rhesus macaque IG genes were designed and validated using cDNA isolated from macaque peripheral blood mononuclear cells. Cloning efficiency was averaged at 90% for variable heavy (VH) and light (VL) domains, and 78.5% of the clones (n = 335) were matched VH and VL pairs. Sequence analysis revealed that diverse IGHV subgroups (for VH) and IGKV and IGLV subgroups (for VL) were represented in the cloned antibodies. The protocol was tested in a study using an experimental dengue vaccine candidate. About 26.6% of the monoclonal antibodies cloned from the vaccinated rhesus macaques react with the dengue vaccine antigens. These results validate the protocol for cloning monoclonal antibodies in response to vaccination from single macaque antibody secreting cells, which have general applicability for determining monoclonal antibody profiles in response to other immunogens or vaccine studies of interest in NHPs.

Does the Macaque Monkey Provide a Good Model for Studying Human Executive Control? A Comparative Behavioral Study of Task Switching

PubMed Central

Caselli, Luana; Chelazzi, Leonardo

2011-01-01

The ability to swiftly and smoothly switch from one task set to another is central to intelligent behavior, because it allows an organism to flexibly adapt to ever changing environmental conditions and internal needs. For this reason, researchers interested in executive control processes have often relied on task-switching paradigms as powerful tools to uncover the underlying cognitive and brain architecture. In order to gather fundamental information at the single-cell level, it would be greatly helpful to demonstrate that non-human primates, especially the macaque monkey, share with us similar behavioral manifestations of task-switching and therefore, in all likelihood, similar underlying brain mechanisms. Unfortunately, prior attempts have provided negative results (e.g., Stoet & Snyder, 2003b), in that it was reported that macaques do not show the typical signature of task-switching operations at the behavioral level, represented by switch costs. If confirmed, this would indicate that the macaque cannot be used as a model approach to explore human executive control mechanisms by means of task-switching paradigms. We have therefore decided to re-explore this issue, by conducting a comparative experiment on a group of human participants and two macaque monkeys, whereby we measured and compared performance costs linked to task switching and resistance to interference across the two species. Contrary to what previously reported, we found that both species display robust task switching costs, thus supporting the claim that macaque monkeys provide an exquisitely suitable model to study the brain mechanisms responsible for maintaining and switching task sets. PMID:21720549

Characterization of a Moraxella species that causes epistaxis in macaques

PubMed Central

Embers, Monica E.; Doyle, Lara A.; Whitehouse, Chris A.; Selby, Edward B.; Chappell, Mark; Philipp, Mario T.

2014-01-01

Bacteria of the genus Moraxella have been isolated from a variety of mammalian hosts. In a prior survey of bacteria that colonize the rhesus macaque nasopharynx, performed at the Tulane National Primate Research Center, organisms of the Moraxella genus were isolated from animals with epistaxis, or “bloody nose syndrome.” They were biochemically identified as Moraxella catarrhalis, and cryopreserved. Another isolate was obtained from an epistatic cynomolgus macaque at the U.S. Army Medical Research Institute of Infectious Diseases. Based on differences in colony and cell morphologies between rhesus and human M. catarrhalis isolates, we hypothesized that the nonhuman primate Moraxella might instead be a different species. Despite morphological differences, the rhesus isolates, by several biochemical tests, were indistinguishable from M. catarrhalis. Analysis of the cynomolgus isolate by Vitek 2 Compact indicated that it belonged to a Moraxella group, but could not differentiate among species. However, sequencing of the 16S ribosomal RNA gene from four representative rhesus isolates and the cynomolgus isolate showed closest homology to Moraxella lincolnii, a human respiratory tract inhabitant, with 90.16% identity. To examine rhesus macaques as potential hosts for M. catarrhalis, eight animals were inoculated with human M. catarrhalis isolates. Only one of the animals was colonized and showed disease, whereas four of four macaques became epistatic after inoculation with the rhesus Moraxella isolate. The nasopharyngeal isolates in this study appear uniquely adapted to a macaque host and, though they share many of the phenotypic characteristics of M. catarrhalis, appear to form a genotypically distinct species. PMID:20667430

A MIV-150/zinc acetate gel inhibits SHIV-RT infection in macaque vaginal explants.

PubMed

Barnable, Patrick; Calenda, Giulia; Ouattara, Louise; Gettie, Agegnehu; Blanchard, James; Jean-Pierre, Ninochka; Kizima, Larisa; Rodríguez, Aixa; Abraham, Ciby; Menon, Radhika; Seidor, Samantha; Cooney, Michael L; Roberts, Kevin D; Sperling, Rhoda; Piatak, Michael; Lifson, Jeffrey D; Fernandez-Romero, Jose A; Zydowsky, Thomas M; Robbiani, Melissa; Teleshova, Natalia

2014-01-01

To extend our observations that single or repeated application of a gel containing the NNRTI MIV-150 (M) and zinc acetate dihydrate (ZA) in carrageenan (CG) (MZC) inhibits vaginal transmission of simian/human immunodeficiency virus (SHIV)-RT in macaques, we evaluated safety and anti-SHIV-RT activity of MZC and related gel formulations ex vivo in macaque mucosal explants. In addition, safety was further evaluated in human ectocervical explants. The gels did not induce mucosal toxicity. A single ex vivo exposure to diluted MZC (1∶30, 1∶100) and MC (1∶30, the only dilution tested), but not to ZC gel, up to 4 days prior to viral challenge, significantly inhibited SHIV-RT infection in macaque vaginal mucosa. MZC's activity was not affected by seminal plasma. The antiviral activity of unformulated MIV-150 was not enhanced in the presence of ZA, suggesting that the antiviral activity of MZC was mediated predominantly by MIV-150. In vivo administration of MZC and CG significantly inhibited ex vivo SHIV-RT infection (51-62% inhibition relative to baselines) of vaginal (but not cervical) mucosa collected 24 h post last gel exposure, indicating barrier effect of CG. Although the inhibitory effect of MZC (65-74%) did not significantly differ from CG (32-45%), it was within the range of protection (∼75%) against vaginal SHIV-RT challenge 24 h after gel dosing. Overall, the data suggest that evaluation of candidate microbicides in macaque explants can inform macaque efficacy and clinical studies design. The data support advancing MZC gel for clinical evaluation.

Non-invasive surveillance for Plasmodium in reservoir macaque species.

PubMed

Siregar, Josephine E; Faust, Christina L; Murdiyarso, Lydia S; Rosmanah, Lis; Saepuloh, Uus; Dobson, Andrew P; Iskandriati, Diah

2015-10-12

Primates are important reservoirs for human diseases, but their infection status and disease dynamics are difficult to track in the wild. Within the last decade, a macaque malaria, Plasmodium knowlesi, has caused disease in hundreds of humans in Southeast Asia. In order to track cases and understand zoonotic risk, it is imperative to be able to quantify infection status in reservoir macaque species. In this study, protocols for the collection of non-invasive samples and isolation of malaria parasites from naturally infected macaques are optimized. Paired faecal and blood samples from 60 Macaca fascicularis and four Macaca nemestrina were collected. All animals came from Sumatra or Java and were housed in semi-captive breeding colonies around West Java. DNA was extracted from samples using a modified protocol. Nested polymerase chain reactions (PCR) were run to detect Plasmodium using primers targeting mitochondrial DNA. Sensitivity of screening faecal samples for Plasmodium was compared to other studies using Kruskal Wallis tests and logistic regression models. The best primer set was 96.7 % (95 % confidence intervals (CI): 83.3-99.4 %) sensitive for detecting Plasmodium in faecal samples of naturally infected macaques (n = 30). This is the first study to produce definitive estimates of Plasmodium sensitivity and specificity in faecal samples from naturally infected hosts. The sensitivity was significantly higher than some other studies involving wild primates. Faecal samples can be used for detection of malaria infection in field surveys of macaques, even when there are no parasites visible in thin blood smears. Repeating samples from individuals will improve inferences of the epidemiology of malaria in wild primates.

The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta).

PubMed

Freeman, Sara M; Inoue, Kiyoshi; Smith, Aaron L; Goodman, Mark M; Young, Larry J

2014-07-01

The rhesus macaque (Macaca mulatta) is an important primate model for social cognition, and recent studies have begun to explore the impact of oxytocin on social cognition and behavior. Macaques have great potential for elucidating the neural mechanisms by which oxytocin modulates social cognition, which has implications for oxytocin-based pharmacotherapies for psychiatric disorders such as autism and schizophrenia. Previous attempts to localize oxytocin receptors (OXTR) in the rhesus macaque brain have failed due to reduced selectivity of radioligands, which in primates bind to both OXTR and the structurally similar vasopressin 1a receptor (AVPR1A). We have developed a pharmacologically-informed competitive binding autoradiography protocol that selectively reveals OXTR and AVPR1A binding sites in primate brain sections. Using this protocol, we describe the neuroanatomical distribution of OXTR in the macaque. Finally, we use in situ hybridization to localize OXTR mRNA. Our results demonstrate that OXTR expression in the macaque brain is much more restricted than AVPR1A. OXTR is largely limited to the nucleus basalis of Meynert, pedunculopontine tegmental nucleus, the superficial gray layer of the superior colliculus, the trapezoid body, and the ventromedial hypothalamus. These regions are involved in a variety of functions relevant to social cognition, including modulating visual attention, processing auditory and multimodal sensory stimuli, and controlling orienting responses to visual stimuli. These results provide insights into the neural mechanisms by which oxytocin modulates social cognition and behavior in this species, which, like humans, uses vision and audition as the primary modalities for social communication. Copyright © 2014 Elsevier Ltd. All rights reserved.

The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta)

PubMed Central

Freeman, Sara M.; Inoue, Kiyoshi; Smith, Aaron L.; Goodman, Mark M.; Young, Larry J.

2014-01-01

The rhesus macaque (Macaca mulatta) is an important primate model for social cognition, and recent studies have begun to explore the impact of oxytocin on social cognition and behavior. Macaques have great potential for elucidating the neural mechanisms by which oxytocin modulates social cognition, which has implications for oxytocin-based pharmacotherapies for psychiatric disorders such as autism and schizophrenia. Previous attempts to localize oxytocin receptors (OXTR) in the rhesus macaque brain have failed due to reduced selectivity of radioligands, which in primates bind to both OXTR and the structurally similar vasopressin 1a receptor (AVPR1A). We have developed a pharmacologically-informed competitive binding autoradiography protocol that selectively reveals OXTR and AVPR1A binding sites in primate brain sections. Using this protocol, we describe the neuroanatomical distribution of OXTR in the macaque. Finally, we use in situ hybridization to localize OXTR mRNA. Our results demonstrate that OXTR expression in the macaque brain is much more restricted than AVPR1A. OXTR is largely limited to the nucleus basalis of Meynert, pedunculopontine tegmental nucleus, the superficial gray layer of the superior colliculus, the trapezoid body, and the ventromedial hypothalamus. These regions are involved in a variety of functions relevant to social cognition, including modulating visual attention, processing auditory and multimodal sensory stimuli, and controlling orienting responses to visual stimuli. These results provide insights into the neural mechanisms by which oxytocin modulates social cognition and behavior in this species, which, like humans, uses vision and audition as the primary modalities for social communication. PMID:24845184

Diagnosis of Amyloidosis and Differentiation from Chronic, Idiopathic Enterocolitis in Rhesus (Macaca mulatta) and Pig-Tailed (M. nemestrina) Macaques

PubMed Central

Rice, Kelly A; Chen, Edward S; Pate, Kelly A Metcalf; Hutchinson, Eric K; Adams, Robert J

2013-01-01

Amyloidosis is a progressive and ultimately fatal disease in which amyloid, an insoluble fibrillar protein, is deposited inappropriately in multiple organs, eventually leading to organ dysfunction. Although this condition commonly affects macaques, there is currently no reliable method of early diagnosis. Changes in clinical pathology parameters have been associated with amyloidosis but occur in late stages of disease, are nonspecific, and resemble those seen in chronic, idiopathic enterocolitis. A review of animal records revealed that amyloidosis was almost always diagnosed postmortem, with prevalences of 15% and 25% in our rhesus and pig-tailed macaque colonies, respectively. As a noninvasive, high-throughput diagnostic approach to improve antemortem diagnosis of amyloidosis in macaques, we evaluated serum amyloid A (SAA), an acute-phase protein and the precursor to amyloid. Using necropsy records and ELISA analysis of banked serum, we found that SAA is significantly elevated in both rhesus and pig-tailed macaques with amyloid compared with those with chronic enterocolitis and healthy controls. At necropsy, 92% of rhesus and 83% of pig-tailed had amyloid deposition in either the intestines or liver. Minimally invasive biopsy techniques including endoscopy of the small intestine, mucosal biopsy of the colon, and ultrasound-guided trucut biopsy of the liver were used to differentiate macaques in our colonies with similar clinical presentations as either having amyloidosis or chronic, idiopathic enterocolitis. Our data suggest that SAA can serve as an effective noninvasive screening tool for amyloidosis and that minimally invasive biopsies can be used to confirm this diagnosis. PMID:23759529

Playing it cool: Characterizing social play, bout termination, and candidate play signals of juvenile and infant Tibetan macaques (Macaca thibetana).

PubMed

Wright, Kaitlin R; Mayhew, Jessica A; Sheeran, Lori K; Funkhouser, Jake A; Wagner, Ronald S; Sun, Li-Xing; Li, Jin-Hua

2018-07-18

Play behaviors and signals during playful interactions with juvenile conspecifics are important for both the social and cognitive development of young animals. The social organization of a species can also influence juvenile social play. We examined the relationships among play behaviors, candidate play signals, and play bout termination in Tibetan macaques (Macaca thibetana) during juvenile and infant social play to characterize the species play style. As Tibetan macaques are despotic and live in groups with strict linear dominance hierarchies and infrequent reconciliation, we predicted that play would be at risk of misinterpretation by both the individuals engaged in the play bout and by those watching, possibly leading to injury of the players. Animals living in such societies might need to frequently and clearly signal playful intent to play partners and other group members to avoid aggressive outcomes. We gathered video data on 21 individually-identified juvenile and infant macaques (one month to five years of age) from the Valley of the Wild Monkeys, Mt. Huangshan, China. We used all-occurrence sampling to record play behaviors and candidate play signals based on an ethogram. We predicted that play groups would use multiple candidate play signals in a variety of contexts and in association with the number of audience members in proximity to the players and play bout length. In the 283 playful interactions we scored, juvenile and infant macaques used multiple body and facial candidate play signals. Our data showed that juvenile and infant Tibetan macaques use a versatile repertoire of play behaviors and signals to sustain play.

Lentiviral Infection of Rhesus Macaques Causes Long-Term Injury to Cortical and Hippocampal Projections of Prostaglandin-Expressing Cholinergic Basal Forebrain Neurons

PubMed Central

Depboylu, Candan; Weihe, Eberhard; Eiden, Lee E.

2011-01-01

The simian immunodeficiency virus (SIV) macaque model resembles human HIV-AIDS and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limiting enzymes for prostaglandin synthesis, cyclooxygenases 1 and 2 (COX1 and 2) in brains of SIV-infected macaques with and without encephalitis and antiretroviral therapy, and uninfected controls. COX1 but not COX2 was co-expressed with markers of cholinergic phenotype, i.e. choline acetyltransferase and vesicular acetylcholine transporter (VAChT), in basal forebrain neurons of monkey, as well as human samples. COX1 was decreased in basal forebrain neurons in macaques with AIDS vs. uninfected and asymptomatic SIV-infected macaques. VAChT-positive fiber density was reduced in frontal, parietal and hippocampal-entorhinal cortex. Although brain SIV burden and associated COX1- and COX2-positive mononuclear and endothelial inflammatory reactions were mostly reversed in AIDS-diseased macaques that received 6-chloro-2′,3′-dideoxyguanosine treatment, decreased VAChT-positive terminal density and reduced cholinergic COX1 expression were not. Thus, COX1 expression is a feature of primate cholinergic basal forebrain neurons; it may be functionally important and a critical biomarker of cholinergic dysregulation accompanying lentiviral encephalopathy. These results imply that insufficiently prompt initiation of antiretroviral therapy in lentiviral infection may lead to neurostructurally unremarkable but neurochemically prominent, irreversible brain damage. PMID:22157616

The nucleus pararaphales in the human, chimpanzee, and macaque monkey.

PubMed

Baizer, Joan S; Weinstock, Nadav; Witelson, Sandra F; Sherwood, Chet C; Hof, Patrick R

2013-03-01

The human cerebral cortex and cerebellum are greatly expanded compared to those of other mammals, including the great apes. This expansion is reflected in differences in the size and organization of precerebellar brainstem structures, such as the inferior olive. In addition, there are cell groups unique to the human brainstem. One such group may be the nucleus pararaphales (PRa); however, there is disagreement among authors about the size and location of this nucleus in the human brainstem. The name "pararaphales" has also been used for neurons in the medulla shown to project to the flocculus in the macaque monkey. We have re-examined the existence and status of the PRa in eight humans, three chimpanzees, and four macaque monkeys using Nissl-stained sections as well as immunohistochemistry. In the human we found a cell group along the midline of the medulla in all cases; it had the form of interrupted cell columns and was variable among cases in rostrocaudal and dorsoventral extent. Cells and processes were highly immunoreactive for non-phosphorylated neurofilament protein (NPNFP); somata were immunoreactive to the synthetic enzyme for nitric oxide, nitric oxide synthase, and for calretinin. In macaque monkey, there was a much smaller oval cell group with NPNFP immunoreactivity. In the chimpanzee, we found a region of NPNFP-immunoreactive cells and fibers similar to what was observed in macaques. These results suggest that the "PRa" in the human may not be the same structure as the flocculus-projecting cell group described in the macaque. The PRa, like the arcuate nucleus, therefore may be unique to humans.

Beyond specific pathogen-free: biology and effect of common viruses in macaques.

PubMed

Lerche, Nicholas W; Simmons, Joe H

2008-02-01

Macaque models have contributed to key advances in our basic knowledge of behavior, anatomy, and physiology as well as to our understanding of a wide variety of human diseases. This issue of Comparative Medicine focuses on several of the viral agents (members of Retroviridae, Herpesviridae and 2 small DNA viruses) that can infect both nonhuman primates and humans as well as confound research studies. Featured articles also address the challenges of developing colonies of macaques and other nonhuman primates that are truly specific pathogen-free for these and other adventitious infectious agents.

Beyond Specific Pathogen-Free: Biology and Effect of Common Viruses in Macaques

PubMed Central

Lerche, Nicholas W; Simmons, Joe H

2008-01-01

Macaque models have contributed to key advances in our basic knowledge of behavior, anatomy, and physiology as well as to our understanding of a wide variety of human diseases. This issue of Comparative Medicine focuses on several of the viral agents (members of Retroviridae, Herpesviridae and 2 small DNA viruses) that can infect both nonhuman primates and humans as well as confound research studies. Featured articles also address the challenges of developing colonies of macaques and other nonhuman primates that are truly specific pathogen-free for these and other adventitious infectious agents. PMID:19793451

The vocal repertoire of Tibetan macaques (Macaca thibetana): A quantitative classification.

PubMed

Bernstein, Sofia K; Sheeran, Lori K; Wagner, R Steven; Li, Jin-Hua; Koda, Hiroki

2016-09-01

Vocal repertoires are basic and essential components for describing vocal communication in animals. Studying the entire suite of vocal signals aids investigations on the variation of acoustic structure across social contexts, comparisons on the complexity of communication systems across taxa, and in exploration of the evolutionary origins of species-specific vocalizations. Here, we describe the vocal repertoire of the largest species in the macaque genus, Macaca thibetana. We extracted thirty acoustic parameters from call recordings. Post hoc validation through quantitative analyses of the a priori repertoire classified eleven call types: coo, squawk, squeal, noisy scream, growl, bark, compound squeak, leap coo, weeping, modulated tonal scream, and pant. In comparison to the rest of the genus, Tibetan macaques uttered a wider array of vocalizations in the context of copulations. Previous reports did not include modulated tonal screams and pants during harassment of copulatory dyads. Furthermore, in comparison to the rest of the genus, Tibetan macaque females emit acoustically distinct copulation calls. The vocal repertoire of Tibetan macaques contributes to the literature on the emergence of species-specific calls in the genus Macaca with potential insights from social, reproductive, and ecological comparisons across species. Am. J. Primatol. 78:937-949, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Reference Intervals for Preprandial and Postprandial Serum Bile Acid in Adult Rhesus Macaques (Macaca mulatta)

PubMed Central

Lemoy, Marie-Josee MF; Westworth, Diccon R; Ardeshir, Amir; Tarara, Ross P

2013-01-01

The purpose of this study was to determine the 12-h fasting preprandial and 2-h postprandial serum bile acid concentration (SBAC) reference intervals for healthy, adult rhesus macaques (Macaca mulatta). We hypothesized that the mean 2-h postprandial SBAC would be significantly higher than the mean preprandial SBAC. We included 40 (24 male, 16 female) macaques after confirming that their health records, physical examinations, CBC, serum chemistry panels, and urinalyses were all within normal limits. In addition, hepatitis A titers were determined, an ultrasound examination of the liver was performed, and two 16-gauge ultrasound guided percutaneous liver biopsies were collected and submitted for histopathology. Macaques were confirmed healthy according to hepatitis A screens and sonographic and histologic evaluation of hepatic tissue. Within 2 wk of the screening procedures, preprandial and postprandial SBACs were measured. Preprandial SBAC (mean ± 1 SD) was 11.1 ± 1.9 µmol/L and postprandial SBAC was 19.7 ± 8.0 µmol/L, which was significantly higher than the preprandial value. Sex and hepatitis titers did not significantly influence preprandial and postprandial SBAC. The current study indicates that the SBAC reference values for rhesus macaques are higher than those reported for humans and companion animals. PMID:23849441

Pharmacokinetics of 2 Formulations of Transdermal Fentanyl in Cynomolgus Macaques (Macaca fascicularis)

PubMed Central

Carlson, Amy M; Kelly, Richard; Fetterer, David P; Rico, Pedro J; Bailey, Emily J

2016-01-01

Fentanyl is a μ-opioid agonist that often is used as the analgesic component for balanced anesthesia in both human and veterinary patients. Minimal information has been published regarding appropriate dosing, and the pharmacokinetics of fentanyl are unknown in NHP. The pharmacokinetic properties of 2 transdermal fentanyl delivery methods, a solution (2.6 and 1.95 mg/kg) and a patch (25 µg/h), were determined when applied topically to the dorsal scapular area of cynomolgus macaques (Macaca fascicularis). Serum fentanyl concentrations were analyzed by using liquid chromatography–mass spectrometry. Compared with the patch, the transdermal fentanyl solution generated higher drug concentrations over longer time. Adverse reactions occurred in the macaques that received the transdermal fentanyl solution at 2.6 mg/kg. Both preparations showed significant interanimal variability in the maximal serum drug levels, time to achieve maximal fentanyl levels, elimination half-life, and AUC values. Both the maximal concentration and the time at which this concentration occurred were increased in macaques compared with most other species after application of the transdermal fentanyl patch and compared with dogs after application of the transdermal fentanyl solution. The pharmacokinetic properties of transdermal fentanyl in macaques are markedly different from those in other veterinary species and preclude its use as a long-acting analgesic drug in NHP. PMID:27423151

No costly prosociality among related long-tailed macaques (Macaca fascicularis).

PubMed

Sterck, Elisabeth H M; Olesen, Caroline U; Massen, Jorg J M

2015-08-01

Altruism, benefiting another at a cost to the donor, may be achieved through prosocial behavior. Studies of nonhuman animals typically investigate prosocial behavior with paradigms in which the donor can choose to give a recipient a food item, and the choice does not affect the donor's reward (which is either present or absent). In such tasks, long-tailed macaques (Macaca fascicularis) show prosocial behavior, especially toward kin. Here, we tested captive long-tailed macaques with related recipients in an alternative task, in which the donor had to give up a preferred reward to benefit the recipient; that is, they had to choose a lower valued reward for themselves to provide food to their kin. Overall, the macaques did not provide their kin with food. The task forced the donor to balance its prosocial behavior with its selfish choice for a higher value reward, a balance that turned out to favor selfish motives. Consequently, our study shows that a prosocial tendency is not sufficient to elicit costly prosocial behavior in long-tailed macaques. Subsequently, we feel that tasks in which the donor must choose a lower value reward to benefit another individual may allow the titration of the strength of prosocial behavior, and thus provides interesting possibilities for future comparative studies. (c) 2015 APA, all rights reserved).

Reference intervals for preprandial and postprandial serum bile acid in adult rhesus macaques (Macaca mulatta).

PubMed

Lemoy, Marie-Josee M F; Westworth, Diccon R; Ardeshir, Amir; Tarara, Ross P

2013-07-01

The purpose of this study was to determine the 12-h fasting preprandial and 2-h postprandial serum bile acid concentration (SBAC) reference intervals for healthy, adult rhesus macaques (Macaca mulatta). We hypothesized that the mean 2-h postprandial SBAC would be significantly higher than the mean preprandial SBAC. We included 40 (24 male, 16 female) macaques after confirming that their health records, physical examinations, CBC, serum chemistry panels, and urinalyses were all within normal limits. In addition, hepatitis A titers were determined, an ultrasound examination of the liver was performed, and two 16-gauge ultrasound guided percutaneous liver biopsies were collected and submitted for histopathology. Macaques were confirmed healthy according to hepatitis A screens and sonographic and histologic evaluation of hepatic tissue. Within 2 wk of the screening procedures, preprandial and postprandial SBACs were measured. Preprandial SBAC (mean ± 1 SD) was 11.1 ± 1.9 μmol/L and postprandial SBAC was 19.7 ± 8.0 μmol/L, which was significantly higher than the preprandial value. Sex and hepatitis titers did not significantly influence preprandial and postprandial SBAC. The current study indicates that the SBAC reference values for rhesus macaques are higher than those reported for humans and companion animals.

Diversification of both KIR and NKG2 natural killer cell receptor genes in macaques - implications for highly complex MHC-dependent regulation of natural killer cells.

PubMed

Walter, Lutz; Petersen, Beatrix

2017-02-01

The killer immunoglobulin-like receptors (KIR) as well as their MHC class I ligands display enormous genetic diversity and polymorphism in macaque species. Signals resulting from interaction between KIR or CD94/NKG2 receptors and their cognate MHC class I proteins essentially regulate the activity of natural killer (NK) cells. Macaque and human KIR share many features, such as clonal expression patterns, gene copy number variations, specificity for particular MHC class I allotypes, or epistasis between KIR and MHC class I genes that influence susceptibility and resistance to immunodeficiency virus infection. In this review article we also annotated publicly available rhesus macaque BAC clone sequences and provide the first description of the CD94-NKG2 genomic region. Besides the presence of genes that are orthologous to human NKG2A and NKG2F, this region contains three NKG2C paralogues. Hence, the genome of rhesus macaques contains moderately expanded and diversified NKG2 genes in addition to highly diversified KIR genes. The presence of two diversified NK cell receptor families in one species has not been described before and is expected to require a complex MHC-dependent regulation of NK cells. © 2016 John Wiley & Sons Ltd.

Complex assembly, crystallization and preliminary X-ray crystallographic studies of rhesus macaque MHC Mamu-A*01 complexed with an immunodominant SIV-Gag nonapeptide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chu, Fuliang; Graduate School, Chinese Academy of Sciences, Beijing; Lou, Zhiyong

2005-06-01

Crystallization of the first rhesus macaque MHC class I complex. Simian immunodeficiency virus (SIV) infection in rhesus macaques has been used as the best model for the study of human immunodeficiency virus (HIV) infection in humans, especially in the cytotoxic T-lymphocyte (CTL) response. However, the structure of rhesus macaque (or any other monkey model) major histocompatibility complex class I (MHC I) presenting a specific peptide (the ligand for CTL) has not yet been elucidated. Here, using in vitro refolding, the preparation of the complex of the rhesus macaque MHC I allele (Mamu-A*01) with human β{sub 2}m and an immunodominant peptide,more » CTPYDINQM (Gag-CM9), derived from SIV Gag protein is reported. The complex (45 kDa) was crystallized; the crystal belongs to space group I422, with unit-cell parameters a = b = 183.8, c = 155.2 Å. The crystal contains two molecules in the asymmetric unit and diffracts X-rays to 2.8 Å resolution. The structure is being solved by molecular replacement and this is the first attempt to determined the crystal structure of a peptide–nonhuman primate MHC complex.« less

Understanding Human-Animal Relations in the Context of Primate Conservation: A Multispecies Ethnographic Approach in North Morocco.

PubMed

Waters, Siân; Bell, Sandra; Setchell, Joanna M

2018-01-01

Strategies for conserving species threatened with extinction are often driven by ecological data. However, in anthropogenic landscapes, understanding and incorporating local people's perceptions may enhance species conservation. We examine the relationships shepherds, living on the periphery of the mixed oak forest of Bouhachem in northern Morocco, have with animals in the context of a conservation project for Barbary macaques (Macaca sylvanus). We analyse ethnographic data to provide insights into shepherds' conceptions of Barbary macaques and the species which bring the shepherds into the forest - goats (Capra hircus), domestic dogs (Canis lupus familiaris), and the African wolf (Canis lupus lupaster). We interpret these data within the framework of boundary theory. Our multispecies ethnographic approach illuminates the different and, in the case of the domestic dog and the Barbary macaque, complex ways shepherds perceive each species. Some shepherds show intrinsic interest in the macaques, revealing potential recruits to conservation activities. As with any ethnographic study, our interpretations of human-animal relations in Bouhachem may not extrapolate to other areas of the Barbary macaque's distribution because of the unique nature of both people and the place. We recommend that conservationists examine complex place-based relations between humans and animals to improve wildlife conservation efforts. © 2018 S. Karger AG, Basel.

Comparison of Saliva Collection Methods for the Determination of Salivary Cortisol Levels in Rhesus Macaques (Macaca mulatta), Cynomolgus Macaques (Macaca fascicularis), and African Green Monkeys (Chlorocebus aethiops)

PubMed Central

Rapp-Santos, Kamala J; Altamura, Louis A; Norris, Sarah L; Lugo-Roman, Luis A; Rico, Pedro J; Hofer, Christian C

2017-01-01

The ability to quickly and accurately determine cortisol as a biomarker for stress is a valuable tool in assessing the wellbeing of NHP. In this study, 2 methods of collecting saliva (a commercial collection device and passive drool) and the resulting free salivary cortisol levels were compared with total serum cortisol concentration in rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis) and African green monkeys (Chlorocebus aethiops) at 2 collection time points. Serum and salivary cortisol levels were determined using a competitive quantitative ELISA. In addition, both saliva collection methods were evaluated for volume collected and ease of use. Compared with passive drool, the experimental collection device was more reliable in collecting sufficient volumes of saliva, and the resulting salivary cortisol values demonstrated stronger correlation with serum cortisol concentration in all species and collection days except cynomolgus macaques on day 1. This saliva collection device allows quick and reliable sample collection for the determination of salivary cortisol levels. In addition, the results might provide a useful tool for evaluating hypothalamic-pituitary-adrenal axis activity or the physiologic stress reaction in NHP as well as a biomarker of psychologic stress states in a variety of situations. PMID:28315649

Durable protection of rhesus macaques immunized with a replicating adenovirus-SIV multigene prime/protein boost vaccine regimen against a second SIVmac251 rectal challenge: role of SIV-specific CD8+ T cell responses.

PubMed

Malkevitch, Nina V; Patterson, L Jean; Aldrich, M Kristine; Wu, Yichen; Venzon, David; Florese, Ruth H; Kalyanaraman, V S; Pal, Ranajit; Lee, Eun Mi; Zhao, Jun; Cristillo, Anthony; Robert-Guroff, Marjorie

2006-09-15

Previously, priming with replication-competent adenovirus-SIV multigenic vaccines and boosting with envelope subunits strongly protected 39% of rhesus macaques against rectal SIV(mac251) challenge. To evaluate protection durability, eleven of the protected and two SIV-infected unimmunized macaques that controlled viremia were re-challenged rectally with SIV(mac251). Strong protection was observed in 8/11 vaccinees, including two exhibiting <50 SIV RNA copies. Decreased viremia compared to naïve controls was observed in the other three. The SIV-infected unimmunized macaques modestly controlled viremia but exhibited CD4 counts < or =200, unlike the protected macaques. Durable protection was associated with significantly increased SIV-specific ELISPOT responses and lymphoproliferative responses to p27 at re-challenge. After CD8 depletion, 2 of 8 re-challenged, protected vaccinees maintained <50 SIV RNA copies; SIV RNA emerged in 6. Re-appearance of CD8 cells and restoration of SIV-specific cellular immunity coincided with viremia suppression. Overall, cellular immunity induced by vaccination and/or low-level, inapparent viremia post-first SIV(mac251) challenge, was associated with durable protection against re-challenge.

Personality structure and social style in macaques.

PubMed

Adams, Mark James; Majolo, Bonaventura; Ostner, Julia; Schülke, Oliver; De Marco, Arianna; Thierry, Bernard; Engelhardt, Antje; Widdig, Anja; Gerald, Melissa S; Weiss, Alexander

2015-08-01

Why regularities in personality can be described with particular dimensions is a basic question in differential psychology. Nonhuman primates can also be characterized in terms of personality structure. Comparative approaches can help reveal phylogenetic constraints and social and ecological patterns associated with the presence or absence of specific personality dimensions. We sought to determine how different personality structures are related to interspecific variation in social style. Specifically, we examined this question in 6 different species of macaques, because macaque social style is well characterized and can be categorized on a spectrum of despotic (Grade 1) versus tolerant (Grade 4) social styles. We derived personality structures from adjectival ratings of Japanese (Macaca fuscata; Grade 1), Assamese (M. assamensis; Grade 2), Barbary (M. sylvanus; Grade 3), Tonkean (M. tonkeana; Grade 4), and crested (M. nigra; Grade 4) macaques and compared these species with rhesus macaques (M. mulatta; Grade 1) whose personality was previously characterized. Using a nonparametric method, fuzzy set analysis, to identify commonalities in personality dimensions across species, we found that all but 1 species exhibited consistently defined Friendliness and Openness dimensions, but that similarities in personality dimensions capturing aggression and social competence reflect similarities in social styles. These findings suggest that social and phylogenetic relationships contribute to the origin, maintenance, and diversification of personality. (c) 2015 APA, all rights reserved.

Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques.

PubMed

Borges, Maria Beatriz; Marchevsky, Renato Sergio; Mendes, Ygara S; Mendes, Luiz Gustavo; Duarte, Ana Claudia; Cruz, Michael; de Filippis, Ana Maria Bispo; Vasconcelos, Pedro Fernando C; Freire, Marcos; Homma, Akira; Mossman, Sally; Lepine, Edith; Vanloubbeeck, Yannick; Lorin, Clarisse; Malice, Marie-Pierre; Caride, Elena; Warter, Lucile

2018-01-01

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model's predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans.

Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques

PubMed Central

Borges, Maria Beatriz; Marchevsky, Renato Sergio; Mendes, Ygara S.; Mendes, Luiz Gustavo; Duarte, Ana Claudia; Cruz, Michael; de Filippis, Ana Maria Bispo; Vasconcelos, Pedro Fernando C.; Freire, Marcos; Homma, Akira; Mossman, Sally; Lepine, Edith; Vanloubbeeck, Yannick; Lorin, Clarisse; Malice, Marie-Pierre; Caride, Elena

2018-01-01

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model’s predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans. PMID:29694440

Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir.

PubMed

Avalos, Claudia R; Abreu, Celina M; Queen, Suzanne E; Li, Ming; Price, Sarah; Shirk, Erin N; Engle, Elizabeth L; Forsyth, Ellen; Bullock, Brandon T; Mac Gabhann, Feilim; Wietgrefe, Stephen W; Haase, Ashley T; Zink, M Christine; Mankowski, Joseph L; Clements, Janice E; Gama, Lucio

2017-08-15

A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are reported in HIV-infected individuals on ART. Biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (CSF) of HIV-infected individuals demonstrate continued effects of HIV in brain and suggest that the central nervous system (CNS) may serve as a viral reservoir. Using a simian immunodeficiency virus (SIV)/macaque model for HIV encephalitis and AIDS, we evaluated whether infected cells persist in brain despite ART. Eight SIV-infected pig-tailed macaques were virally suppressed with ART, and plasma and CSF viremia levels were analyzed longitudinally. To assess whether virus persisted in brain macrophages (BrMΦ) in these macaques, we used a macrophage quantitative viral outgrowth assay (MΦ-QVOA), PCR, and in situ hybridization (ISH) to measure the frequency of infected cells and the levels of viral RNA and DNA in brain. Viral RNA in brain tissue of suppressed macaques was undetectable, although viral DNA was detected in all animals. The MΦ-QVOA demonstrated that the majority of suppressed animals contained latently infected BrMΦ. We also showed that virus produced in the MΦ-QVOAs was replication competent, suggesting that latently infected BrMΦ are capable of reestablishing productive infection upon treatment interruption. This report provides the first confirmation of the presence of replication-competent SIV in BrMΦ of ART-suppressed macaques and suggests that the highly debated issue of viral latency in macrophages, at least in brain, has been addressed in SIV-infected macaques treated with ART. IMPORTANCE Resting CD4 + T cells are currently the only cells that fit the definition of a latent reservoir. However, recent evidence suggests that HIV/SIV-infected macrophages persist despite ART. Markers of macrophage activation and neuronal damage are observed in the CSF of HIV-infected individuals and of SIV-infected macaques on suppressive ART regimens, suggesting that the CNS has continued virus infection and latent infection. A controversy exists as to whether brain macrophages represent a latent source of replication-competent virus capable of reestablishing infection upon treatment interruption. In this study, we demonstrated the presence of the latent macrophage reservoir in brains of SIV-infected ART-treated macaques and analyzed the reservoir using our established outgrowth assay to quantitate macrophages harboring replication-competent SIV genomes. Our results support the idea of the existence of other latent reservoirs in addition to resting CD4 + T cells and underscore the importance of macrophages in developing strategies to eradicate HIV. Copyright © 2017 Avalos et al.

Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia

PubMed Central

Fahrmann, Johannes; Grapov, Dmitry; Yang, Jun; Hammock, Bruce; Fiehn, Oliver; Bell, Graeme I.

2015-01-01

Nonobese diabetic (NOD) mice are a commonly used model of type 1 diabetes (T1D). However, not all animals will develop overt diabetes despite undergoing similar autoimmune insult. In this study, a comprehensive metabolomic approach, consisting of gas chromatography time-of-flight (GC-TOF) mass spectrometry (MS), ultra-high-performance liquid chromatography-accurate mass quadruple time-of-flight (UHPLC-qTOF) MS and targeted UHPLC-tandem mass spectrometry-based methodologies, was used to capture metabolic alterations in the metabolome and lipidome of plasma from NOD mice progressing or not progressing to T1D. Using this multi-platform approach, we identified >1,000 circulating lipids and metabolites in male and female progressor and nonprogressor animals (n = 71). Statistical and multivariate analyses were used to identify age- and sex-independent metabolic markers, which best differentiated metabolic profiles of progressors and nonprogressors. Key T1D-associated perturbations were related with 1) increases in oxidation products glucono-δ-lactone and galactonic acid and reductions in cysteine, methionine and threonic acid, suggesting increased oxidative stress; 2) reductions in circulating polyunsaturated fatty acids and lipid signaling mediators, most notably arachidonic acid (AA) and AA-derived eicosanoids, implying impaired states of systemic inflammation; 3) elevations in circulating triacylglyercides reflective of hypertriglyceridemia; and 4) reductions in major structural lipids, most notably lysophosphatidylcholines and phosphatidylcholines. Taken together, our results highlight the systemic perturbations that accompany a loss of glycemic control and development of overt T1D. PMID:25852003

miRNAs that associate with conjunctival inflammation and ocular Chlamydia trachomatis infection do not predict progressive disease.

PubMed

Derrick, Tamsyn; Ramadhani, Athumani M; Mtengai, Karim; Massae, Patrick; Burton, Matthew J; Holland, Martin J

2017-03-01

We previously showed that conjunctival miR-147b and miR-1285 were upregulated in Gambian adults with inflammatory scarring trachoma, and miR-155 and miR-184 expression was strongly associated with conjunctival inflammation and ocular Chlamydia trachomatis infection in children from Guinea-Bissau. We investigated whether the single or combined expression of miR-147b, miR-1285, miR-155 and miR-184 was able to identify individuals with increased risk of incident or progressive scarring trachoma. Conjunctival swab samples were collected from 506 children between the ages of 4 and 12 living in northern Tanzania. These 506 samples formed the baseline sample set of a 4-year longitudinal study. Chlamydia trachomatis infection was diagnosed by droplet digital PCR and expression of miR-155, miR-184, miR-1285 and miR-147b was tested by qPCR. Individuals were assessed for incidence and progression of conjunctival scarring by comparison of conjunctival photographs taken at baseline and 4 years later. miR-184 and miR-155 were strongly associated with inflammation and infection at baseline; however, no miR was associated with 4-year scarring incidence or progression. miR-184 expression was more strongly downregulated during inflammation in non-progressors relative to progressors, suggesting that a disequilibrium in the efficiency of wound healing is a significant determinant of progressive conjunctival fibrosis. © FEMS 2017.

Longitudinal sensitivity to change of MRI-based muscle cross-sectional area versus isometric strength analysis in osteoarthritic knees with and without structural progression: pilot data from the Osteoarthritis Initiative.

PubMed

Dannhauer, Torben; Sattler, Martina; Wirth, Wolfgang; Hunter, David J; Kwoh, C Kent; Eckstein, Felix

2014-08-01

Biomechanical measurement of muscle strength represents established technology in evaluating limb function. Yet, analysis of longitudinal change suffers from relatively large between-measurement variability. Here, we determine the sensitivity to change of magnetic resonance imaging (MRI)-based measurement of thigh muscle anatomical cross sectional areas (ACSAs) versus isometric strength in limbs with and without structural progressive knee osteoarthritis (KOA), with focus on the quadriceps. Of 625 "Osteoarthritis Initiative" participants with radiographic KOA, 20 had MRI cartilage and radiographic joint space width loss in the right knee isometric muscle strength measurement and axial T1-weighted spin-echo acquisitions of the thigh. Muscle ACSAs were determined from manual segmentation at 33% femoral length (distal to proximal). In progressor knees, the reduction in quadriceps ACSA between baseline and 2-year follow-up was -2.8 ± 7.9 % (standardized response mean [SRM] = -0.35), and it was -1.8 ± 6.8% (SRM = -0.26) in matched, non-progressive KOA controls. The decline in extensor strength was more variable than that in ACSAs, both in progressors (-3.9 ± 20%; SRM = -0.20) and in non-progressive controls (-4.5 ± 28%; SRM = -0.16). MRI-based analysis of quadriceps muscles ACSAs appears to be more sensitive to longitudinal change than isometric extensor strength and is suggestive of greater loss in limbs with structurally progressive KOA than in non-progressive controls.

Plasma Metabolomics Biosignature According to HIV Stage of Infection, Pace of Disease Progression, Viremia Level and Immunological Response to Treatment

PubMed Central

Scarpelini, Bruno; Zanoni, Michelle; Sucupira, Maria Cecilia Araripe; Truong, Hong-Ha M.; Janini, Luiz Mario Ramos; Segurado, Ismael Dale Cotrin; Diaz, Ricardo Sobhie

2016-01-01

Background We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non-responders (INR), before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment. Results Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. β-oxidation and sphingosine‐1‐phosphate-phosphatase-1 activity were down-regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl-coenzyme A dehydrogenase deficiency [MADD]) was detected. Conclusions Blood-based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease. PMID:27941971

The Intracytoplasmic Domain of the Env Transmembrane Protein Is a Locus for Attenuation of Simian Immunodeficiency Virus SIVmac in Rhesus Macaques

PubMed Central

Shacklett, Barbara L.; Weber, Claudia Jo; Shaw, Karen E. S.; Keddie, Elise M.; Gardner, Murray B.; Sonigo, Pierre; Luciw, Paul A.

2000-01-01

The human and simian immunodeficiency virus (HIV-1 and SIVmac) transmembrane proteins contain unusually long intracytoplasmic domains (ICD-TM). These domains are suggested to play a role in envelope fusogenicity, interaction with the viral matrix protein during assembly, viral infectivity, binding of intracellular calmodulin, disruption of membranes, and induction of apoptosis. Here we describe a novel mutant virus, SIVmac-M4, containing multiple mutations in the coding region for the ICD-TM of pathogenic molecular clone SIVmac239. Parental SIVmac239-Nef+ produces high-level persistent viremia and simian AIDS in both juvenile and newborn rhesus macaques. The ICD-TM region of SIVmac-M4 contains three stop codons, a +1 frameshift, and mutation of three highly conserved, charged residues in the conserved C-terminal alpha-helix referred to as lentivirus lytic peptide 1 (LLP-1). Overlapping reading frames for tat, rev, and nef are not affected by these changes. In this study, four juvenile macaques received SIVmac-M4 by intravenous injection. Plasma viremia, as measured by branched-DNA (bDNA) assay, reached a peak at 2 weeks postinoculation but dropped to below detectable levels by 12 weeks. At over 1.5 years postinoculation, all four juvenile macaques remain healthy and asymptomatic. In a subsequent experiment, four neonatal rhesus macaques were given SIVmac-M4 intravenously. These animals exhibited high levels of viremia in the acute phase (2 weeks postinoculation) but are showing a relatively low viral load in the chronic phase of infection, with no clinical signs of disease for 1 year. These findings demonstrated that the intracytoplasmic domain of the transmembrane Env (Env-TM) is a locus for attenuation in rhesus macaques. PMID:10846063

Sagittal Plane Kinematics of the Jaw and Hyolingual Apparatus During Swallowing in Macaca mulatta

PubMed Central

Iriarte-Diaz, Jose; Arce-McShane, Fritzie; Orsbon, Courtney P.; Brown, Kevin A.; Eastment, McKenna; Avivi-Arber, Limor; Sessle, Barry J.; Inoue, Makoto; Hatsopoulos, Nicholas G.; Ross, Callum F.

2018-01-01

Studies of mechanisms of feeding behavior are important in a society where aging- and disease-related feeding disorders are increasingly prevalent. It is important to evaluate the clinical relevance of animal models of the disease and the control. Our present study quantifies macaque hyolingual and jaw kinematics around swallowing cycles to determine the extent to which macaque swallowing resembles that of humans. One female and one male adult Macaca mulatta were trained to feed in a primate chair. Videofluoroscopy was used to record kinematics in a sagittal view during natural feeding on solid food, and the kinematics of the hyoid bone, thyroid cartilage, mandibular jaw, and anterior-, middle-, and posterior-tongue. Jaw gape cycles were defined by consecutive maximum gapes, and the kinematics of the swallow cycles were compared with those of the two consecutive non-swallow cycles preceding and succeeding the swallow cycles. Although there are size differences between macaques and humans, and macaques have shorter durations of jaw gape cycles and hyoid and thyroid upward movements, there are several important similarities between our macaque data and human data reported in the literature: (1) The durations of jaw gape cycles during swallow cycles are longer than those of non-swallow cycles as a result of an increased duration of the jaw-opening phase; (2) Hyoid and thyroid upward movement is linked with a posterior tongue movement and is faster during swallow than non-swallow cycles; (3) Tongue elevation propagates from anterior to posterior during swallow and non-swallow cycles. These findings suggest that macaques can be a useful experimental model for human swallowing studies. PMID:28528492

Bridging the Gap between the Human and Macaque Connectome: A Quantitative Comparison of Global Interspecies Structure-Function Relationships and Network Topology

PubMed Central

Miranda-Dominguez, Oscar; Mills, Brian D.; Grayson, David; Woodall, Andrew; Grant, Kathleen A.; Kroenke, Christopher D.

2014-01-01

Resting state functional connectivity MRI (rs-fcMRI) may provide a powerful and noninvasive “bridge” for comparing brain function between patients and experimental animal models; however, the relationship between human and macaque rs-fcMRI remains poorly understood. Here, using a novel surface deformation process for species comparisons in the same anatomical space (Van Essen, 2004, 2005), we found high correspondence, but also unique hub topology, between human and macaque functional connectomes. The global functional connectivity match between species was moderate to strong (r = 0.41) and increased when considering the top 15% strongest connections (r = 0.54). Analysis of the match between functional connectivity and the underlying anatomical connectivity, derived from a previous retrograde tracer study done in macaques (Markov et al., 2012), showed impressive structure–function correspondence in both the macaque and human. When examining the strongest structural connections, we found a 70–80% match between structural and functional connectivity matrices in both species. Finally, we compare species on two widely used metrics for studying hub topology: degree and betweenness centrality. The data showed topological agreement across the species, with nodes of the posterior cingulate showing high degree and betweenness centrality. In contrast, nodes in medial frontal and parietal cortices were identified as having high degree and betweenness in the human as opposed to the macaque. Our results provide: (1) a thorough examination and validation for a surface-based interspecies deformation process, (2) a strong theoretical foundation for making interspecies comparisons of rs-fcMRI, and (3) a unique look at topological distinctions between the species. PMID:24741045

Early Whole Blood Transcriptional Signatures Are Associated with Severity of Lung Inflammation in Cynomolgus Macaques with Mycobacterium tuberculosis Infection.

PubMed

Gideon, Hannah P; Skinner, Jason A; Baldwin, Nicole; Flynn, JoAnne L; Lin, Philana Ling

2016-12-15

Whole blood transcriptional profiling offers great diagnostic and prognostic potential. Although studies identified signatures for pulmonary tuberculosis (TB) and transcripts that predict the risk for developing active TB in humans, the early transcriptional changes immediately following Mycobacterium tuberculosis infection have not been evaluated. We evaluated the gene expression changes in the cynomolgus macaque model of TB, which recapitulates all clinical aspects of human M. tuberculosis infection, using a human microarray and analytics platform. We performed genome-wide blood transcriptional analysis on 38 macaques at 11 postinfection time points during the first 6 mo of M. tuberculosis infection. Of 6371 differentially expressed transcripts between preinfection and postinfection, the greatest change in transcriptional activity occurred 20-56 d postinfection, during which fluctuation of innate and adaptive immune response-related transcripts was observed. Modest transcriptional differences between active TB and latent infection were observed over the time course with substantial overlap. The pattern of module activity previously published for human active TB was similar in macaques with active disease. Blood transcript activity was highly correlated with lung inflammation (lung [ 18 F]fluorodeoxyglucose [FDG] avidity) measured by positron emission tomography and computed tomography at early time points postinfection. The differential signatures between animals with high and low lung FDG were stronger than between clinical outcomes. Analysis of preinfection signatures of macaques revealed that IFN signatures could influence eventual clinical outcomes and lung FDG avidity, even before infection. Our data support that transcriptional changes in the macaque model are translatable to human M. tuberculosis infection and offer important insights into early events of M. tuberculosis infection. Copyright © 2016 by The American Association of Immunologists, Inc.

Partial protection against multiple RT-SHIV162P3 vaginal challenge of rhesus macaques by a silicone elastomer vaginal ring releasing the NNRTI MC1220

PubMed Central

Fetherston, Susan M.; Geer, Leslie; Veazey, Ronald S.; Goldman, Laurie; Murphy, Diarmaid J.; Ketas, Thomas J.; Klasse, Per Johan; Blois, Sylvain; La Colla, Paolo; Moore, John P.; Malcolm, R. Karl

2013-01-01

Objectives The non-nucleoside reverse transcriptase inhibitor MC1220 has potent in vitro activity against HIV type 1 (HIV-1). A liposome gel formulation of MC1220 has previously been reported to partially protect rhesus macaques against vaginal challenge with a simian HIV (SHIV). Here, we describe the pre-clinical development of an MC1220-releasing silicone elastomer vaginal ring (SEVR), including pharmacokinetic (PK) and efficacy studies in macaques. Methods In vitro release studies were conducted on SEVRs loaded with 400 mg of MC1220, using simulated vaginal fluid (SVF, n = 4) and 1 : 1 isopropanol/water (IPA/H2O, n = 4) as release media. For PK evaluation, SEVRs were inserted into adult female macaques (n = 6) for 30 days. Following a 1week washout period, fresh rings were placed in the same animals, which were then challenged vaginally with RT-SHIV162P3 once weekly for 4 weeks. Results SEVRs released 1.66 and 101 mg of MC1220 into SVF and IPA/H2O, respectively, over 30 days, the differential reflecting the low aqueous solubility of the drug. In macaque PK studies, MC1220 was consistently detected in vaginal fluid (peak 845 ng/mL) and plasma (peak 0.91 ng/mL). Kaplan–Meier analysis over 9weeks showed significantly lower infection rates for animals given MC1220-containing SEVRs than placebo rings (hazard ratio 0.20, P = 0.0037). Conclusions An MC1220-releasing SEVR partially protected macaques from vaginal challenge. Such ring devices are a practical method for providing sustained, coitally independent protection against vaginal exposure to HIV-1. PMID:23109186

Molecular Cytogenetic Analysis of One African and Five Asian Macaque Species Reveals Identical Karyotypes as in Mandrill.

PubMed

Sangpakdee, Wiwat; Tanomtong, Alongkoad; Chaveerach, Arunrat; Pinthong, Krit; Trifonov, Vladimir; Loth, Kristina; Hensel, Christiana; Liehr, Thomas; Weise, Anja; Fan, Xiaobo

2018-04-01

The question how evolution and speciation work is one of the major interests of biology. Especially, genetic including karyotypic evolution within primates is of special interest due to the close phylogenetic position of Macaca and Homo sapiens and the role as in vivo models in medical research, neuroscience, behavior, pharmacology, reproduction and Acquired Immune Deficiency Syndrome (AIDS). Karyotypes of five macaque species from South East Asia and of one macaque species as well as mandrill from Africa were analyzed by high resolution molecular cytogenetics to obtain new insights into karyotypic evolution of old world monkeys. Molecular cytogenetics applying human probes and probe sets was applied in chromosomes of Macaca arctoides, M. fascicularis, M. nemestrina, M. assamensis, M. sylvanus, M. mulatta and Mandrillus sphinx. Established two- to multicolor-fluorescence in situ hybridization (FISH) approaches were applied. Locus-specific probes, whole and partial chromosome paint probes were hybridized. Especially the FISH-banding approach multicolor-banding (MCB) as well as probes oriented towards heterochromatin turned out to be highly efficient for interspecies comparison. Karyotypes of all seven studied species could be characterized in detail. Surprisingly, no evolutionary conserved differences were found among macaques, including mandrill. Between the seven here studied and phenotypically so different species we expected several via FISH detectable karyoypic and submicroscopic changes and were surprised to find none of them on a molecular cytogenetic level. Spatial separation, may explain the speciation and different evolution for some of them, like African M. sylvanus, Mandrillus sphinx and the South Asian macaques. However, for the partially or completely overlapping habitats of the five studied South Asian macaques the species separation process can also not be deduced to karyotypic separation.

Improved Xenobiotic Metabolism and Reduced Susceptibility to Cancer in Gluten-Sensitive Macaques upon Introduction of a Gluten-Free Diet

PubMed Central

Sestak, Karol; Conroy, Lauren; Aye, Pyone P.; Mehra, Smriti; Doxiadis, Gaby G.; Kaushal, Deepak

2011-01-01

Background A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta). Methodology Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies),targeting expression of over 20,000 genes. Principal Findings When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories - cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function - this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes. Conclusions/Significance A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research. PMID:21533263

Pharmacokinetic profile of raltegravir, elvitegravir and dolutegravir in plasma and mucosal secretions in rhesus macaques.

PubMed

Massud, Ivana; Martin, Amy; Dinh, Chuong; Mitchell, James; Jenkins, Leecresia; Heneine, Walid; Pau, Chou-Pong; García-Lerma, J Gerardo

2015-05-01

Pharmacokinetic studies in animal models are important for assessing the prophylactic potential of antiretroviral drugs for HIV prevention. This study sought to identify clinically relevant doses of the marketed integrase inhibitors raltegravir, elvitegravir and dolutegravir in macaques and investigate drug penetration and antiviral activity in mucosal secretions. Macaques received one oral dose of raltegravir, elvitegravir or dolutegravir alone or in combination with emtricitabine and tenofovir disoproxil fumarate followed by drug level measurements in blood and rectal and vaginal secretions. Antiviral activity was investigated in TZM-bl cells exposed to SHIV162p3 in the presence of rectal secretions collected from treated animals. Plasma drug concentrations with 50 mg/kg raltegravir or elvitegravir were within the range seen in humans receiving 400-800 mg of raltegravir or 800 mg of unboosted elvitegravir but lower than with 150 mg of elvitegravir boosted with cobicistat. AUC0-24 values for dolutegravir increased proportionally with the dose, with a calculated human-equivalent dose of 20 mg/kg. Elvitegravir showed the highest penetration in rectal and vaginal fluids despite the absence of pharmacological boosting, followed by raltegravir and dolutegravir. Rectal secretions collected at 24 h from treated macaques blocked infection of TZM-bl cells by 50% at dilutions of 1/1000 (raltegravir), 1/800 (dolutegravir) and >1/30 000 (elvitegravir). We defined macaque doses of HIV integrase inhibitors that recapitulate human clinical doses, which will facilitate efficacy and dose escalation studies in macaques. High and sustained drug concentrations and activity in mucosal secretions suggest that integrase inhibitors are promising candidates for HIV prevention. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Partial protection against multiple RT-SHIV162P3 vaginal challenge of rhesus macaques by a silicone elastomer vaginal ring releasing the NNRTI MC1220.

PubMed

Fetherston, Susan M; Geer, Leslie; Veazey, Ronald S; Goldman, Laurie; Murphy, Diarmaid J; Ketas, Thomas J; Klasse, Per Johan; Blois, Sylvain; La Colla, Paolo; Moore, John P; Malcolm, R Karl

2013-02-01

The non-nucleoside reverse transcriptase inhibitor MC1220 has potent in vitro activity against HIV type 1 (HIV-1). A liposome gel formulation of MC1220 has previously been reported to partially protect rhesus macaques against vaginal challenge with a simian HIV (SHIV). Here, we describe the pre-clinical development of an MC1220-releasing silicone elastomer vaginal ring (SEVR), including pharmacokinetic (PK) and efficacy studies in macaques. In vitro release studies were conducted on SEVRs loaded with 400 mg of MC1220, using simulated vaginal fluid (SVF, n = 4) and 1 : 1 isopropanol/water (IPA/H(2)O, n = 4) as release media. For PK evaluation, SEVRs were inserted into adult female macaques (n = 6) for 30 days. Following a 1 week washout period, fresh rings were placed in the same animals, which were then challenged vaginally with RT-SHIV162P3 once weekly for 4 weeks. SEVRs released 1.66 and 101 mg of MC1220 into SVF and IPA/H(2)O, respectively, over 30 days, the differential reflecting the low aqueous solubility of the drug. In macaque PK studies, MC1220 was consistently detected in vaginal fluid (peak 845 ng/mL) and plasma (peak 0.91 ng/mL). Kaplan-Meier analysis over 9 weeks showed significantly lower infection rates for animals given MC1220-containing SEVRs than placebo rings (hazard ratio 0.20, P = 0.0037). An MC1220-releasing SEVR partially protected macaques from vaginal challenge. Such ring devices are a practical method for providing sustained, coitally independent protection against vaginal exposure to HIV-1.

Sequence variation in the env gene of simian immunodeficiency virus recovered from immunized macaques is predominantly in the V1 region.

PubMed

Almond, N; Jenkins, A; Heath, A B; Kitchin, P

1993-05-01

Three cynomolgus macaques were immunized with recombinant envelope protein preparations derived from simian immunodeficiency virus (SIV). Although humoral and cellular responses were elicited by the immunization regime, all macaques became infected upon challenge with 10 MID50 of the 11/88 virus challenge stock of SIVmac251-32H. The polymerase chain reaction was used to amplify proviral SIV gp120 sequences present in the blood of both immunized and control macaques at 2 months post-infection. A comparison of the predominant sequences found in the region from V2 to V5 of gp120 failed to differentiate provirus recovered from either immunized or control animals. A detailed investigation of sequences obtained from the hypervariable V1 region identified a mixture of sequences in both immunized and control macaques. Some sequences were identical to those previously detected in the virus challenge stock, whereas others had not been detected previously. Phenogram analysis of the new V1 sequences found in immunized animals revealed that they were quite distinct from those from the virus challenge stock and that they included alterations to potential N-linked glycosylation sites. In contrast, new sequence variants recovered from the control animals were closely related to sequences from the virus challenge stock. The difference in diversity of new V1 sequences recovered from immunized and control macaques was highly significant (P < 0.001). Thus, the presence of pre-existing immune responses to SIV envelope protein is associated with greater genetic change in the V1 region of gp120. These data are discussed in relation to the epitopes of SIV gp120 that may confer protection from in vivo challenge.

The role of anthropic, ecological, and social factors in sleeping site choice by long-tailed macaques (Macaca fascicularis).

PubMed

Brotcorne, Fany; Maslarov, Cindy; Wandia, I Nengah; Fuentes, Agustin; Beudels-Jamar, Roseline C; Huynen, Marie-Claude

2014-12-01

When choosing their sleeping sites, primates make adaptive trade-offs between various biotic and abiotic constraints. In human-modified environments, anthropic factors may play a role. We assessed the influence of ecological (predation), social (intergroup competition), and anthropic (proximity to human settlements) factors in sleeping site choice by long-tailed macaques (Macaca fascicularis) occupying a habitat at the interface of natural forests and human-modified zones in Bali Barat National Park, Indonesia. Over the course of 56 nights, we collected data relating to physical features of sleeping trees, patterns of the use of sleeping sites within the home range, pre-sleep behavior, diurnal ranging patterns and availability of natural and human food. Overall, the macaques used 17 sleeping sites with 37 sleeping trees. When the monkeys slept in forest zones, they selected sleeping trees that had larger trunks but were not significantly taller than surrounding trees. Though the macaques rarely re-used sleeping sites on consecutive nights, they frequently re-used four sites over the study period. The group favored sleeping within the core area of its home range, despite the occurrence of frequent agonistic intergroup encounters there. Macaques preferentially selected sleeping trees located within or near human-modified zones, especially when human food was abundant and natural food was scarce. These results partially support the hypothesis that long-tailed macaques choose their sleeping sites to avoid predation; proximity to human settlements appears to be the primary factor influencing sleeping site choice in this primate species. Our results reflect the strong influence that anthropic factors have on primates, which subsist in increasingly human-dominated landscapes. © 2014 Wiley Periodicals, Inc.

Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251.

PubMed

Andrews, Chasity D; Bernard, Leslie St; Poon, Amanda Yee; Mohri, Hiroshi; Gettie, Natanya; Spreen, William R; Gettie, Agegnehu; Russell-Lodrigue, Kasi; Blanchard, James; Hong, Zhi; Ho, David D; Markowitz, Martin

2017-02-20

We evaluated the effectiveness of cabotegravir (CAB; GSK1265744 or GSK744) long acting as preexposure prophylaxis (PrEP) against intravenous simian immunodeficiency virus (SIV) challenge in a model that mimics blood transfusions based on the per-act probability of infection. CAB long acting is an integrase strand transfer inhibitor formulated as a 200 mg/ml injectable nanoparticle suspension that is an effective PrEP agent against rectal and vaginal simian/human immunodeficiency virus transmission in macaques. Three groups of rhesus macaques (n = 8 per group) were injected intramuscularly with CAB long acting and challenged intravenously with 17 animal infectious dose 50% SIVmac251 on week 2. Group 1 was injected with 50 mg/kg on week 0 and 4 to evaluate the protective efficacy of the CAB long-acting dose used in macaque studies mimicking sexual transmission. Group 2 was injected with 50 mg/kg on week 0 to evaluate the necessity of the second injection of CAB long acting for protection against intravenous challenge. Group 3 was injected with 25 mg/kg on week 0 and 50 mg/kg on week 4 to correlate CAB plasma concentrations at the time of challenge with protection. Five additional macaques remained untreated as controls. CAB long acting was highly protective with 21 of the 24 CAB long-acting-treated macaques remaining aviremic, resulting in 88% protection. The plasma CAB concentration at the time of virus challenge appeared to be more important for protection than sustaining therapeutic plasma concentrations with the second CAB long acting injection. These results support the clinical investigation of CAB long acting as PrEP in people who inject drugs.

Lentiviral infection of rhesus macaques causes long-term injury to cortical and hippocampal projections of prostaglandin-expressing cholinergic basal forebrain neurons.

PubMed

Depboylu, Candan; Weihe, Eberhard; Eiden, Lee E

2012-01-01

The simian immunodeficiency virus (SIV) macaque model resembles human immunodeficiency virus-acquired immunodeficiency syndrome (AIDS) and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limiting enzymes for prostaglandin synthesis, cyclooxygenase isotypes 1 and 2 (COX1 and COX2) in the brains of SIV-infected macaques with or without encephalitis and antiretroviral therapy and uninfected controls.Cyclooxygenase isotype 1, but not COX2, was coexpressed with markers of cholinergic phenotype, that is, choline acetyltransferase and vesicular acetylcholine transporter (VAChT), in basal forebrain neurons of monkey, as well as human, brain. Cyclooxygenase isotype 1 was decreased in basal forebrain neurons in macaques with AIDS versus uninfected and asymptomatic SIV-infected macaques. The VAChT-positive fiber density was reduced in frontal, parietal, and hippocampal-entorhinal cortex. Although brain SIV burden and associated COX1- and COX2-positive mononuclear and endothelial inflammatory reactions were mostly reversed in AIDS-diseased macaques that received 6-chloro-2',3'-dideoxyguanosine treatment, decreased VAChT-positive terminal density and reduced cholinergic COX1 expression were not. Thus, COX1 expression is a feature of primate cholinergic basal forebrain neurons; it may be functionally important and a critical biomarker of cholinergic dysregulation accompanying lentiviral encephalopathy. These results further imply that insufficiently prompt initiation of antiretroviral therapy in lentiviral infection may lead to neurostructurally unremarkable but neurochemically prominent irreversible brain damage.

Primates, Provisioning and Plants: Impacts of Human Cultural Behaviours on Primate Ecological Functions.

PubMed

Sengupta, Asmita; McConkey, Kim R; Radhakrishna, Sindhu

2015-01-01

Human provisioning of wildlife with food is a widespread global practice that occurs in multiple socio-cultural circumstances. Provisioning may indirectly alter ecosystem functioning through changes in the eco-ethology of animals, but few studies have quantified this aspect. Provisioning of primates by humans is known to impact their activity budgets, diets and ranging patterns. Primates are also keystone species in tropical forests through their role as seed dispersers; yet there is no information on how provisioning might affect primate ecological functions. The rhesus macaque is a major human-commensal species but is also an important seed disperser in the wild. In this study, we investigated the potential impacts of provisioning on the role of rhesus macaques as seed dispersers in the Buxa Tiger Reserve, India. We studied a troop of macaques which were provisioned for a part of the year and were dependent on natural resources for the rest. We observed feeding behaviour, seed handling techniques and ranging patterns of the macaques and monitored availability of wild fruits. Irrespective of fruit availability, frugivory and seed dispersal activities decreased when the macaques were provisioned. Provisioned macaques also had shortened daily ranges implying shorter dispersal distances. Finally, during provisioning periods, seeds were deposited on tarmac roads that were unconducive for germination. Provisioning promotes human-primate conflict, as commensal primates are often involved in aggressive encounters with humans over resources, leading to negative consequences for both parties involved. Preventing or curbing provisioning is not an easy task as feeding wild animals is a socio-cultural tradition across much of South and South-East Asia, including India. We recommend the initiation of literacy programmes that educate lay citizens about the ill-effects of provisioning and strongly caution them against the practice.

Analysis of a library of macaque nuclear mitochondrial sequences confirms macaque origin of divergent sequences from old oral polio vaccine samples.

PubMed

Vartanian, Jean-Pierre; Wain-Hobson, Simon

2002-05-28

Nuclear mtDNA sequences (numts) are a widespread family of paralogs evolving as pseudogenes in chromosomal DNA [Zhang, D. E. & Hewitt, G. M. (1996) TREE 11, 247-251 and Bensasson, D., Zhang, D., Hartl, D. L. & Hewitt, G. M. (2001) TREE 16, 314-321]. When trying to identify the species origin of an unknown DNA sample by way of an mtDNA locus, PCR may amplify both mtDNA and numts. Indeed, occasionally numts dominate confounding attempts at species identification [Bensasson, D., Zhang, D. X. & Hewitt, G. M. (2000) Mol. Biol. Evol. 17, 406-415; Wallace, D. C., et al. (1997) Proc. Natl. Acad. Sci. USA 94, 14900-14905]. Rhesus and cynomolgus macaque mtDNA haplotypes were identified in a study of oral polio vaccine samples dating from the late 1950s [Blancou, P., et al. (2001) Nature (London) 410, 1045-1046]. They were accompanied by a number of putative numts. To confirm that these putative numts were of macaque origin, a library of numts corresponding to a small segment of 12S rDNA locus has been made by using DNA from a Chinese rhesus macaque. A broad distribution was found with up to 30% sequence variation. Phylogenetic analysis showed that the evolutionary trajectories of numts and bona fide mtDNA haplotypes do not overlap with the signal exception of the host species; mtDNA fragments are continually crossing over into the germ line. In the case of divergent mtDNA sequences from old oral polio vaccine samples [Blancou, P., et al. (2001) Nature (London) 410, 1045-1046], all were closely related to numts in the Chinese macaque library.

Macaques at the margins: the biogeography and extinction of Macaca sylvanus in Europe

NASA Astrophysics Data System (ADS)

Elton, Sarah; O'Regan, Hannah J.

2014-07-01

The genus Macaca (Primates: Cercopithecidae) originated in Africa, dispersed into Europe in the Late Miocene and resided there until the Late Pleistocene. In this contribution, we provide an overview of the evolutionary history of Macaca in Europe, putting it into context with the wider late Miocene, Pliocene and Pleistocene European monkey fossil record (also comprising Mesopithecus, Paradolichopithecus, Dolichopithecus and Theropithecus). The Pliocene and Pleistocene European Macaca fossil material is largely regarded as Macaca sylvanus, the same species as the extant Barbary macaque in North Africa. The M. sylvanus specimens found at West Runton in Norfolk (53°N) during the Middle Pleistocene are among the most northerly euprimates ever discovered. Our simple time-budget model indicates that short winter day lengths would have imposed a significant constraint on activity at such relatively high latitudes, so macaque populations in Britain may have been at the limit of their ecological tolerance. Two basic models using climatic and topographic data for the Last Interglacial and the Last Glacial Maximum alongside Middle and Late Pleistocene fossil distributions indicate that much of Europe may have been suitable habitat for macaques. The models also indicate that areas of southern Europe in the present day have a climate that could support macaque populations. However, M. sylvanus became locally extinct in the Late Pleistocene, possibly at a similar time as the straight-tusked elephant, Palaeoloxodon antiquus, and narrow-nosed rhinoceros, Stephanorhinus hemitoechus. Its extinction may be related to vegetation change or increased predation from Homo, although other factors (such as stochastic factors occurring as a result of small population sizes) cannot be ruled out. Notwithstanding the cause of extinction, the European macaque may thus be a previously overlooked member of the Late Pleistocene faunal turnover.

Sex and rank affect how infant rhesus macaques look at faces

PubMed Central

Paukner, Annika; Slonecker, Emily M.; Murphy, Ashley M.; Wooddell, Lauren J.; Dettmer, Amanda M.

2017-01-01

We investigated how differences in infant sex and mothers’ dominance status affect infant rhesus macaques’ (Macaca mulatta) interest in visually exploring emotional facial expressions. Thirty-eight infants were presented with animated avatars of macaque facial expressions during the first month of life. Sons of high-ranking mothers looked more at faces, especially the eye region, than sons of low-ranking mothers, but no difference in looking duration was found for daughters. Males looked significantly more at eyes than females, but this effect was reversed in infants who were reared without mothers in a primate nursery facility. In addition, in mother-infant interactions, mothers of sons were more likely to gaze at their infant’s face compared to mothers of daughters. Combined with previous research indicating that rhesus macaque mothers interact differently with infants based on their own rank and infant’s sex, these results support the view that social experiences shape early face preferences in rhesus macaques. PMID:29165801

A structural comparison of female-male and female-female mounting in Japanese macaques (Macaca fuscata).

PubMed

Ottenheimer Carrier, Lydia; Leca, Jean-Baptiste; Pellis, Sergio; Vasey, Paul L

2015-10-01

In certain populations, female Japanese macaques (Macaca fuscata) mount both males and females. Vasey (2007) proposed that female-female sexual mounting in Japanese macaques may be a neutral evolutionary by-product of a purported adaptation, namely, female-male mounting. In this study, we aim to further examine the proposed link between female-male and female-female mounting in Japanese macaques by comparing the structural characteristics that define both forms of mounting. We do so using Eshkol-Wachman Movement Notation (EWMN), a globographic reference system that can be used to describe the position of body segments. No significant differences were observed in the female mounters' positioning of eight different body segments (i.e., lower torso, mid-torso, upper torso, upper arm, lower arm, upper leg, lower leg, and foot) during female-male and female-female mounting. This finding lends support to the conclusion that female-female and female-male mounting are structurally, and thus, evolutionarily, related. Copyright © 2015 Elsevier B.V. All rights reserved.

Surface-based atlases of cerebellar cortex in the human, macaque, and mouse.

PubMed

Van Essen, David C

2002-12-01

This study describes surface reconstructions and associated flat maps that represent the highly convoluted shape of cerebellar cortex in three species: human, macaque, and mouse. The reconstructions were based on high-resolution structural MRI data obtained from other laboratories. The surface areas determined for the fiducial reconstructions are about 600 cm(2) for the human, 60 cm(2) for the macaque, and 0.8 cm(2) for the mouse. As expected from the ribbon-like pattern of cerebellar folding, the cerebellar flat maps are elongated along the axis parallel to the midline. However, the degree of elongation varies markedly across species. The macaque flat map is many times longer than its mean width, whereas the mouse flat map is only slightly elongated and the human map is intermediate in its aspect ratio. These cerebellar atlases, along with associated software for visualization and for mapping experimental data onto the atlas, are freely available to the neuroscience community (see http:/brainmap.wustl.edu).

Comparison of the vaginal environment in rhesus and cynomolgus macaques pre- and post-lactobacillus colonization.

PubMed

Daggett, Gregory J; Zhao, Chunxia; Connor-Stroud, Fawn; Oviedo-Moreno, Patricia; Moon, Hojin; Cho, Michael W; Moench, Thomas; Anderson, Deborah J; Villinger, Francois

2017-10-01

Rhesus and cynomologus macaques are valuable animal models for the study of human immunodeficiency virus (HIV) prevention strategies. However, for such studies focused on the vaginal route of infection, differences in vaginal environment may have deterministic impact on the outcome of such prevention, providing the rationale for this study. We tested the vaginal environment of rhesus and cynomolgus macaques longitudinally to characterize the normal microflora based on Nugent scores and pH. This evaluation was extended after colonization of the vaginal space with Lactobacilli in an effort to recreate NHP models representing the healthy human vaginal environment. Nugent scores and pH differed significantly between species, although data from both species were suggestive of stable bacterial vaginosis. Colonization with Lactobacilli was successful in both species leading to lower Nugent score and pH, although rhesus macaques appeared better able to sustain Lactobacillus spp over time. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Roles of Dopamine D2 Receptor in the Social Hierarchy of Rodents and Primates.

PubMed

Yamaguchi, Yoshie; Lee, Young-A; Kato, Akemi; Jas, Emanuel; Goto, Yukiori

2017-02-24

Dopamine (DA) plays significant roles in regulation of social behavior. In social groups of humans and other animals, social hierarchy exists, which is determined by several behavioral characteristics such as aggression and impulsivity as well as social affiliations. In this study, we investigated the effects of pharmacological blockade of DA D2 receptor on social hierarchy of Japanese macaque and mouse social groups. We found acute administration of the D2 antagonist, sulpiride, in socially housed Japanese macaques attenuated social dominance when the drug was given to high social class macaques. A similar attenuation of social dominance was observed in high social class mice with D2 antagonist administration. In contrast, D2 antagonist administration in low social class macaque resulted in more stable social hierarchy of the group, whereas such effect was not observed in mouse social group. These results suggest that D2 receptor signaling may play important roles in establishment and maintenance of social hierarchy in social groups of several species of animals.

The Roles of Dopamine D2 Receptor in the Social Hierarchy of Rodents and Primates

PubMed Central

Yamaguchi, Yoshie; Lee, Young-A.; Kato, Akemi; Jas, Emanuel; Goto, Yukiori

2017-01-01

Dopamine (DA) plays significant roles in regulation of social behavior. In social groups of humans and other animals, social hierarchy exists, which is determined by several behavioral characteristics such as aggression and impulsivity as well as social affiliations. In this study, we investigated the effects of pharmacological blockade of DA D2 receptor on social hierarchy of Japanese macaque and mouse social groups. We found acute administration of the D2 antagonist, sulpiride, in socially housed Japanese macaques attenuated social dominance when the drug was given to high social class macaques. A similar attenuation of social dominance was observed in high social class mice with D2 antagonist administration. In contrast, D2 antagonist administration in low social class macaque resulted in more stable social hierarchy of the group, whereas such effect was not observed in mouse social group. These results suggest that D2 receptor signaling may play important roles in establishment and maintenance of social hierarchy in social groups of several species of animals. PMID:28233850

Pigeon paramyxovirus type 1 from a fatal human case induces pneumonia in experimentally infected cynomolgus macaques (Macaca fascicularis).

PubMed

Kuiken, Thijs; Buijs, Pascal; van Run, Peter; van Amerongen, Geert; Koopmans, Marion; van den Hoogen, Bernadette

2017-11-21

Although avian paramyxovirus type 1 is known to cause mild transient conjunctivitis in human beings, there are two recent reports of fatal respiratory disease in immunocompromised human patients infected with the pigeon lineage of the virus (PPMV-1). In order to evaluate the potential of PPMV-1 to cause respiratory tract disease, we inoculated a PPMV-1 isolate (hPPMV-1/Netherlands/579/2003) from an immunocompromised human patient into three healthy cynomolgus macaques (Macaca fascicularis) and examined them by clinical, virological, and pathological assays. In all three macaques, PPMV-1 replication was restricted to the respiratory tract and caused pulmonary consolidation affecting up to 30% of the lung surface. Both alveolar and bronchiolar epithelial cells expressed viral antigen, which co-localized with areas of diffuse alveolar damage. The results of this study demonstrate that PPMV-1 is a primary respiratory pathogen in cynomolgus macaques, and support the conclusion that PPMV-1 may cause fatal respiratory disease in immunocompromised human patients.

Fetal demise and failed antibody therapy during Zika virus infection of pregnant macaques.

PubMed

Magnani, Diogo M; Rogers, Thomas F; Maness, Nicholas J; Grubaugh, Nathan D; Beutler, Nathan; Bailey, Varian K; Gonzalez-Nieto, Lucas; Gutman, Martin J; Pedreño-Lopez, Núria; Kwal, Jaclyn M; Ricciardi, Michael J; Myers, Tereance A; Julander, Justin G; Bohm, Rudolf P; Gilbert, Margaret H; Schiro, Faith; Aye, Pyone P; Blair, Robert V; Martins, Mauricio A; Falkenstein, Kathrine P; Kaur, Amitinder; Curry, Christine L; Kallas, Esper G; Desrosiers, Ronald C; Goldschmidt-Clermont, Pascal J; Whitehead, Stephen S; Andersen, Kristian G; Bonaldo, Myrna C; Lackner, Andrew A; Panganiban, Antonito T; Burton, Dennis R; Watkins, David I

2018-04-24

Zika virus (ZIKV) infection of pregnant women is associated with pathologic complications of fetal development. Here, we infect pregnant rhesus macaques (Macaca mulatta) with a minimally passaged ZIKV isolate from Rio de Janeiro, where a high rate of fetal development complications was observed. The infection of pregnant macaques with this virus results in maternal viremia, virus crossing into the amniotic fluid (AF), and in utero fetal deaths. We also treated three additional ZIKV-infected pregnant macaques with a cocktail of ZIKV-neutralizing human monoclonal antibodies (nmAbs) at peak viremia. While the nmAbs can be effective in clearing the virus from the maternal sera of treated monkeys, it is not sufficient to clear ZIKV from AF. Our report suggests that ZIKV from Brazil causes fetal demise in non-human primates (NHPs) without additional mutations or confounding co-factors. Treatment with a neutralizing anti-ZIKV nmAb cocktail is insufficient to fully stop vertical transmission.

Process Versus Product in Social Learning: Comparative Diffusion Tensor Imaging of Neural Systems for Action Execution–Observation Matching in Macaques, Chimpanzees, and Humans

PubMed Central

Hecht, Erin E.; Gutman, David A.; Preuss, Todd M.; Sanchez, Mar M.; Parr, Lisa A.; Rilling, James K.

2013-01-01

Social learning varies among primate species. Macaques only copy the product of observed actions, or emulate, while humans and chimpanzees also copy the process, or imitate. In humans, imitation is linked to the mirror system. Here we compare mirror system connectivity across these species using diffusion tensor imaging. In macaques and chimpanzees, the preponderance of this circuitry consists of frontal–temporal connections via the extreme/external capsules. In contrast, humans have more substantial temporal–parietal and frontal–parietal connections via the middle/inferior longitudinal fasciculi and the third branch of the superior longitudinal fasciculus. In chimpanzees and humans, but not in macaques, this circuitry includes connections with inferior temporal cortex. In humans alone, connections with superior parietal cortex were also detected. We suggest a model linking species differences in mirror system connectivity and responsivity with species differences in behavior, including adaptations for imitation and social learning of tool use. PMID:22539611

Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in newborn macaques

PubMed Central

Hessell, Ann J.; Jaworski, J. Pablo; Epson, Erin; Matsuda, Kenta; Pandey, Shilpi; Kahl, Christoph; Reed, Jason; Sutton, William F.; Hammond, Katherine B.; Cheever, Tracy A.; Barnette, Philip T.; Legasse, Alfred W.; Planer, Shannon; Stanton, Jeffrey J.; Pegu, Amarendra; Chen, Xuejun; Wang, Keyun; Siess, Don; Burke, David; Park, Byung S.; Axthelm, Michael K.; Lewis, Anne; Hirsch, Vanessa M.; Graham, Barney S.; Mascola, John R.; Sacha, Jonah B.; Haigwood, Nancy L.

2016-01-01

Prevention of mother to child transmission (MTCT) of HIV remains a major objective where antenatal care is not readily accessible. We tested anti-HIV-1 human neutralizing monoclonal antibodies (NmAb) as post-exposure therapy in an infant macaque model for intrapartum MTCT. One-month-old rhesus macaques were inoculated orally with SHIVSF162P3. On days 1, 4, 7, and 10 after virus exposure, we injected animals subcutaneously with NmAbs and quantified systemic distribution of NmAbs in multiple tissues within 24 h following administration. Replicating virus was found in multiple tissues by day 1 in animals without treatment. All NmAb-treated macaques were free of virus in blood and tissues at 6 months post-exposure. We detected no anti-SHIV T cell responses in blood or tissues at necropsy, and no virus emerged following CD8+ T cell depletion. These results suggest early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs. PMID:26998834

A simian hemorrhagic fever virus isolate from persistently infected baboons efficiently induces hemorrhagic fever disease in Japanese macaques

PubMed Central

Vatter, Heather A.; Donaldson, Eric F.; Huynh, Jeremy; Rawlings, Stephanie; Manoharan, Minsha; Legasse, Alfred; Planer, Shannon; Dickerson, Mary F.; Lewis, Anne D.; Colgin, Lois M.A.; Axthelm, Michael K.; Pecotte, Jerilyn K.; Baric, Ralph S.; Wong, Scott W.; Brinton, Margo A.

2014-01-01

Simian hemorrhagic fever virus is an arterivirus that naturally infects species of African nonhuman primates causing acute or persistent asymptomatic infections. Although it was previously estimated that 1% of baboons are SHFV-positive, more than 10% of wild-caught and captive-bred baboons tested were SHFV positive and the infections persisted for more than 10 years with detectable virus in the blood (100–1000 genomes/ml). The sequences of two baboon SHFV isolates that were amplified by a single passage in primary macaque macrophages showed a very high degree of identity to each other as well as to the genome of SHFV-LVR, a laboratory strain isolated in the 1960s. Infection of Japanese macaques with 100 PFU of a baboon isolate consistently produced high level viremia, pro-inflammatory cytokines, elevated tissue factor levels and clinical signs indicating coagulation defects. The baboon virus isolate provides a reliable BSL2 model of viral hemorrhagic fever disease in macaques. PMID:25463617

A simian hemorrhagic fever virus isolate from persistently infected baboons efficiently induces hemorrhagic fever disease in Japanese macaques.

PubMed

Vatter, Heather A; Donaldson, Eric F; Huynh, Jeremy; Rawlings, Stephanie; Manoharan, Minsha; Legasse, Alfred; Planer, Shannon; Dickerson, Mary F; Lewis, Anne D; Colgin, Lois M A; Axthelm, Michael K; Pecotte, Jerilyn K; Baric, Ralph S; Wong, Scott W; Brinton, Margo A

2015-01-01

Simian hemorrhagic fever virus is an arterivirus that naturally infects species of African nonhuman primates causing acute or persistent asymptomatic infections. Although it was previously estimated that 1% of baboons are SHFV-positive, more than 10% of wild-caught and captive-bred baboons tested were SHFV positive and the infections persisted for more than 10 years with detectable virus in the blood (100-1000 genomes/ml). The sequences of two baboon SHFV isolates that were amplified by a single passage in primary macaque macrophages had a high degree of identity to each other as well as to the genome of SHFV-LVR, a laboratory strain isolated in the 1960s. Infection of Japanese macaques with 100PFU of a baboon isolate consistently produced high level viremia, pro-inflammatory cytokines, elevated tissue factor levels and clinical signs indicating coagulation defects. The baboon virus isolate provides a reliable BSL2 model of viral hemorrhagic fever disease in macaques. Copyright © 2014 Elsevier Inc. All rights reserved.

Surface-based atlases of cerebellar cortex in the human, macaque, and mouse

NASA Technical Reports Server (NTRS)

Van Essen, David C.

2002-01-01

This study describes surface reconstructions and associated flat maps that represent the highly convoluted shape of cerebellar cortex in three species: human, macaque, and mouse. The reconstructions were based on high-resolution structural MRI data obtained from other laboratories. The surface areas determined for the fiducial reconstructions are about 600 cm(2) for the human, 60 cm(2) for the macaque, and 0.8 cm(2) for the mouse. As expected from the ribbon-like pattern of cerebellar folding, the cerebellar flat maps are elongated along the axis parallel to the midline. However, the degree of elongation varies markedly across species. The macaque flat map is many times longer than its mean width, whereas the mouse flat map is only slightly elongated and the human map is intermediate in its aspect ratio. These cerebellar atlases, along with associated software for visualization and for mapping experimental data onto the atlas, are freely available to the neuroscience community (see http:/brainmap.wustl.edu).

Alpha-beta and gamma rhythms subserve feedback and feedforward influences among human visual cortical areas

PubMed Central

Michalareas, Georgios; Vezoli, Julien; van Pelt, Stan; Schoffelen, Jan-Mathijs; Kennedy, Henry; Fries, Pascal

2016-01-01

Primate visual cortex is hierarchically organized. Bottom-up and top-down influences are exerted through distinct frequency channels, as was recently revealed in macaques by correlating inter-areal influences with laminar anatomical projection patterns. Because this anatomical data cannot be obtained in human subjects, we selected seven homologous macaque and human visual areas, and correlated the macaque laminar projection patterns to human inter-areal directed influences as measured with magnetoencephalography. We show that influences along feedforward projections predominate in the gamma band, whereas influences along feedback projections predominate in the alpha-beta band. Rhythmic inter-areal influences constrain a functional hierarchy of the seven homologous human visual areas that is in close agreement with the respective macaque anatomical hierarchy. Rhythmic influences allow an extension of the hierarchy to 26 human visual areas including uniquely human brain areas. Hierarchical levels of ventral and dorsal stream visual areas are differentially affected by inter-areal influences in the alpha-beta band. PMID:26777277

Hematologic abnormalities associated with simian immunodeficieny virus (SIV) infection mimic those in HIV infection.

PubMed

Gill, Amy F; Ahsan, Muhammad H; Lackner, Andrew A; Veazey, Ronald S

2012-06-01

Studies of hematologic abnormalities in HIV-infected patients are confounded by a multitude of factors. A retrospective data analysis of simian immunodeficieny virus (SIV)-infected rhesus macaques (RM) of Indian origin was performed to determine the prevalence of hematologic abnormalities free of these confounds. Hematologic data from RM inoculated with SIV and without antiviral therapy were examined pre-inoculation, and throughout infection and the development of AIDS. Anemia, thrombocytopenia, lymphopenia, eosinophilia, and neutropenia all increased in prevalence with SIV infection. Significant increases in prevalence for both neutropenia and neutrophilia were also detected in SIV-infected macaques. SIV-infected macaques also had lower lymphocyte counts and increased prevalence of lymphopenia compared with non-infected subjects. The prevalence of eosinophilia was significantly increased during SIV infection. Concordance of hematologic abnormalities during SIV infection of macaques with similar changes in HIV infection of humans suggests that, like in HIV infection, hematologic abnormalities are major complications of SIV infection. © 2012 John Wiley & Sons A/S.

Selection of unadapted, pathogenic SHIVs encoding newly transmitted HIV-1 envelope proteins.

PubMed

Del Prete, Gregory Q; Ailers, Braiden; Moldt, Brian; Keele, Brandon F; Estes, Jacob D; Rodriguez, Anthony; Sampias, Marissa; Oswald, Kelli; Fast, Randy; Trubey, Charles M; Chertova, Elena; Smedley, Jeremy; LaBranche, Celia C; Montefiori, David C; Burton, Dennis R; Shaw, George M; Markowitz, Marty; Piatak, Michael; KewalRamani, Vineet N; Bieniasz, Paul D; Lifson, Jeffrey D; Hatziioannou, Theodora

2014-09-10

Infection of macaques with chimeric viruses based on SIVMAC but expressing the HIV-1 envelope (Env) glycoproteins (SHIVs) remains the most powerful model for evaluating prevention and therapeutic strategies against AIDS. Unfortunately, only a few SHIVs are currently available. Furthermore, their generation has required extensive adaptation of the HIV-1 Env sequences in macaques so they may not accurately represent HIV-1 Env proteins circulating in humans, potentially limiting their translational utility. We developed a strategy for generating large numbers of SHIV constructs expressing Env proteins from newly transmitted HIV-1 strains. By inoculating macaques with cocktails of multiple SHIV variants, we selected SHIVs that can replicate and cause AIDS-like disease in immunologically intact rhesus macaques without requiring animal-to-animal passage. One of these SHIVs could be transmitted mucosally. We demonstrate the utility of the SHIVs generated by this method for evaluating neutralizing antibody administration as a protection against mucosal SHIV challenge. Copyright © 2014 Elsevier Inc. All rights reserved.

Pharmacokinetics of a Novel, Transdermal Fentanyl Solution in Rhesus Macaques (Macaca mulatta)

PubMed Central

Salyards, Gregory W; Lemoy, Marie-Josee; Knych, Heather K; Hill, Ashley E; Christe, Kari L

2017-01-01

Rhesus macaques (Macaca mulatta) are the most commonly used NHP biomedical model and experience both research and clinical procedures requiring analgesia. Opioids are a mainstay of analgesic therapy. A novel, transdermal fentanyl solution (TFS) has been developed as a long-acting, single-administration topical opioid and was reported to provide at least 4 d of effective plasma concentrations in beagles (Canis familiaris). To evaluate the pharmacokinetic profile of TFS in healthy adult rhesus macaques, we used a 2-period, 2-treatment crossover study of a single topical administration of 1.3 (25) and 2.6 mg/kg (50 μL/kg) TFS. TFS was applied to the clipped dorsal skin of adult rhesus macaques (n = 6; 3 male, 3 female) under ketamine sedation (10 mg/kg IM). We hypothesized that TFS in rhesus macaques would provide at least 4 d of effective plasma concentrations (assumed to be ≥ 0.2 ng/mL, based on human studies). Plasma fentanyl concentrations were determined by liquid chromatography–tandem mass spectrometry before drug administration and at 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 60, 72, 96, 120, 144, 168, 240, 336, 408, and 504 h afterward. Noncompartmental pharmacokinetic analysis was performed. For each dose (1.3 and 2.6 mg/kg), respectively, the maximal plasma concentration was 1.95 ± 0.40 and 4.19 ± 0.69 ng/mL, occurring at 21.3 ± 4.1 and 30.7 ± 8.7 h; the AUC was 227.3 ± 31.7 and 447.0 ± 49.1 h/ng/mL, and the terminal elimination half-life was 93.7 ± 7.1 and 98.8 ± 5.4 h. No adverse effects were noted after drug administration at either dose. Macaques maintained plasma fentanyl concentrations of 0.2 ng/mL or greater for at least 7 d after 1.3 mg/kg and at least 10 d after 2.6 mg/kg topical administration of TFS. A single TFS dose may provide efficacious analgesia to rhesus macaques and reduce stress, discomfort, and risk to animals and personnel. PMID:28724494

Efferent-Mediated Responses in Vestibular Nerve Afferents of the Alert Macaque

PubMed Central

Sadeghi, Soroush G.; Goldberg, Jay M.; Minor, Lloyd B.; Cullen, Kathleen E.

2009-01-01

The peripheral vestibular organs have long been known to receive a bilateral efferent innervation from the brain stem. However, the functional role of the efferent vestibular system has remained elusive. In this study, we investigated efferent-mediated responses in vestibular afferents of alert behaving primates (macaque monkey). We found that efferent-mediated rotational responses could be obtained from vestibular nerve fibers innervating the semicircular canals after conventional afferent responses were nulled by placing the corresponding canal plane orthogonal to the plane of motion. Responses were type III, i.e., excitatory for rotational velocity trapezoids (peak velocity, 320°/s) in both directions of rotation, consistent with those previously reported in the decerebrate chinchilla. Responses consisted of both fast and slow components and were larger in irregular (∼10 spikes/s) than in regular afferents (∼2 spikes/s). Following unilateral labyrinthectomy (UL) on the side opposite the recording site, similar responses were obtained. To confirm the vestibular source of the efferent-mediated responses, the ipsilateral horizontal and posterior canals were plugged following the UL. Responses to high-velocity rotations were drastically reduced when the superior canal (SC), the only intact canal, was in its null position, compared with when the SC was pitched 50° upward from the null position. Our findings show that vestibular afferents in alert primates show efferent-mediated responses that are related to the discharge regularity of the afferent, are of vestibular origin, and can be the result of both afferent excitation and inhibition. PMID:19091917

Efferent-mediated responses in vestibular nerve afferents of the alert macaque.

PubMed

Sadeghi, Soroush G; Goldberg, Jay M; Minor, Lloyd B; Cullen, Kathleen E

2009-02-01

The peripheral vestibular organs have long been known to receive a bilateral efferent innervation from the brain stem. However, the functional role of the efferent vestibular system has remained elusive. In this study, we investigated efferent-mediated responses in vestibular afferents of alert behaving primates (macaque monkey). We found that efferent-mediated rotational responses could be obtained from vestibular nerve fibers innervating the semicircular canals after conventional afferent responses were nulled by placing the corresponding canal plane orthogonal to the plane of motion. Responses were type III, i.e., excitatory for rotational velocity trapezoids (peak velocity, 320 degrees/s) in both directions of rotation, consistent with those previously reported in the decerebrate chinchilla. Responses consisted of both fast and slow components and were larger in irregular (approximately 10 spikes/s) than in regular afferents (approximately 2 spikes/s). Following unilateral labyrinthectomy (UL) on the side opposite the recording site, similar responses were obtained. To confirm the vestibular source of the efferent-mediated responses, the ipsilateral horizontal and posterior canals were plugged following the UL. Responses to high-velocity rotations were drastically reduced when the superior canal (SC), the only intact canal, was in its null position, compared with when the SC was pitched 50 degrees upward from the null position. Our findings show that vestibular afferents in alert primates show efferent-mediated responses that are related to the discharge regularity of the afferent, are of vestibular origin, and can be the result of both afferent excitation and inhibition.

Innate immunity and HIV-1 infection.

PubMed

Lehner, T; Wang, Y; Whittall, T; Seidl, T

2011-04-01

HIV-1 is predominantly transmitted through mucosal tissues, targeting CD4(+)CCR5(+) T cells, 50% of which are destroyed within 2 weeks of infection. Conventional vaccination strategies have so far failed to prevent HIV-1 infection. Neither antibodies nor cytotoxic lymphocytes are capable of mounting a sufficiently rapid immune response to prevent early destruction of these cells. However, innate immunity is an early-response system, largely independent of prior encounter with a pathogen. Innate immunity can be classified into cellular, extracellular, and intracellular components, each of which is exemplified in this review by γδ T cells, CC chemokines, and APOBEC3G, respectively. First, γδ T cells are found predominantly in mucosal tissues and produce cytokines, CC chemokines, and antiviral factors. Second, the CC chemokines CCL-3, CCL-4, and CCL-5 can be upregulated by immunization of macaques with SIVgp120 and gag p27, and these can bind and downmodulate CCR5, thereby inhibiting HIV-1 entry into the host cells. Third, APOBEC3G is generated and maintained following rectal mucosal immunization in rhesus macaques for over 17 weeks, and the innate anti-SIV factor is generated by CD4(+)CD95(+)CCR7(-) effector memory T cells. Thus, innate anti-HIV-1 or SIV immunity can be linked with immune memory, mediated by CD4(+) T cells generating APOBEC3G. The multiple innate functions may mount an early anti-HIV-1 response and either prevent viral transmission or contain the virus until an effective adaptive immune response develops.

Critical Role for Monocytes/Macrophages in Rapid Progression to AIDS in Pediatric Simian Immunodeficiency Virus-Infected Rhesus Macaques.

PubMed

Sugimoto, Chie; Merino, Kristen M; Hasegawa, Atsuhiko; Wang, Xiaolei; Alvarez, Xavier A; Wakao, Hiroshi; Mori, Kazuyasu; Kim, Woong-Ki; Veazey, Ronald S; Didier, Elizabeth S; Kuroda, Marcelo J

2017-09-01

Infant humans and rhesus macaques infected with the human or simian immunodeficiency virus (HIV or SIV), respectively, express higher viral loads and progress more rapidly to AIDS than infected adults. Activated memory CD4 + T cells in intestinal tissues are major primary target cells for SIV/HIV infection, and massive depletion of these cells is considered a major cause of immunodeficiency. Monocytes and macrophages are important cells of innate immunity and also are targets of HIV/SIV infection. We reported previously that a high peripheral blood monocyte turnover rate was predictive for the onset of disease progression to AIDS in SIV-infected adult macaques. The purpose of this study was to determine if earlier or higher infection of monocytes/macrophages contributes to the more rapid progression to AIDS in infants. We observed that uninfected infant rhesus macaques exhibited higher physiologic baseline monocyte turnover than adults. Early after SIV infection, the monocyte turnover further increased, and it remained high during progression to AIDS. A high percentage of terminal deoxynucleotidyltransferase dUTP nick end label (TUNEL)-positive macrophages in the lymph nodes (LNs) and intestine corresponded with an increasing number of macrophages derived from circulating monocytes (bromodeoxyuridine positive [BrdU + ] CD163 + ), suggesting that the increased blood monocyte turnover was required to rapidly replenish destroyed tissue macrophages. Immunofluorescence analysis further demonstrated that macrophages were a significant portion of the virus-producing cells found in LNs, intestinal tissues, and lungs. The higher baseline monocyte turnover in infant macaques and subsequent macrophage damage by SIV infection may help explain the basis of more rapid disease progression to AIDS in infants. IMPORTANCE HIV infection progresses much more rapidly in pediatric cases than in adults; however, the mechanism for this difference is unclear. Using the rhesus macaque model, this work was performed to address why infants infected with SIV progress more quickly to AIDS than do adults. Earlier we reported that in adult rhesus macaques, increasing monocyte turnover reflected tissue macrophage damage by SIV and was predictive of terminal disease progression to AIDS. Here we report that uninfected infant rhesus macaques exhibited a higher physiological baseline monocyte turnover rate than adults. Furthermore, once infected with SIV, infants displayed further increased monocyte turnover that may have facilitated the accelerated progression to AIDS. These results support a role for monocytes and macrophages in the pathogenesis of SIV/HIV and begin to explain why infants are more prone to rapid disease progression. Copyright © 2017 American Society for Microbiology.

Critical Role for Monocytes/Macrophages in Rapid Progression to AIDS in Pediatric Simian Immunodeficiency Virus-Infected Rhesus Macaques

PubMed Central

Sugimoto, Chie; Merino, Kristen M.; Hasegawa, Atsuhiko; Wang, Xiaolei; Alvarez, Xavier A.; Wakao, Hiroshi; Kim, Woong-Ki; Veazey, Ronald S.; Didier, Elizabeth S.

2017-01-01

ABSTRACT Infant humans and rhesus macaques infected with the human or simian immunodeficiency virus (HIV or SIV), respectively, express higher viral loads and progress more rapidly to AIDS than infected adults. Activated memory CD4+ T cells in intestinal tissues are major primary target cells for SIV/HIV infection, and massive depletion of these cells is considered a major cause of immunodeficiency. Monocytes and macrophages are important cells of innate immunity and also are targets of HIV/SIV infection. We reported previously that a high peripheral blood monocyte turnover rate was predictive for the onset of disease progression to AIDS in SIV-infected adult macaques. The purpose of this study was to determine if earlier or higher infection of monocytes/macrophages contributes to the more rapid progression to AIDS in infants. We observed that uninfected infant rhesus macaques exhibited higher physiologic baseline monocyte turnover than adults. Early after SIV infection, the monocyte turnover further increased, and it remained high during progression to AIDS. A high percentage of terminal deoxynucleotidyltransferase dUTP nick end label (TUNEL)-positive macrophages in the lymph nodes (LNs) and intestine corresponded with an increasing number of macrophages derived from circulating monocytes (bromodeoxyuridine positive [BrdU+] CD163+), suggesting that the increased blood monocyte turnover was required to rapidly replenish destroyed tissue macrophages. Immunofluorescence analysis further demonstrated that macrophages were a significant portion of the virus-producing cells found in LNs, intestinal tissues, and lungs. The higher baseline monocyte turnover in infant macaques and subsequent macrophage damage by SIV infection may help explain the basis of more rapid disease progression to AIDS in infants. IMPORTANCE HIV infection progresses much more rapidly in pediatric cases than in adults; however, the mechanism for this difference is unclear. Using the rhesus macaque model, this work was performed to address why infants infected with SIV progress more quickly to AIDS than do adults. Earlier we reported that in adult rhesus macaques, increasing monocyte turnover reflected tissue macrophage damage by SIV and was predictive of terminal disease progression to AIDS. Here we report that uninfected infant rhesus macaques exhibited a higher physiological baseline monocyte turnover rate than adults. Furthermore, once infected with SIV, infants displayed further increased monocyte turnover that may have facilitated the accelerated progression to AIDS. These results support a role for monocytes and macrophages in the pathogenesis of SIV/HIV and begin to explain why infants are more prone to rapid disease progression. PMID:28566378

Prevalence of Entamoeba nuttalli infection in wild rhesus macaques in Nepal and characterization of the parasite isolates.

PubMed

Tachibana, Hiroshi; Yanagi, Tetsuo; Lama, Chamala; Pandey, Kishor; Feng, Meng; Kobayashi, Seiki; Sherchand, Jeevan B

2013-04-01

We have recently resurrected the name Entamoeba nuttalli Castellani, 1908 for a potentially virulent ameba isolate, P19-061405, obtained from a rhesus macaque in Kathmandu, Nepal. The ameba was morphologically indistinguishable from Entamoeba histolytica/Entamoeba dispar/Entamoeba moshkovskii, but located phylogenetically between E. histolytica and E. dispar. To evaluate the prevalence of E. nuttalli infection in wild rhesus macaques, 112 fecal samples were collected in four locations of the Kathmandu Valley. PCR analysis of DNA extracted from the feces showed positive rates of E. nuttalli, E. dispar, E. histolytica and E. moshkovskii of 51%, 12%, 0% and 0%, respectively. A total of 14 E. nuttalli isolates were obtained from four locations, of which 6 were established as axenic cultures. The sequences of the serine-rich protein gene of E. nuttalli isolates differed among four locations although no differences were found in the composition of sequence motifs. Isoenzyme pattern was analyzed in 8 isolates obtained from three locations. In hexokinase, the mobility of the slower migrating band was located between E. histolytica and E. dispar regardless of the culture conditions. These results demonstrate that E. nuttalli is highly prevalent in wild rhesus macaques in Nepal. Rhesus macaques appear to be one of the natural hosts and heterogeneity of the serine-rich protein gene might be useful for geographical typing of isolates. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Optimization of HIV-1 Envelope DNA Vaccine Candidates within Three Different Animal Models, Guinea Pigs, Rabbits and Cynomolgus Macaques.

PubMed

Borggren, Marie; Vinner, Lasse; Andresen, Betina Skovgaard; Grevstad, Berit; Repits, Johanna; Melchers, Mark; Elvang, Tara Laura; Sanders, Rogier W; Martinon, Frédéric; Dereuddre-Bosquet, Nathalie; Bowles, Emma Joanne; Stewart-Jones, Guillaume; Biswas, Priscilla; Scarlatti, Gabriella; Jansson, Marianne; Heyndrickx, Leo; Grand, Roger Le; Fomsgaard, Anders

2013-07-19

HIV-1 DNA vaccines have many advantageous features. Evaluation of HIV-1 vaccine candidates often starts in small animal models before macaque and human trials. Here, we selected and optimized DNA vaccine candidates through systematic testing in rabbits for the induction of broadly neutralizing antibodies (bNAb). We compared three different animal models: guinea pigs, rabbits and cynomolgus macaques. Envelope genes from the prototype isolate HIV-1 Bx08 and two elite neutralizers were included. Codon-optimized genes, encoded secreted gp140 or membrane bound gp150, were modified for expression of stabilized soluble trimer gene products, and delivered individually or mixed. Specific IgG after repeated i.d. inoculations with electroporation confirmed in vivo expression and immunogenicity. Evaluations of rabbits and guinea pigs displayed similar results. The superior DNA construct in rabbits was a trivalent mix of non-modified codon-optimized gp140 envelope genes. Despite NAb responses with some potency and breadth in guinea pigs and rabbits, the DNA vaccinated macaques displayed less bNAb activity. It was concluded that a trivalent mix of non-modified gp140 genes from rationally selected clinical isolates was, in this study, the best option to induce high and broad NAb in the rabbit model, but this optimization does not directly translate into similar responses in cynomolgus macaques.

Optimization of HIV-1 Envelope DNA Vaccine Candidates within Three Different Animal Models, Guinea Pigs, Rabbits and Cynomolgus Macaques

PubMed Central

Borggren, Marie; Vinner, Lasse; Andresen, Betina Skovgaard; Grevstad, Berit; Repits, Johanna; Melchers, Mark; Elvang, Tara Laura; Sanders, Rogier W; Martinon, Frédéric; Dereuddre-Bosquet, Nathalie; Bowles, Emma Joanne; Stewart-Jones, Guillaume; Biswas, Priscilla; Scarlatti, Gabriella; Jansson, Marianne; Heyndrickx, Leo; Le Grand, Roger; Fomsgaard, Anders

2013-01-01

HIV-1 DNA vaccines have many advantageous features. Evaluation of HIV-1 vaccine candidates often starts in small animal models before macaque and human trials. Here, we selected and optimized DNA vaccine candidates through systematic testing in rabbits for the induction of broadly neutralizing antibodies (bNAb). We compared three different animal models: guinea pigs, rabbits and cynomolgus macaques. Envelope genes from the prototype isolate HIV-1 Bx08 and two elite neutralizers were included. Codon-optimized genes, encoded secreted gp140 or membrane bound gp150, were modified for expression of stabilized soluble trimer gene products, and delivered individually or mixed. Specific IgG after repeated i.d. inoculations with electroporation confirmed in vivo expression and immunogenicity. Evaluations of rabbits and guinea pigs displayed similar results. The superior DNA construct in rabbits was a trivalent mix of non-modified codon-optimized gp140 envelope genes. Despite NAb responses with some potency and breadth in guinea pigs and rabbits, the DNA vaccinated macaques displayed less bNAb activity. It was concluded that a trivalent mix of non-modified gp140 genes from rationally selected clinical isolates was, in this study, the best option to induce high and broad NAb in the rabbit model, but this optimization does not directly translate into similar responses in cynomolgus macaques. PMID:26344115

Effects of Transportation on Antioxidant Status in Cynomolgus Macaques (Macaca fascicularis).

PubMed

Pan, Xueying; Lu, Liang; Zeng, Xiancheng; Chang, Yan; Hua, Xiuguo

2016-01-01

To evaluate the effects of transportation on oxidative stress in cynomolgus monkeys, we measured serum levels of reduced glutathione (GSH), malondialdehyde, and protein carbonyl (PC) and the activities of total antioxidant capacity (TAOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase in cynomolgus macaques before transportation (day 0), on the day of arrival (day 1), and on days 7, 14, and 21 after transportation. Compared with that on day 0, TAOC and catalase activities on days 1, 7, and 14 after transportation were significantly decreased, reached their nadirs on day 7, and increased thereafter to reach their pretransportation levels by day 21 after transportation. Compared with day 0 levels, mean SOD activity and GSH concentration were decreased significantly on day 1; they thereafter increased to reach their pretransportation measures by day 7 after transportation. In contrast, PC and malondialdehyde concentrations in serum and the activity of GSH-Px were increased on day 1 compared with day 0 and thereafter decreased to reach their pretransportation levels by day 14 after transportation. In summary, GSH, TAOC, catalase, and SOD levels decreased and malondialdehyde, PC, and GSH-Px concentrations increased in cynomolgus macaques after transportation. These results suggest that transportation might imbalance oxidant and antioxidant levels to create excess oxidative stress in cynomolgus macaques. Therefore, cynomolgus macaques should have at least 21 d to recover after transportation and regain their healthy status.

Septic arthritis due to moraxella osloensis in a rhesus macaque (Macaca mulatta).

PubMed

Wren, Melissa A; Caskey, John R; Liu, David X; Embers, Monica E

2013-01-01

A 5.5-y-old Chinese-origin female rhesus macaque (Macaca mulatta) presented for bilateral hindlimb lameness. The primate had been group-reared in an SPF breeding colony and was seronegative for Macacine herpesvirus 1, SIV, simian retrovirus type D, and simian T-lymphotropic virus. The macaque's previous medical history included multiple occasions of swelling in the left tarsus, and trauma to the right arm and bilateral hands. In addition, the macaque had experienced osteomyelitis of the left distal tibia and rupture of the right cranial cruciate ligament that had been surgically repaired. Abnormal physical examination findings on presentation included a thin body condition, mild dehydration, and bilaterally swollen stifles that were warm to the touch, with the right stifle more severely affected. Mild instability in the left stifle was noted, and decreased range of motion and muscle atrophy were present bilaterally. Hematologic findings included marked neutrophilia and lymphopenia and moderate anemia. Arthrocentesis and culture of joint fluid revealed Moraxella-like organisms. Treatment with enrofloxacin was initiated empirically and subsequently switched to cephalexin, which over time alleviated the joint swelling and inflammation. Definitive diagnosis of Moraxella osloensis septic arthritis was made through isolation of the organism and sequencing of the 16S rDNA region. To our knowledge, this report is the first description of Moraxella osloensis septic arthritis in a rhesus macaque.

Septic Arthritis Due to Moraxella osloensis in a Rhesus Macaque (Macaca mulatta)

PubMed Central

Wren, Melissa A; Caskey, John R; Liu, David X; Embers, Monica E

2013-01-01

A 5.5-y-old Chinese-origin female rhesus macaque (Macaca mulatta) presented for bilateral hindlimb lameness. The primate had been group-reared in an SPF breeding colony and was seronegative for Macacine herpesvirus 1, SIV, simian retrovirus type D, and simian T-lymphotropic virus. The macaque's previous medical history included multiple occasions of swelling in the left tarsus, and trauma to the right arm and bilateral hands. In addition, the macaque had experienced osteomyelitis of the left distal tibia and rupture of the right cranial cruciate ligament that had been surgically repaired. Abnormal physical examination findings on presentation included a thin body condition, mild dehydration, and bilaterally swollen stifles that were warm to the touch, with the right stifle more severely affected. Mild instability in the left stifle was noted, and decreased range of motion and muscle atrophy were present bilaterally. Hematologic findings included marked neutrophilia and lymphopenia and moderate anemia. Arthrocentesis and culture of joint fluid revealed Moraxella-like organisms. Treatment with enrofloxacin was initiated empirically and subsequently switched to cephalexin, which over time alleviated the joint swelling and inflammation. Definitive diagnosis of Moraxella osloensis septic arthritis was made through isolation of the organism and sequencing of the 16S rDNA region. To our knowledge, this report is the first description of Moraxella osloensis septic arthritis in a rhesus macaque. PMID:24326229

Lack of in vitro-in vivo correlation for a UC781-releasing vaginal ring in macaques.

PubMed

McConville, Christopher; Smith, James M; McCoy, Clare F; Srinivasan, Priya; Mitchell, James; Holder, Angela; Otten, Ron A; Butera, Salvatore; Doncel, Gustavo F; Friend, David R; Malcolm, R Karl

2015-02-01

This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside reverse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities considered sufficient to maintain vaginal fluid concentrations at levels 82-860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal transmission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median concentrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo-in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mechanism rather than the expected diffusion-controlled mechanism.

Complete Taiwanese Macaque (Macaca cyclopis) Mitochondrial Genome: Reference-Assisted de novo Assembly with Multiple k-mer Strategy.

PubMed

Huang, Yu-Feng; Midha, Mohit; Chen, Tzu-Han; Wang, Yu-Tai; Smith, David Glenn; Pei, Kurtis Jai-Chyi; Chiu, Kuo Ping

2015-01-01

The Taiwanese (Formosan) macaque (Macaca cyclopis) is the only nonhuman primate endemic to Taiwan. This primate species is valuable for evolutionary studies and as subjects in medical research. However, only partial fragments of the mitochondrial genome (mitogenome) of this primate species have been sequenced, not mentioning its nuclear genome. We employed next-generation sequencing to generate 2 x 90 bp paired-end reads, followed by reference-assisted de novo assembly with multiple k-mer strategy to characterize the M. cyclopis mitogenome. We compared the assembled mitogenome with that of other macaque species for phylogenetic analysis. Our results show that, the M. cyclopis mitogenome consists of 16,563 nucleotides encoding for 13 protein-coding genes, 2 ribosomal RNAs and 22 transfer RNAs. Phylogenetic analysis indicates that M. cyclopis is most closely related to M. mulatta lasiota (Chinese rhesus macaque), supporting the notion of Asia-continental origin of M. cyclopis proposed in previous studies based on partial mitochondrial sequences. Our work presents a novel approach for assembling a mitogenome that utilizes the capabilities of de novo genome assembly with assistance of a reference genome. The availability of the complete Taiwanese macaque mitogenome will facilitate the study of primate evolution and the characterization of genetic variations for the potential usage of this species as a non-human primate model for medical research.

Ranking network of a captive rhesus macaque society: a sophisticated corporative kingdom.

PubMed

Fushing, Hsieh; McAssey, Michael P; Beisner, Brianne; McCowan, Brenda

2011-03-15

We develop a three-step computing approach to explore a hierarchical ranking network for a society of captive rhesus macaques. The computed network is sufficiently informative to address the question: Is the ranking network for a rhesus macaque society more like a kingdom or a corporation? Our computations are based on a three-step approach. These steps are devised to deal with the tremendous challenges stemming from the transitivity of dominance as a necessary constraint on the ranking relations among all individual macaques, and the very high sampling heterogeneity in the behavioral conflict data. The first step simultaneously infers the ranking potentials among all network members, which requires accommodation of heterogeneous measurement error inherent in behavioral data. Our second step estimates the social rank for all individuals by minimizing the network-wide errors in the ranking potentials. The third step provides a way to compute confidence bounds for selected empirical features in the social ranking. We apply this approach to two sets of conflict data pertaining to two captive societies of adult rhesus macaques. The resultant ranking network for each society is found to be a sophisticated mixture of both a kingdom and a corporation. Also, for validation purposes, we reanalyze conflict data from twenty longhorn sheep and demonstrate that our three-step approach is capable of correctly computing a ranking network by eliminating all ranking error.

Effects of Transportation on Antioxidant Status in Cynomolgus Macaques (Macaca fascicularis)

PubMed Central

Pan, Xueying; Lu, Liang; Zeng, Xiancheng; Chang, Yan; Hua, Xiuguo

2016-01-01

To evaluate the effects of transportation on oxidative stress in cynomolgus monkeys, we measured serum levels of reduced glutathione (GSH), malondialdehyde, and protein carbonyl (PC) and the activities of total antioxidant capacity (TAOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase in cynomolgus macaques before transportation (day 0), on the day of arrival (day 1), and on days 7, 14, and 21 after transportation. Compared with that on day 0, TAOC and catalase activities on days 1, 7, and 14 after transportation were significantly decreased, reached their nadirs on day 7, and increased thereafter to reach their pretransportation levels by day 21 after transportation. Compared with day 0 levels, mean SOD activity and GSH concentration were decreased significantly on day 1; they thereafter increased to reach their pretransportation measures by day 7 after transportation. In contrast, PC and malondialdehyde concentrations in serum and the activity of GSH-Px were increased on day 1 compared with day 0 and thereafter decreased to reach their pretransportation levels by day 14 after transportation. In summary, GSH, TAOC, catalase, and SOD levels decreased and malondialdehyde, PC, and GSH-Px concentrations increased in cynomolgus macaques after transportation. These results suggest that transportation might imbalance oxidant and antioxidant levels to create excess oxidative stress in cynomolgus macaques. Therefore, cynomolgus macaques should have at least 21 d to recover after transportation and regain their healthy status. PMID:27657707

Use of ultrasound imaging for the diagnosis of abnormal uterine bleeding in the bonnet macaque ( Macaca radiata).

PubMed

Chaudhari, Uddhav K; Imran, M; Manjramkar, Dhananjay D; Metkari, Siddhanath M; Sable, Nilesh P; Gavhane, Dnyaneshwar S; Katkam, Rajendra R; Sachdeva, Geetanjali; Thakur, Meenakshi H; Kholkute, Sanjeeva D

2017-02-01

Ultrasound is a powerful, low-cost, non-invasive medical tool used by laboratory animal veterinarians for diagnostic imaging. Sonohysterography and transvaginal ultrasound are frequently used to assess uterine anomalies in women presenting with abnormal uterine bleeding (AUB). In the present study, we have evaluated the abdominal ultrasound of bonnet monkeys ( n = 8) showing spontaneous ovulatory ( n = 5) and anovulatory ( n = 3) AUB. The ovulatory ( n = 5) macaques showed cyclic AUB for 7-8 days. The anovulatory ( n = 3) macaques had irregular AUB with menstrual cycles of 40-45 days. The B-mode abdominal, colour Doppler and 3D ultrasound scans were performed during the proliferative phase of the menstrual cycle. Ultrasound examination revealed endometrial polyps in five macaques and endometrial hyperplasia in three animals. The width and length of endometrial polyps was around 0.5-1 cm (average 0.51 ± 0.23 cm × 0.96 ± 0.16 cm) with significant increase in endometrial thickness ( P < 0.0002). 3D ultrasound also showed a homogeneous mass in the uterine cavity and colour Doppler ultrasound showed increased vascularity in the endometrial polyps. Endometrial hyperplasia characteristically appeared as a thickened echogenic endometrium ( P < 0.0002). This study demonstrates the use of non-invasive ultrasound techniques in the diagnosis of AUB in macaques.

Developmental and Cross-Situational Stability in Infant Pigtailed Macaque Temperament

ERIC Educational Resources Information Center

Sussman, Adrienne; Ha, James

2011-01-01

We assessed developmental stability and context generalizability of temperament in pigtailed macaques ("Macaca nemestrina") from the University of Washington Infant Primate Research Lab. A principal components analysis condensed 6 behavioral measures into 2 components, interpreted as reactivity and boldness. Changes in these measures over the 1st…

Meningoencephalitis Due to Listeria monocytogenes in a Pregnant Rhesus Macaque (Macaca mulatta)

PubMed Central

Lemoy, Marie-Josee MF; Lopes, Danielle A; Reader, J Rachel; Westworth, Diccon R; Tarara, Ross P

2012-01-01

We here report a spontaneous case of meningoencephalitis due to Listeria monocytogenes in an adult primiparous rhesus macaque (Macaca mulatta) during an outbreak of listeriosis in an outdoor enclosure. Clinical signs included tremors, abnormal posture, and altered mental status. Hematology and analyses of cerebrospinal fluid were consistent with bacterial infection. Pure cultures of L. monocytogenes were recovered from the placenta–abortus, cerebrospinal fluid, and brain tissue. The macaque did not respond to treatment and was euthanized. Histopathologic examination of the brain revealed acute meningoencephalitis. This case represents an unusual clinical and pathologic presentation of listeriosis in a nonhuman primate in which the dam and fetus both were affected. PMID:23114049

Demonstration of vaginal colonization with GusA-expressing Lactobacillus jensenii following oral delivery in rhesus macaques

PubMed Central

Lagenaur, Laurel A; Lee, Peter P; Hamer, Dean H; Sanders-Beer, Brigitte E

2012-01-01

The vaginal microbiome, which harbors beneficial Lactobacillus strains, is believed to be a major host defense mechanism for preventing infections of the urogenital tract. It has been suggested that the gastrointestinal tract serves as a reservoir for lactobacilli that colonize the vagina. Using rhesus macaques, we examined whether oral delivery of human vaginal Lactobacillus jensenii-1153-1646, a GusA-producing strain, would result in colonization of the rectum and the vagina. Lactobacilli were identified from the vagina tracts of three macaques on the basis of β-glucuronidase enzyme production, 16S rRNA gene sequence and DNA homology using a repetitive sequence-based polymerase chain reaction. PMID:21907793

C5A Protects Macaques from Vaginal Simian-Human Immunodeficiency Virus Challenge.

PubMed

Veazey, Ronald S; Chatterji, Udayan; Bobardt, Michael; Russell-Lodrigue, Kasi E; Li, Jian; Wang, Xiaolei; Gallay, Philippe A

2016-01-01

A safe and effective vaginal microbicide could decrease human immunodeficiency virus (HIV) transmission in women. Here, we evaluated the safety and microbicidal efficacy of a short amphipathic peptide, C5A, in a rhesus macaque model. We found that a vaginal application of C5A protects 89% of the macaques from a simian-human immunodeficiency virus (SHIV-162P3) challenge. We observed no signs of lesions or inflammation in animals vaginally treated with repeated C5A applications. With its noncellular cytotoxic activity and rare mechanism of action, C5A represents an attractive microbicidal candidate. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Plasticity of Ability to Form Cross-Modal Representations in Infant Japanese Macaques

ERIC Educational Resources Information Center

Adachi, Ikuma; Kuwahata, Hiroko; Fujita, Kazuo; Tomonaga, Masaki; Matsuzawa, Tetsuro

2009-01-01

In a previous study, Adachi, Kuwahata, Fujita, Tomonaga & Matsuzawa demonstrated that infant Japanese macaques (Macaca fuscata) form cross-modal representations of conspecifics but not of humans. However, because the subjects in the experiment were raised in a large social group and had considerably less exposure to humans than to…

Neutralizing antibody fails to impact the course of Ebola virus infection in monkeys.

PubMed

Oswald, Wendelien B; Geisbert, Thomas W; Davis, Kelly J; Geisbert, Joan B; Sullivan, Nancy J; Jahrling, Peter B; Parren, Paul W H I; Burton, Dennis R

2007-01-01

Prophylaxis with high doses of neutralizing antibody typically offers protection against challenge with viruses producing acute infections. In this study, we have investigated the ability of the neutralizing human monoclonal antibody, KZ52, to protect against Ebola virus in rhesus macaques. This antibody was previously shown to fully protect guinea pigs from infection. Four rhesus macaques were given 50 mg/kg of neutralizing human monoclonal antibody KZ52 intravenously 1 d before challenge with 1,000 plaque-forming units of Ebola virus, followed by a second dose of 50 mg/kg antibody 4 d after challenge. A control animal was exposed to virus in the absence of antibody treatment. Passive transfer of the neutralizing human monoclonal antibody not only failed to protect macaques against challenge with Ebola virus but also had a minimal effect on the explosive viral replication following infection. We show that the inability of antibody to impact infection was not due to neutralization escape. It appears that Ebola virus has a mechanism of infection propagation in vivo in macaques that is uniquely insensitive even to high concentrations of neutralizing antibody.

Deer Mates: A Quantitative Study of Heterospecific Sexual Behaviors Performed by Japanese Macaques Toward Sika Deer.

PubMed

Gunst, Noëlle; Vasey, Paul L; Leca, Jean-Baptiste

2018-05-01

This is the first quantitative study of heterospecific sexual behavior between a non-human primate and a non-primate species. We observed multiple occurrences of free-ranging adolescent female Japanese macaques (Macaca fuscata) performing mounts and sexual solicitations toward sika deer (Cervus nippon) at Minoo, central Japan. Our comparative description of monkey-deer versus monkey-monkey interactions supported the "heterospecific sexual behavior" hypothesis: the mounts and demonstrative solicitations performed by adolescent female Japanese macaques toward sika deer were sexual in nature. In line with our previous research on the development of homospecific sexual behavior in immature female Japanese macaques, this study will allow us to test other hypotheses in the future, such as the "practice for homospecific sex," the "safe sex," the "homospecific sex deprivation," the "developmental by-product," and the "cultural heterospecific sex" hypotheses. Further research will be necessary to ascertain whether this group-specific sexual behavior was a short-lived fad or an incipient cultural phenomenon and may also contribute to better understanding the proximate and ultimate causes of reproductive interference.

Using porches to decrease feces painting in rhesus macaques (Macaca mulatta).

PubMed

Gottlieb, Daniel H; O'Connor, Jillann Rawlins; Coleman, Kristine

2014-11-01

The goal of this project was to evaluate the efficacy of a porch in decreasing feces painting in captive rhesus macaques. The porch is a small extension that is hung on the outside of a monkey's primary home cage. Porches provide many potential benefits to indoor-housed macaques, including opportunities to perch above the ground, additional space, and increased field of view. Rates of feces painting, an abnormal behavior in which the animal smears or rubs feces on a surface, were compared in 3 situations: with porch enrichment, with 'smear board' enrichment (a foraging device commonly used to decrease feces painting), and without either enrichment item. Feces painting was evaluated daily by using a 5-point scale that ranged from 0, no feces present, to 4, multiple large areas of feces. We found that subjects received significantly lower feces painting scores when given porch enrichment or smear board enrichment compared with baseline. Furthermore, subjects received significantly lower feces painting scores with porch enrichment than smear board enrichment. These results demonstrate that the porch is an effective tool to decrease feces painting in captive macaques.

Using Porches to Decrease Feces Painting in Rhesus Macaques (Macaca mulatta)

PubMed Central

Gottlieb, Daniel H; O'Connor, Jillann Rawlins; Coleman, Kristine

2014-01-01

The goal of this project was to evaluate the efficacy of a porch in decreasing feces painting in captive rhesus macaques. The porch is a small extension that is hung on the outside of a monkey's primary home cage. Porches provide many potential benefits to indoor-housed macaques, including opportunities to perch above the ground, additional space, and increased field of view. Rates of feces painting, an abnormal behavior in which the animal smears or rubs feces on a surface, were compared in 3 situations: with porch enrichment, with ‘smear board’ enrichment (a foraging device commonly used to decrease feces painting), and without either enrichment item. Feces painting was evaluated daily by using a 5-point scale that ranged from 0, no feces present, to 4, multiple large areas of feces. We found that subjects received significantly lower feces painting scores when given porch enrichment or smear board enrichment compared with baseline. Furthermore, subjects received significantly lower feces painting scores with porch enrichment than smear board enrichment. These results demonstrate that the porch is an effective tool to decrease feces painting in captive macaques. PMID:25650971

Neonatal imitation predicts infant rhesus macaque (Macaca mulatta) social and anxiety-related behaviours at one year

PubMed Central

Kaburu, Stefano S. K.; Paukner, Annika; Simpson, Elizabeth A.; Suomi, Stephen J.; Ferrari, Pier F.

2016-01-01

The identification of early markers that predict the development of specific social trajectories is critical to understand the developmental and neurobiological underpinnings of healthy social development. We investigated, in infant rhesus macaques (Macaca mulatta), whether newborns’ capacity to imitate facial gestures is a valid predictive marker for the emergence of social competencies later in development, at one year of age. Here we first assessed whether infant macaques (N = 126) imitate lipsmacking gestures (a macaque affiliative expression) performed by a human experimenter in their first week of life. We then collected data on infants’ social interactions (aggression, grooming, and play) and self-scratching (a proxy indicator of anxiety) at 11–14 months when infants were transferred into a new enclosure with a large social group. Our results show that neonatal imitators exhibit more dominant behaviours, are less anxious, and, for males only, spend more time in play at one year old. These findings suggest that neonatal imitation may be an early predictor of infant sociality and may help identify infants at risk of neurodevelopmental social deficits. PMID:27725768

Contrasting Specializations for Facial Motion Within the Macaque Face-Processing System

PubMed Central

Fisher, Clark; Freiwald, Winrich A.

2014-01-01

SUMMARY Facial motion transmits rich and ethologically vital information [1, 2], but how the brain interprets this complex signal is poorly understood. Facial form is analyzed by anatomically distinct face patches in the macaque brain [3, 4], and facial motion activates these patches and surrounding areas [5, 6]. Yet it is not known whether facial motion is processed by its own distinct and specialized neural machinery, and if so, what that machinery’s organization might be. To address these questions, we used functional magnetic resonance imaging (fMRI) to monitor the brain activity of macaque monkeys while they viewed low- and high-level motion and form stimuli. We found that, beyond classical motion areas and the known face patch system, moving faces recruited a heretofore-unrecognized face patch. Although all face patches displayed distinctive selectivity for face motion over object motion, only two face patches preferred naturally moving faces, while three others preferred randomized, rapidly varying sequences of facial form. This functional divide was anatomically specific, segregating dorsal from ventral face patches, thereby revealing a new organizational principle of the macaque face-processing system. PMID:25578903

Venezuelan Equine Encephalitis Virus Replicon Particle Vaccine Protects Nonhuman Primates from Intramuscular and Aerosol Challenge with Ebolavirus

PubMed Central

Herbert, Andrew S.; Kuehne, Ana I.; Barth, James F.; Ortiz, Ramon A.; Nichols, Donald K.; Zak, Samantha E.; Stonier, Spencer W.; Muhammad, Majidat A.; Bakken, Russell R.; Prugar, Laura I.; Olinger, Gene G.; Groebner, Jennifer L.; Lee, John S.; Pratt, William D.; Custer, Max; Kamrud, Kurt I.; Smith, Jonathan F.; Hart, Mary Kate

2013-01-01

There are no vaccines or therapeutics currently approved for the prevention or treatment of ebolavirus infection. Previously, a replicon vaccine based on Venezuelan equine encephalitis virus (VEEV) demonstrated protective efficacy against Marburg virus in nonhuman primates. Here, we report the protective efficacy of Sudan virus (SUDV)- and Ebola virus (EBOV)-specific VEEV replicon particle (VRP) vaccines in nonhuman primates. VRP vaccines were developed to express the glycoprotein (GP) of either SUDV or EBOV. A single intramuscular vaccination of cynomolgus macaques with VRP expressing SUDV GP provided complete protection against intramuscular challenge with SUDV. Vaccination against SUDV and subsequent survival of SUDV challenge did not fully protect cynomolgus macaques against intramuscular EBOV back-challenge. However, a single simultaneous intramuscular vaccination with VRP expressing SUDV GP combined with VRP expressing EBOV GP did provide complete protection against intramuscular challenge with either SUDV or EBOV in cynomolgus macaques. Finally, intramuscular vaccination with VRP expressing SUDV GP completely protected cynomolgus macaques when challenged with aerosolized SUDV, although complete protection against aerosol challenge required two vaccinations with this vaccine. PMID:23408633

Venezuelan equine encephalitis virus replicon particle vaccine protects nonhuman primates from intramuscular and aerosol challenge with ebolavirus.

PubMed

Herbert, Andrew S; Kuehne, Ana I; Barth, James F; Ortiz, Ramon A; Nichols, Donald K; Zak, Samantha E; Stonier, Spencer W; Muhammad, Majidat A; Bakken, Russell R; Prugar, Laura I; Olinger, Gene G; Groebner, Jennifer L; Lee, John S; Pratt, William D; Custer, Max; Kamrud, Kurt I; Smith, Jonathan F; Hart, Mary Kate; Dye, John M

2013-05-01

There are no vaccines or therapeutics currently approved for the prevention or treatment of ebolavirus infection. Previously, a replicon vaccine based on Venezuelan equine encephalitis virus (VEEV) demonstrated protective efficacy against Marburg virus in nonhuman primates. Here, we report the protective efficacy of Sudan virus (SUDV)- and Ebola virus (EBOV)-specific VEEV replicon particle (VRP) vaccines in nonhuman primates. VRP vaccines were developed to express the glycoprotein (GP) of either SUDV or EBOV. A single intramuscular vaccination of cynomolgus macaques with VRP expressing SUDV GP provided complete protection against intramuscular challenge with SUDV. Vaccination against SUDV and subsequent survival of SUDV challenge did not fully protect cynomolgus macaques against intramuscular EBOV back-challenge. However, a single simultaneous intramuscular vaccination with VRP expressing SUDV GP combined with VRP expressing EBOV GP did provide complete protection against intramuscular challenge with either SUDV or EBOV in cynomolgus macaques. Finally, intramuscular vaccination with VRP expressing SUDV GP completely protected cynomolgus macaques when challenged with aerosolized SUDV, although complete protection against aerosol challenge required two vaccinations with this vaccine.

Anti-CeHV1 antibodies of two cynomolgus macaques cross-react with HSV2 but not HSV1 antigens in ELISA.

PubMed

Coutrot, Edwin; Blancher-Sardou, Marie; Blancher, Antoine

2008-02-01

The aim of the study was to compare the cross-reactivity of macaque anti-CeHV1 antibodies with type 1 and type 2 human herpes simplex viruses (HSV1 and HSV2). We studied the serum of 344 animals which had been tested either positive (n = 39) or negative (n = 305) for the presence of CeHV1 antibodies by expert laboratories. Macaque serums were studied by means of two ELISA: one based on HSV1 antigen-coated wells, the other on polystyrene beads coated with HSV1 and HSV2 antigens in approximately equal proportions. In the serum of two animals originating from Vietnam, we found anti-CeHV1 antibodies cross-reacting with HSV2 but not with HSV1 antigens. For the serum with the highest titer, inhibition by soluble antigens confirmed the high affinity of the antibodies for HSV2 antigens. Tests using HSV1 and HSV2 in a combined way are better suited to macaque screening than tests using only HSV1 antigens.

Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques.

PubMed

Hessell, Ann J; Jaworski, J Pablo; Epson, Erin; Matsuda, Kenta; Pandey, Shilpi; Kahl, Christoph; Reed, Jason; Sutton, William F; Hammond, Katherine B; Cheever, Tracy A; Barnette, Philip T; Legasse, Alfred W; Planer, Shannon; Stanton, Jeffrey J; Pegu, Amarendra; Chen, Xuejun; Wang, Keyun; Siess, Don; Burke, David; Park, Byung S; Axthelm, Michael K; Lewis, Anne; Hirsch, Vanessa M; Graham, Barney S; Mascola, John R; Sacha, Jonah B; Haigwood, Nancy L

2016-04-01

Prevention of mother-to-child transmission (MTCT) of HIV remains a major objective where antenatal care is not readily accessible. We tested HIV-1-specific human neutralizing monoclonal antibodies (NmAbs) as a post-exposure therapy in an infant macaque model for intrapartum MTCT. One-month-old rhesus macaques were inoculated orally with the simian-human immunodeficiency virus SHIVSF162P3. On days 1, 4, 7 and 10 after virus exposure, we injected animals subcutaneously with NmAbs and quantified systemic distribution of NmAbs in multiple tissues within 24 h after antibody administration. Replicating virus was found in multiple tissues by day 1 in animals that were not treated. All NmAb-treated macaques were free of virus in blood and tissues at 6 months after exposure. We detected no anti-SHIV T cell responses in blood or tissues at necropsy, and no virus emerged after CD8(+) T cell depletion. These results suggest that early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs.

Quantitative stability of hematopoietic stem and progenitor cell clonal output in rhesus macaques receiving transplants

PubMed Central

Koelle, Samson J.

2017-01-01

Autologous transplantation of hematopoietic stem and progenitor cells lentivirally labeled with unique oligonucleotide barcodes flanked by sequencing primer targets enables quantitative assessment of the self-renewal and differentiation patterns of these cells in a myeloablative rhesus macaque model. Compared with other approaches to clonal tracking, this approach is highly quantitative and reproducible. We documented stable multipotent long-term hematopoietic clonal output of monocytes, granulocytes, B cells, and T cells from a polyclonal pool of hematopoietic stem and progenitor cells in 4 macaques observed for up to 49 months posttransplantation. A broad range of clonal behaviors characterized by contribution level and biases toward certain cell types were extremely stable over time. Correlations between granulocyte and monocyte clonalities were greatest, followed by correlations between these cell types and B cells. We also detected quantitative expansion of T cell–biased clones consistent with an adaptive immune response. In contrast to recent data from a nonquantitative murine model, there was little evidence for clonal succession after initial hematopoietic reconstitution. These findings have important implications for human hematopoiesis, given the similarities between macaque and human physiologies. PMID:28087539

Thoracic Radiography as a Refinement Methodology for the Study of H1N1 Influenza in Cynomologus Macaques (Macaca fascicularis)

PubMed Central

Brining, Douglas L; Mattoon, John S; Kercher, Lisa; LaCasse, Rachael A; Safronetz, David; Feldmann, Heinz; Parnell, Michael J

2010-01-01

Recent advances in the technology associated with digital radiography have created new opportunities for biomedical research applications. Here we evaluated the use of thoracic radiography as a noninvasive refinement methodology for the cynomologus macaque (Macaca fascicularis) model of H1N1 infection. Thoracic radiographic evaluations of macaques infected with any of 3 strains of emerging H1N1 swine-associated influenza virus isolated during the recent pandemic were compared with those of macaques infected with the currently circulating Kawasaki strain of H1N1 influenza. Ventrodorsal, right, and left lateral thoracic radiographs were obtained at days 0, 1, 6, 8, 11, and 14 after infection. A board-certified veterinary radiologist who was blinded to the study design evaluated the images. Numeric scores of extent and severity of lung involvement assigned to each radiograph were compared and demonstrated a significant and substantial difference among groups. The radiographic evaluation allowed for noninvasive assessment of lung involvement, disease onset, progression, and resolution of radiographic changes associated with H1N1 influenza infection. PMID:21262125

Four-gene Pan-African Blood Signature Predicts Progression to Tuberculosis.

PubMed

Suliman, Sara; Thompson, Ethan; Sutherland, Jayne; Weiner Rd, January; Ota, Martin O C; Shankar, Smitha; Penn-Nicholson, Adam; Thiel, Bonnie; Erasmus, Mzwandile; Maertzdorf, Jeroen; Duffy, Fergal J; Hill, Philip C; Hughes, E Jane; Stanley, Kim; Downing, Katrina; Fisher, Michelle L; Valvo, Joe; Parida, Shreemanta K; van der Spuy, Gian; Tromp, Gerard; Adetifa, Ifedayo M O; Donkor, Simon; Howe, Rawleigh; Mayanja-Kizza, Harriet; Boom, W Henry; Dockrell, Hazel; Ottenhoff, Tom H M; Hatherill, Mark; Aderem, Alan; Hanekom, Willem A; Scriba, Thomas J; Kaufmann, Stefan He; Zak, Daniel E; Walzl, Gerhard

2018-04-06

Contacts of tuberculosis (TB) patients constitute an important target population for preventative measures as they are at high risk of infection with Mycobacterium tuberculosis and progression to disease. We investigated biosignatures with predictive ability for incident tuberculosis. In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, polymerase chain reaction (PCR) and the Pair Ratio algorithm in a training/test set approach. Overall, 79 progressors, who developed tuberculosis between 3 and 24 months following exposure, and 328 matched non-progressors, who remained healthy during 24 months of follow-up, were investigated. A four-transcript signature (RISK4), derived from samples in a South African and Gambian training set, predicted progression up to two years before onset of disease in blinded test set samples from South Africa, The Gambia and Ethiopia with little population-associated variability and also validated on an external cohort of South African adolescents with latent Mycobacterium tuberculosis infection. By contrast, published diagnostic or prognostic tuberculosis signatures predicted on samples from some but not all 3 countries, indicating site-specific variability. Post-hoc meta-analysis identified a single gene pair, C1QC/TRAV27, that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events. Collectively, we developed a simple whole blood-based PCR test to predict tuberculosis in household contacts from diverse African populations, with potential for implementation in national TB contact investigation programs.

Detection of Progressive Retinal Nerve Fiber Layer Loss in Glaucoma Using Scanning Laser Polarimetry with Variable Corneal Compensation

PubMed Central

Medeiros, Felipe A.; Alencar, Luciana M.; Zangwill, Linda M.; Bowd, Christopher; Vizzeri, Gianmarco; Sample, Pamela A.; Weinreb, Robert N.

2010-01-01

Purpose To evaluate the ability of scanning laser polarimetry with variable corneal compensation to detect progressive retinal nerve fiber layer (RNFL) loss in glaucoma patients and patients suspected of having the disease. Methods This was an observational cohort study that included 335 eyes of 195 patients. Images were obtained annually with the GDx VCC scanning laser polarimeter, along with optic disc stereophotographs and standard automated perimetry (SAP) visual fields. The median follow-up time was 3.94 years. Progression was determined using commercial software for SAP and by masked assessment of optic disc stereophotographs performed by expert graders. Random coefficient models were used to evaluate the relationship between RNFL thickness measurements over time and progression as determined by SAP and/or stereophotographs. Results From the 335 eyes, 34 (10%) showed progression over time by stereophotographs and/or SAP. Average GDx VCC measurements decreased significantly over time for both progressors as well as non-progressors. However, the rate of decline was significantly higher in the progressing group (−0.70 μm/year) compared to the non-progressing group (−0.14 μm/year; P = 0.001). Black race and male sex were significantly associated with higher rates of RNFL loss during follow-up. Conclusions The GDx VCC scanning laser polarimeter was able to identify longitudinal RNFL loss in eyes that showed progression in optic disc stereophotographs and/or visual fields. These findings suggest that this technology could be useful to detect and monitor progressive disease in patients with established diagnosis of glaucoma or suspected of having the disease. PMID:19029038

Predicting the onset of Addison's disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies

PubMed Central

Baker, Peter R.; Nanduri, Priyaanka; Gottlieb, Peter A.; Yu, Liping; Klingensmith, Georgeanna J.; Eisenbarth, George S.; Barker, Jennifer M.

2016-01-01

Summary Context Autoantibodies to 21-hydroxylase (21OH-AA) precede onset of autoimmune Addison's disease (AD). Progression to AD can take months to years, and early detection of metabolic decompensation may prevent morbidity and mortality. Objective To define optimal methods of predicting progression to overt AD (defined by subnormal peak cortisol response to Cosyntropin) in 21OH-AA+ individuals. Design, Setting and Participants Individuals were screened for 21OH-AA at the Barbara Davis Center from 1993 to 2011. Subjects positive for 21OH-AA (n = 87) were tested, and the majority prospectively followed for the development of Addison's disease, including seven diagnosed with AD upon 21OH-AA discovery (discovered), seven who progressed to AD (progressors) and 73 nonprogressors. Main Outcome Measured Plasma renin activity (PRA), ACTH, baseline cortisol, peak cortisol and 21OH-AA were measured at various time points relative to diagnosis of AD or last AD-free follow-up. Results Compared with nonprogressors, in the time period 2 months–2 years prior to the onset of AD, progressors were significantly more likely to have elevated ACTH (11–22 pm, P < 1E-4), with no significant differences in mean PRA (P = 0·07) or baseline cortisol (P = 0·08), and significant but less distinct differences seen with 21OH-AA levels (P < 1E-4) and poststimulation cortisol levels (P = 6E-3). Conclusion Moderately elevated ACTH is a more useful early indicator of impending AD than 21OH-AA, PRA or peak cortisol, in the 2 months–2 years preceding the onset of AD. PMID:22066755

Predicting the onset of Addison's disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies.

PubMed

Baker, Peter R; Nanduri, Priyaanka; Gottlieb, Peter A; Yu, Liping; Klingensmith, Georgeanna J; Eisenbarth, George S; Barker, Jennifer M

2012-05-01

Autoantibodies to 21-hydroxylase (21OH-AA) precede onset of autoimmune Addison's disease (AD). Progression to AD can take months to years, and early detection of metabolic decompensation may prevent morbidity and mortality. To define optimal methods of predicting progression to overt AD (defined by subnormal peak cortisol response to Cosyntropin) in 21OH-AA+ individuals. Individuals were screened for 21OH-AA at the Barbara Davis Center from 1993 to 2011. Subjects positive for 21OH-AA (n = 87) were tested, and the majority prospectively followed for the development of Addison's disease, including seven diagnosed with AD upon 21OH-AA discovery (discovered), seven who progressed to AD (progressors) and 73 nonprogressors. Plasma renin activity (PRA), ACTH, baseline cortisol, peak cortisol and 21OH-AA were measured at various time points relative to diagnosis of AD or last AD-free follow-up. Compared with nonprogressors, in the time period 2 months-2 years prior to the onset of AD, progressors were significantly more likely to have elevated ACTH (11-22 pM, P < 1E-4), with no significant differences in mean PRA (P = 0·07) or baseline cortisol (P = 0·08), and significant but less distinct differences seen with 21OH-AA levels (P < 1E-4) and poststimulation cortisol levels (P = 6E-3). Moderately elevated ACTH is a more useful early indicator of impending AD than 21OH-AA, PRA or peak cortisol, in the 2 months-2 years preceding the onset of AD. © 2012 Blackwell Publishing Ltd.

CD8(+) T-cell Cytotoxic Capacity Associated with Human Immunodeficiency Virus-1 Control Can Be Mediated through Various Epitopes and Human Leukocyte Antigen Types.

PubMed

Migueles, Stephen A; Mendoza, Daniel; Zimmerman, Matthew G; Martins, Kelly M; Toulmin, Sushila A; Kelly, Elizabeth P; Peterson, Bennett A; Johnson, Sarah A; Galson, Eric; Poropatich, Kate O; Patamawenu, Andy; Imamichi, Hiromi; Ober, Alexander; Rehm, Catherine A; Jones, Sara; Hallahan, Claire W; Follmann, Dean A; Connors, Mark

2015-01-01

Understanding natural immunologic control over Human Immunodeficiency Virus (HIV)-1 replication, as occurs in rare long-term nonprogressors/elite controllers (LTNP/EC), should inform the design of efficacious HIV vaccines and immunotherapies. Durable control in LTNP/EC is likely mediated by highly functional virus-specific CD8(+) T-cells. Protective Human Leukocyte Antigen (HLA) class I alleles, like B*27 and B*57, are present in most, but not all LTNP/EC, providing an opportunity to investigate features shared by their HIV-specific immune responses. To better understand the contribution of epitope targeting and conservation to immune control, we compared the CD8(+) T-cell specificity and function of B*27/57(neg) LTNP/EC (n = 23), B*27/57(pos) LTNP/EC (n = 23) and B*27/57(neg) progressors (n = 13). Fine mapping revealed 11 previously unreported immunodominant responses. Although B*27/57(neg) LTNP/EC did not target more highly conserved epitopes, their CD8(+) T-cell cytotoxic capacity was significantly higher than progressors. Similar to B*27/57(pos) LTNP/EC, this superior cytotoxicity was mediated by preferential expansion of immunodominant responses and lysis through the predicted HLA. These findings suggest that increased CD8(+) T-cell cytotoxic capacity is a common mechanism of control in most LTNP/EC regardless of HLA type. They also suggest that potent cytotoxicity can be mediated through various epitopes and HLA molecules and could, in theory, be induced in most people.

CD8+ T-cell Cytotoxic Capacity Associated with Human Immunodeficiency Virus-1 Control Can Be Mediated through Various Epitopes and Human Leukocyte Antigen Types

PubMed Central

Migueles, Stephen A.; Mendoza, Daniel; Zimmerman, Matthew G.; Martins, Kelly M.; Toulmin, Sushila A.; Kelly, Elizabeth P.; Peterson, Bennett A.; Johnson, Sarah A.; Galson, Eric; Poropatich, Kate O.; Patamawenu, Andy; Imamichi, Hiromi; Ober, Alexander; Rehm, Catherine A.; Jones, Sara; Hallahan, Claire W.; Follmann, Dean A.; Connors, Mark

2014-01-01

Understanding natural immunologic control over Human Immunodeficiency Virus (HIV)-1 replication, as occurs in rare long-term nonprogressors/elite controllers (LTNP/EC), should inform the design of efficacious HIV vaccines and immunotherapies. Durable control in LTNP/EC is likely mediated by highly functional virus-specific CD8+ T-cells. Protective Human Leukocyte Antigen (HLA) class I alleles, like B*27 and B*57, are present in most, but not all LTNP/EC, providing an opportunity to investigate features shared by their HIV-specific immune responses. To better understand the contribution of epitope targeting and conservation to immune control, we compared the CD8+ T-cell specificity and function of B*27/57neg LTNP/EC (n = 23), B*27/57pos LTNP/EC (n = 23) and B*27/57neg progressors (n = 13). Fine mapping revealed 11 previously unreported immunodominant responses. Although B*27/57neg LTNP/EC did not target more highly conserved epitopes, their CD8+ T-cell cytotoxic capacity was significantly higher than progressors. Similar to B*27/57pos LTNP/EC, this superior cytotoxicity was mediated by preferential expansion of immunodominant responses and lysis through the predicted HLA. These findings suggest that increased CD8+ T-cell cytotoxic capacity is a common mechanism of control in most LTNP/EC regardless of HLA type. They also suggest that potent cytotoxicity can be mediated through various epitopes and HLA molecules and could, in theory, be induced in most people. PMID:26137533

Low CD1c + myeloid dendritic cell counts correlated with a high risk of rapid disease progression during early HIV-1 infection.

PubMed

Diao, Yingying; Geng, Wenqing; Fan, Xuejie; Cui, Hualu; Sun, Hong; Jiang, Yongjun; Wang, Yanan; Sun, Amy; Shang, Hong

2015-08-19

During early HIV-1 infection (EHI), the interaction between the immune response and the virus determines disease progression. Although CD1c + myeloid dendritic cells (mDCs) can trigger the immune response, the relationship between CD1c + mDC alteration and disease progression has not yet been defined. EHI changes in CD1c + mDC counts, surface marker (CD40, CD86, CD83) expression, and IL-12 secretion were assessed by flow cytometry in 29 patients. When compared with the normal controls, patients with EHI displayed significantly lower CD1c + mDC counts and IL-12 secretion and increased surface markers. CD1c + mDC counts were positively correlated with CD4+ T cell counts and inversely associated with viral loads. IL-12 secretion was only positively associated with CD4+ T cell counts. Rapid progressors had lower counts, CD86 expression, and IL-12 secretion of CD1c + mDCs comparing with typical progressors. Kaplan-Meier analysis and Cox regression models suggested patients with low CD1c + mDC counts (<10 cells/μL) had a 4-fold higher risk of rapid disease progression than those with high CD1c + mDC counts. However, no relationship was found between surface markers or IL-12 secretion and disease progression. During EHI, patients with low CD1c + mDC counts were more likely to experience rapid disease progression than those with high CD1c + mDC counts.

A multivariate ecogeographic analysis of macaque craniodental variation.

PubMed

Grunstra, Nicole D S; Mitteroecker, Philipp; Foley, Robert A

2018-06-01

To infer the ecogeographic conditions that underlie the evolutionary diversification of macaques, we investigated the within- and between-species relationships of craniodental dimensions, geography, and environment in extant macaque species. We studied evolutionary processes by contrasting macroevolutionary patterns, phylogeny, and within-species associations. Sixty-three linear measurements of the permanent dentition and skull along with data about climate, ecology (environment), and spatial geography were collected for 711 specimens of 12 macaque species and analyzed by a multivariate approach. Phylogenetic two-block partial least squares was used to identify patterns of covariance between craniodental and environmental variation. Phylogenetic reduced rank regression was employed to analyze spatial clines in morphological variation. Between-species associations consisted of two distinct multivariate patterns. The first represents overall craniodental size and is negatively associated with temperature and habitat, but positively with latitude. The second pattern shows an antero-posterior tooth size contrast related to diet, rainfall, and habitat productivity. After controlling for phylogeny, however, the latter dimension was diminished. Within-species analyses neither revealed significant association between morphology, environment, and geography, nor evidence of isolation by distance. We found evidence for environmental adaptation in macaque body and craniodental size, primarily driven by selection for thermoregulation. This pattern cannot be explained by the within-species pattern, indicating an evolved genetic basis for the between-species relationship. The dietary signal in relative tooth size, by contrast, can largely be explained by phylogeny. This cautions against adaptive interpretations of phenotype-environment associations when phylogeny is not explicitly modelled. © 2018 Wiley Periodicals, Inc.

Young macaques (Macaca fascicularis) preferentially bias attention towards closer, older, and better tool users.

PubMed

Tan, Amanda W Y; Hemelrijk, Charlotte K; Malaivijitnond, Suchinda; Gumert, Michael D

2018-05-12

Examining how animals direct social learning during skill acquisition under natural conditions, generates data for examining hypotheses regarding how transmission biases influence cultural change in animal populations. We studied a population of macaques on Koram Island, Thailand, and examined model-based biases during interactions by unskilled individuals with tool-using group members. We first compared the prevalence of interactions (watching, obtaining food, object exploration) and proximity to tool users during interactions, in developing individuals (infants, juveniles) versus mature non-learners (adolescents, adults), to provide evidence that developing individuals are actively seeking information about tool use from social partners. All infants and juveniles, but only 49% of mature individuals carried out interacted with tool users. Macaques predominantly obtained food by scrounging or stealing, suggesting maximizing scrounging opportunities motivates interactions with tool users. However, while interactions by adults was limited to obtaining food, young macaques and particularly infants also watched tool users and explored objects, indicating additional interest in tool use itself. We then ran matrix correlations to identify interaction biases, and what attributes of tool users influenced these. Biases correlated with social affiliation, but macaques also preferentially targeted tool users that potentially increase scrounging and learning opportunities. Results suggest that social structure may constrain social learning, but the motivation to bias interactions towards tool users to maximize feeding opportunities may also socially modulate learning by facilitating close proximity to better tool users, and further interest in tool-use actions and materials, especially during development.

Low autocrine interferon beta production as a gene therapy approach for AIDS: Infusion of interferon beta-engineered lymphocytes in macaques chronically infected with SIVmac251

PubMed Central

Gay, Wilfried; Lauret, Evelyne; Boson, Bertrand; Larghero, Jérome; Matheux, Franck; Peyramaure, Sophie; Rousseau, Véronique; Dormont, Dominique; De Maeyer, Edward; Le Grand, Roger

2004-01-01

Background The aim of this study was to evaluate gene therapy for AIDS based on the transduction of circulating lymphocytes with a retroviral vector giving low levels of constitutive macaque interferon β production in macaques chronically infected with a pathogenic isolate of SIVmac251. Results Two groups of three animals infected for more than one year with a pathogenic primary isolate of SIVmac251 were included in this study. The macaques received three infusions of their own lymphocytes transduced ex vivo with the construct encoding macaque IFN-β (MaIFN-β or with a vector carrying a version of the MaIFN-β gene with a deletion preventing translation of the mRNA. Cellular or plasma viremia increased transiently following injection in most cases, regardless of the retroviral construct used. Transduced cells were detected only transiently after each infusion, among the peripheral blood mononuclear cells of all the animals, with copy numbers of 10 to 1000 per 106 peripheral mononuclear cells. Conclusion Long-term follow-up indicated that the transitory presence of such a small number of cells producing such small amounts of MaIFN-β did not prevent animals from the progressive decrease in CD4+ cell count typical of infection with simian immunodeficiency virus. These results reveal potential pitfalls for future developments of gene therapy strategies of HIV infection. PMID:15447786

Local and Systemic Changes Associated with Long-term, Percutaneous, Static Implantation of Titanium Alloys in Rhesus Macaques (Macaca mulatta)

PubMed Central

Frydman, Galit H; Marini, Robert P; Bakthavatchalu, Vasudevan; Biddle, Kathleen E; Muthupalani, Sureshkumar; Vanderburg, Charles R; Lai, Barry; Bendapudi, Pavan K; Tompkins, Ronald G; Fox, James G

2017-01-01

Metal alloys are frequently used as implant materials in veterinary medicine. Recent studies suggest that many alloys induce both local and systemic inflammatory responses. In this study, 37 rhesus macaques with long-term skull-anchored percutaneous titanium alloy implants (duration, 0 to 14 y) were evaluated for changes in their hematology, coagulation, and serum chemistry profiles. Negative controls (n = 28) did not have implants. Macaques with implants had higher plasma D-dimer and lower antithrombin III concentrations than nonimplanted animals. In addition, animals with implants had higher globulin and lower albumin and calcium concentrations compared with nonimplanted macaques. Many of these changes were positively correlated with duration of implantation and the number of implants. Chronic bacterial infection of the skin was present around many of the implant sites and within deeper tissues. Representative histopathology around the implant site of 2 macaques revealed chronic suppurative to pyogranulomatous inflammation extending from the skin to the dura mater. X-ray fluorescence microscopy of tissue biopsies from the implant site of the same 2 animals revealed significantly higher levels of free metal ions in the tissue, including titanium and iron. The higher levels of free metal ions persisted in the tissues for as long as 6 mo after explantation. These results suggest that long-term skull-anchored percutaneous titanium alloy implants can be associated with localized inflammation, chronic infection, and leaching of metal ions into local tissues. PMID:28381317

Clinical and microbiological parameters of naturally occurring periodontitis in the non-human primate Macaca mulatta

PubMed Central

Colombo, A. P. V.; Paster, B. J.; Grimaldi, G.; Lourenço, T. G. B.; Teva, A.; Campos-Neto, A.; McCluskey, J.; Kleanthous, H.; Van Dyke, T. E.; Stashenko, P.

2017-01-01

ABSTRACT Background: Non-human primates appear to represent the most faithful model of human disease, but to date the oral microbiome in macaques has not been fully characterized using next-generation sequencing. Objective: In the present study, we characterized the clinical and microbiological features of naturally occurring periodontitis in non-human primates (Macaca mulatta). Design: Clinical parameters of periodontitis including probing pocket depth (PD) and bleeding on probing (BOP) were measured in 40 adult macaques (7–22 yrs), at six sites per tooth. Subgingival plaque was collected from diseased and healthy sites, and subjected to 16S rDNA sequencing and identification at the species or higher taxon level. Results: All macaques had mild periodontitis at minimum, with numerous sites of PD ≥ 4 mm and BOP. A subset (14/40) had moderate-severe disease, with >2 sites with PD ≥ 5mm, deeper mean PD, and more BOP. Animals with mild vs moderate-severe disease were identical in age, suggesting genetic heterogeneity. 16S rDNA sequencing revealed that all macaques had species that were identical to those in humans or closely related to human counterparts, including Porphyromonas gingivalis which was present in all animals. Diseased and healthy sites harboured distinct microbiomes; however there were no significant differences in the microbiomes in moderate-severe vs. mild periodontitis. Conclusions: Naturally occurring periodontitis in older macaques closely resembles human adult periodontitis, thus validating a useful model to evaluate novel anti-microbial therapies. PMID:29805776

Naive, captive long-tailed macaques (Macaca fascicularis fascicularis) fail to individually and socially learn pound-hammering, a tool-use behaviour

PubMed Central

Tennie, Claudio

2018-01-01

A subspecies of long-tailed macaques (Macaca fascicularis aurea; Mfa) has been reported to use stone tools and a specific technique to process nuts in Southeast Asia, a behaviour known as ‘pound-hammering’. The aim of this study was to examine the development of pound-hammering in long-tailed macaques: whether this behavioural form can be individually learnt or whether it has to rely on some forms of social learning. Given the absence of Mfa from captivity, long-tailed macaques of a highly related subspecies (Macaca fascicularis fascicularis; Mff) were experimentally tested by providing them with the ecological materials necessary to show pound-hammering. A baseline was first carried out to observe whether pound-hammering would emerge spontaneously without social information. As this was not the case, different degrees of social information, culminating in a full demonstration of the behaviour, were provided. None of the subjects (n = 31) showed pound-hammering in any of the individual or social learning conditions. Although these data do not support the hypothesis that individual learning underlies this behaviour, no evidence was found that (at least) Mff learn pound-hammering socially either. We propose that other—potentially interacting—factors may determine whether this behaviour emerges in the various subspecies of long-tailed macaques, and provide a novel methodology to test the role of social and individual learning in the development of animal tool-use. PMID:29892375

From the mouths of monkeys: Detection of Mycobacterium tuberculosis complex DNA from buccal swabs of synanthropic macaques

PubMed Central

Wilbur, AK; Engel, G; Rompis, A; Putra, IGA A; Lee, BP Y-H; Aggimarangsee, N; Chalise, M; Shaw, E; Oh, G; Schillaci, MA; Jones-Engel, L

2012-01-01

Although the Mycobacterium tuberculosis complex (MTBC) infects a third of all humans, little is known regarding the prevalence of mycobacterial infection in nonhuman primates (NHP). For more than a century, tuberculosis has been regarded as a serious infectious threat to NHP species. Advances in the detection of MTBC open new possibilities for investigating the effects of this poorly understood pathogen in diverse populations of NHP. Here we report results of a cross-sectional study using well-described molecular methods to detect a nucleic acid sequence (IS6110) unique to the MTBC. Sample collection was focused on the oral cavity, the presumed route of transmission of MTBC. Buccal swabs were collected from 263 macaques representing 11 species in four Asian countries and Gibraltar. Contexts of contact with humans included free ranging, pets, performing monkeys, zoos, and monkey temples. Following DNA isolation from buccal swabs, the PCR amplified IS6110 from 84 (31.9%) of the macaques. In general, prevalence of MTBC DNA was higher among NHP in countries where the World Health Organization reports higher prevalence of humans infected with MTBC. This is the first demonstration of MTBC DNA in the mouths of macaques. Further research is needed to establish the significance of this finding at both the individual and population levels. PCR of buccal samples holds promise as a method to elucidate the mycobacterial landscape among NHP, particularly macaques that thrive in areas of high human MTBC prevalence. PMID:22644580

Is male rhesus macaque red color ornamentation attractive to females?

PubMed Central

Dubuc, Constance; Allen, William L.; Maestripieri, Dario; Higham, James P.

2014-01-01

Male sexually-selected traits can evolve through different mechanisms: conspicuous and colorful ornaments usually evolve through inter-sexual selection, while weapons usually evolve through intra-sexual selection. Male ornaments are rare among mammals in comparison to birds, leading to the notion that female mate choice generally plays little role in trait evolution in this taxon. Supporting this view, when ornaments are present in mammals they typically indicate social status and are products of male-male competition. This general mammalian pattern, however, may not apply to rhesus macaques (Macaca mulatta). Males of this species display conspicuous skin coloration, but this expression is not correlated to dominance rank, and is therefore unlikely to have evolved due to male-male competition. Here, we investigate whether male color expression influences female proceptivity towards males in the Cayo Santiago free-ranging rhesus macaque population. We collected face images of 24 adult males varying in dominance rank and age at the peak of the mating season, and modeled these to rhesus macaque visual perception. We also recorded female socio-sexual behaviors towards these males. Results show that dark red males received more sexual solicitations, by more females, than pale pink ones. Together with previous results, our study suggests that male color ornaments are more likely to be a product of inter- rather than intra-sexual selection. This may especially be the case in rhesus macaques due to the particular characteristics of male-male competition in this species. PMID:25246728

Focal damage to macaque photoreceptors produces persistent visual loss

PubMed Central

Strazzeri, Jennifer M.; Hunter, Jennifer J.; Masella, Benjamin D.; Yin, Lu; Fischer, William S.; DiLoreto, David A.; Libby, Richard T.; Williams, David R.; Merigan, William H.

2014-01-01

Insertion of light-gated channels into inner retina neurons restores neural light responses, light evoked potentials, visual optomotor responses and visually-guided maze behavior in mice blinded by retinal degeneration. This method of vision restoration bypasses damaged outer retina, providing stimulation directly to retinal ganglion cells in inner retina. The approach is similar to that of electronic visual protheses, but may offer some advantages, such as avoidance of complex surgery and direct targeting of many thousands of neurons. However, the promise of this technique for restoring human vision remains uncertain because rodent animal models, in which it has been largely developed, are not ideal for evaluating visual perception. On the other hand, psychophysical vision studies in macaque can be used to evaluate different approaches to vision restoration in humans. Furthermore, it has not been possible to test vision restoration in macaques, the optimal model for human-like vision, because there has been no macaque model of outer retina degeneration. In this study, we describe development of a macaque model of photoreceptor degeneration that can in future studies be used to test restoration of perception by visual prostheses. Our results show that perceptual deficits caused by focal light damage are restricted to locations at which photoreceptors are damaged, that optical coherence tomography (OCT) can be used to track such lesions, and that adaptive optics retinal imaging, which we recently used for in vivo recording of ganglion cell function, can be used in future studies to examine these lesions. PMID:24316158

An Automated ELISA Using Recombinant Antigens for Serologic Diagnosis of B Virus Infections in Macaques

PubMed Central

Katz, David; Shi, Wei; Patrusheva, Irina; Perelygina, Ludmila; Gowda, Manjunath S; Krug, Peter W; Filfili, Chadi N; Ward, John A; Hilliard, Julia K

2012-01-01

B virus (Macacine herpesvirus 1) occurs naturally in macaques and can cause lethal zoonotic infections in humans. Detection of B virus (BV) antibodies in macaques is essential for the development of SPF breeding colonies and for diagnosing infection in macaques that are involved in human exposures. Traditionally, BV infections are monitored for presence of antibodies by ELISA (a screening assay) and western blot analysis (WBA; a confirmatory test). Both tests use lysates of infected cells as antigens. Because WBA often fails to confirm the presence of low-titer serum antibodies detected by ELISA, we examined a recombinant-based ELISA as a potential alternative confirmatory test. We compared a high-throughput ELISA using 384-well plates for simultaneous antibody screening against 4 BV-related, recombinant proteins with the standard ELISA and WBA. The recombinant ELISA results confirmed more ELISA-positive sera than did WBA. The superiority of the recombinant ELISA over WBA was particularly prominent for sera with low (<500 ELISA units) antibody titers. Among low-titer sera, the relative sensitivity of the recombinant ELISA ranged from 36.7% to 45.0% as compared with 3.3% to 10.0% for WBA. In addition, the screening and confirmatory assays can be run simultaneously, providing results more rapidly. We conclude that the recombinant ELISA is an effective replacement for WBA as a confirmatory assay for the evaluation of macaque serum antibodies to BV. PMID:23561887

Resource use of Japanese macaques in heavy snowfall areas: implications for habitat management.

PubMed

Enari, Hiroto; Sakamaki-Enari, Haruka

2013-07-01

Populations of Japanese macaque (Macaca fuscata) that inhabit the northernmost distribution of any nonhuman primates have been listed as endangered in Japan; however, macaques are widely known for being pests that cause agricultural damage. This study identified priority areas for the conservation and management of macaque habitats, by comparing the resource use of troops occupying remote mountains (montane troops) against troops inhabiting disturbed forests adjacent to settlements (rural troops). We collected species presence data across 2 years by radio-tracking two montane troops and two rural troops in the Shirakami Mountains. We developed seasonal utilization distributions by using the kernel method, and identified habitat characteristics by using ecological-niche factor analysis (ENFA). Our results indicate that environmental factors influencing the potential habitat varied widely with season in montane troops as compared with that in rural troops. ENFA results demonstrated that rural troops exhibited more biased resource use and narrower niche breadths than montane troops. Based on our findings, we propose that (1) primary broadleaf forests are the spring habitat conservation priority of montane troops; (2) the habitat unit--the product of habitat suitability index and its surface area--for montane troops is enhanced by removing old conifer plantations from the forest edge at low elevations; (3) such removal around settlements may also contribute toward removing a frontline refuge for rural troops intruding farmlands; and (4) intensive prevention measures against macaque intrusions into settlements during the bottleneck snowy season contribute toward reducing the habitat unit of rural troops.

Occurrence and distribution of Indian primates

USGS Publications Warehouse

Karanth, K.K.; Nichols, J.D.; Hines, J.E.

2010-01-01

Global and regional species conservation efforts are hindered by poor distribution data and range maps. Many Indian primates face extinction, but assessments of population status are hindered by lack of reliable distribution data. We estimated the current occurrence and distribution of 15 Indian primates by applying occupancy models to field data from a country-wide survey of local experts. We modeled species occurrence in relation to ecological and social covariates (protected areas, landscape characteristics, and human influences), which we believe are critical to determining species occurrence in India. We found evidence that protected areas positively influence occurrence of seven species and for some species are their only refuge. We found evergreen forests to be more critical for some primates along with temperate and deciduous forests. Elevation negatively influenced occurrence of three species. Lower human population density was positively associated with occurrence of five species, and higher cultural tolerance was positively associated with occurrence of three species. We find that 11 primates occupy less than 15% of the total land area of India. Vulnerable primates with restricted ranges are Golden langur, Arunachal macaque, Pig-tailed macaque, stump-tailed macaque, Phayre's leaf monkey, Nilgiri langur and Lion-tailed macaque. Only Hanuman langur and rhesus macaque are widely distributed. We find occupancy modeling to be useful in determining species ranges, and in agreement with current species ranking and IUCN status. In landscapes where monitoring efforts require optimizing cost, effort and time, we used ecological and social covariates to reliably estimate species occurrence and focus species conservation efforts. ?? Elsevier Ltd.

Multidetector computed tomographic morphology of ovaries in cynomolgus macaques (Macaca fascicularis).

PubMed

Jones, Jeryl C; Appt, Susan E; Bourland, J Daniel; Hoyer, Patricia B; Clarkson, Thomas B; Kaplan, Jay R

2007-09-01

Macaques are important models for menopause and associated diseases in women. A sensitive, noninvasive technique for quantifying changes in ovarian morphology would facilitate longitudinal studies focused on the health-related sequelae of naturally occurring or experimentally induced alterations in ovarian structure and function. Multidetector computed tomography (MDCT) is a fast, non-invasive imaging technique that uses X-rays, multiple rows of detectors, and computers to generate detailed slice images of structures. The purpose of this study was to describe the utility of MDCT for reliably characterizing ovarian morphology in macaques. Five macaques were scanned using contrast-enhanced MDCT. The following characteristics were described: 1) appearance of ovaries and adjacent landmarks, 2) effects of varying technical protocols on ovarian image quality, 3) radiation doses delivered to the pelvic region during scanning, and 4) MDCT estimates of ovarian volume and antral follicle counts versus those measured directly in ovarian tissue. Ovaries were distinguishable in all MDCT scans and exhibited heterogeneous contrast enhancement. Antral follicles appeared as focal areas of nonenhancement. Ovarian image quality with 5 pediatric scanning protocols was sufficient for discriminating ovarian margins. Pelvic region radiation doses ranged from 0.5 to 0.7 rad. Antral follicles counted using MDCT ranged from 3 to 5 compared with 3 to 4 counted using histology. Ovarian volumes measured using MDCT ranged from 0.41 to 0.67 ml compared with 0.40 to 0.65 ml by water displacement. MDCT is a promising technique for measuring longitudinal changes in macaque ovarian morphology reliably and noninvasively.

In vivo virulence of MHC-adapted AIDS virus serially-passaged through MHC-mismatched hosts

PubMed Central

Yamamoto, Hiroyuki; Ishii, Hiroshi; Matsuoka, Saori; Mizuta, Kazuta; Sakawaki, Hiromi; Miura, Tomoyuki; Naruse, Taeko K.; Kimura, Akinori

2017-01-01

CD8+ T-cell responses exert strong suppressive pressure on HIV replication and select for viral escape mutations. Some of these major histocompatibility complex class I (MHC-I)-associated mutations result in reduction of in vitro viral replicative capacity. While these mutations can revert after viral transmission to MHC-I-disparate hosts, recent studies have suggested that these MHC-I-associated mutations accumulate in populations and make viruses less pathogenic in vitro. Here, we directly show an increase in the in vivo virulence of an MHC-I-adapted virus serially-passaged through MHC-I-mismatched hosts in a macaque AIDS model despite a reduction in in vitro viral fitness. The first passage simian immunodeficiency virus (1pSIV) obtained 1 year after SIVmac239 infection in a macaque possessing a protective MHC-I haplotype 90-120-Ia was transmitted into 90-120-Ia- macaques, whose plasma 1 year post-infection was transmitted into other 90-120-Ia- macaques to obtain the third passage SIV (3pSIV). Most of the 90-120-Ia-associated mutations selected in 1pSIV did not revert even in 3pSIV. 3pSIV showed lower in vitro viral fitness but induced persistent viremia in 90-120-Ia- macaques. Remarkably, 3pSIV infection in 90-120-Ia+ macaques resulted in significantly higher viral loads and reduced survival compared to wild-type SIVmac239. These results indicate that MHC-I-adapted SIVs serially-transmitted through MHC-I-mismatched hosts can have higher virulence in MHC-I-matched hosts despite their lower in vitro viral fitness. This study suggests that multiply-passaged HIVs could result in loss of HIV-specific CD8+ T cell responses in human populations and the in vivo pathogenic potential of these escaped viruses may be enhanced. PMID:28931083

Interactions between visitors and Formosan macaques (Macaca cyclopis) at Shou-Shan Nature Park, Taiwan.

PubMed

Hsu, Minna J; Kao, Chien-Ching; Agoramoorthy, Govindasamy

2009-03-01

Ecotourism involving feeding wildlife has raised public attention and is a controversial issue, especially concerning nonhuman primates. Between July 2002 and April 2005, the behavior of monkeys and tourists was collected through scan samplings, focal samplings and behavior samplings at the Shou-Shan Nature Park located in Taiwan's second largest city--Kaohsiung. In addition, the number of tourists and monkeys was counted in different hours and places within the park. Four hundred visitors were interviewed using a questionnaire to gather data on sex, age, purpose and frequency of visit to the park. The number of tourists was significantly higher during weekends than in weekdays in all locations. Humans dominated in the initiation of interspecies interactions--the overall ratio of human-initiated and monkey-initiated interactions was 2.44:1. Human-monkey conflicts accounted for only 16.4% of the total interactions (n=2,166), and adult human males and adult male macaques participated in higher rates than other age/sex groups in these conflicts. Visitors showed more affiliative behavior (15.9%) than agonistic behavior (8%) toward the macaques. In response to visitors' threat or attack, the Formosan macaques mostly showed submissive behavior with bared teeth, squealed or ran away to avoid confrontation (69.1%)--only few responded with counteraggression (18.7%). This study for the first time provided evidence that food provisioning increased both the frequency and duration of aggression among Formosan macaques (P<0.001). During food provisioning, the average frequency and the duration of agonistic events of macaques were more than 4 times higher compared with those without food provisioning. The average frequency of food provision by tourists was 0.73 times/hr--more than twice the incident that monkeys grabbed the food from tourists (0.34 times/hr). If people refrain from feeding monkeys and destroying the city park's natural vegetation, monkeys can be used to educate public about nature conservation in an urban setting. (c) 2008 Wiley-Liss, Inc.

Asian Elephant (Elephas maximus), Pig-Tailed Macaque (Macaca nemestrina) and Tiger (Panthera tigris) Populations at Tourism Venues in Thailand and Aspects of Their Welfare

PubMed Central

Schmidt-Burbach, Jan; Ronfot, Delphine; Srisangiam, Rossukon

2015-01-01

This study focused on determining the size and welfare aspects of Asian elephant, pig-tailed macaque and tiger populations at facilities open to tourists in Thailand. Data were gathered from 118 venues through direct observations and interviews with staff. A score sheet-based welfare assessment was used to calculate scores between 1 and 10, indicating each venue’s welfare situation. Factors such as freedom of movement for the animals, access to veterinary care, environmental noise quality, hygiene standards and work intensity were included in the score sheet. 1688 elephants, 371 macaques and 621 tigers were found at the venues. 89 venues exclusively kept elephants, 9 designated ‘Monkey schools’ offered macaque shows, 4 venues kept primarily tigers, mostly for petting and photo opportunities, and the remaining venues kept a mix of these animals. A strong imbalance in female to male gender ratios was recorded with about 4:1 for adult elephants and 1:4 for adult macaques. Severely inadequate welfare conditions were common, with 75% of macaques and 99% of tigers being kept at venues with scores less than 5. 86% of elephants were kept in inadequate conditions at venues with scores between 3 and 5, but a significant number of venues with scores above 5 were found. 4.6% of elephants were provided commendable conditions, reaching assessment scores of 8 and above. 71% of venues did not offer any sort of education about animals to visitors. This study is the first to assess welfare aspects of captive wild animals at tourism venues across Thailand. It concludes that significant concerns exist about the welfare of wild animals in the tourism sector of Thailand. Urgent attention needs to be given to address these concerns and prevent further suffering. But also to ensure the demand for wild animals doesn’t have a negative impact on wild populations. PMID:26407173

[Analysis on content of serum monoamine neurotransmitters in macaques with anger-in-induced premenstrual syndrome and liver-qi depression syndrome].

PubMed

Wei, Sheng; Hou, Jin-Liang; Chao, Yu-Bin; Du, Xi-Yang; Zong, Shao-Bo

2012-08-01

To observe the changes in content of monoamine neurotransmitters in the serum of rhesus macaques, and explore the role of serum monoamine neurotransmitters in premenstrual syndrome (PMS) and liver-qi depression induced by anger-in emotion. Social level pressure was applied on 24 female macaques to induce the angry emotional reaction, and then nine of the low-status macaques with anger-in emotional reaction were screened out and were divided into anger-in emotion group, PMS and liver-qi depression group (model group) and Jingqianshu Granule group. Macaques in the last two groups were suffered extruding in a pack cage for inducing PMS liver-qi depression. After 5 d of extruding, experimental animals were evaluated according to the emotional evaluation scale, meanwhile, macaque serum of follicular phase and middle-late luteal phase was collected to analyze the content of serum norepinephrine, dopamine, and 5-hydroxytryptamine. Compared with the normal control group, the scores of depression of the model group and the anger-in emotion group evaluated with emotional evaluation scale were significantly increased (P<0.01, P<0.05); while the score of the model group was significantly higher than that of the anger-in emotion group (P<0.05), and it returned to normal after Jingqianshu Granule treatment. As compared to the normal control group, serum monoamine neurotransmitter levels of the model group and the anger-in emotion group were increased (P<0.05, P<0.01), and the serum monoamine neurotransmitter levels of the model group were significantly higher than those of the anger-in emotion group (P<0.05), while there was no significant difference when compared with the normal control group after the treatment. Anger-in emotion can induce liver-qi depression syndrome which is related to the changes in monoamine neurotransmitters.

Antibody-mediated protection against mucosal simian-human immunodeficiency virus challenge of macaques immunized with alphavirus replicon particles and boosted with trimeric envelope glycoprotein in MF59 adjuvant.

PubMed

Barnett, Susan W; Burke, Brian; Sun, Yide; Kan, Elaine; Legg, Harold; Lian, Ying; Bost, Kristen; Zhou, Fengmin; Goodsell, Amanda; Zur Megede, Jan; Polo, John; Donnelly, John; Ulmer, Jeffrey; Otten, Gillis R; Miller, Christopher J; Vajdy, Michael; Srivastava, Indresh K

2010-06-01

We have previously shown that rhesus macaques were partially protected against high-dose intravenous challenge with simian-human immunodeficiency virus SHIV(SF162P4) following sequential immunization with alphavirus replicon particles (VRP) of a chimeric recombinant VEE/SIN alphavirus (derived from Venezuelan equine encephalitis virus [VEE] and the Sindbis virus [SIN]) encoding human immunodeficiency virus type 1 HIV-1(SF162) gp140DeltaV2 envelope (Env) and trimeric Env protein in MF59 adjuvant (R. Xu, I. K. Srivastava, C. E. Greer, I. Zarkikh, Z. Kraft, L. Kuller, J. M. Polo, S. W. Barnett, and L. Stamatatos, AIDS Res. Hum. Retroviruses 22:1022-1030, 2006). The protection did not require T-cell immune responses directed toward simian immunodeficiency virus (SIV) Gag. We extend those findings here to demonstrate antibody-mediated protection against mucosal challenge in macaques using prime-boost regimens incorporating both intramuscular and mucosal routes of delivery. The macaques in the vaccination groups were primed with VRP and then boosted with Env protein in MF59 adjuvant, or they were given VRP intramuscular immunizations alone and then challenged with SHIV(SF162P4) (intrarectal challenge). The results demonstrated that these vaccines were able to effectively protect the macaques to different degrees against subsequent mucosal SHIV challenge, but most noteworthy, all macaques that received the intramuscular VRP prime plus Env protein boost were completely protected. A statistically significant association was observed between the titer of virus neutralizing and binding antibodies as well as the avidity of anti-Env antibodies measured prechallenge and protection from infection. These results highlight the merit of the alphavirus replicon vector prime plus Env protein boost vaccine approach for the induction of protective antibody responses and are of particular relevance to advancing our understanding of the potential correlates of immune protection against HIV infection at a relevant mucosal portal of entry.

Within-Host Evolution of Simian Arteriviruses in Crab-Eating Macaques

PubMed Central

Moncla, Louise H.; Weiler, Andrea M.; Barry, Gabrielle; Weinfurter, Jason T.; Dinis, Jorge M.; Charlier, Olivia; Lauck, Michael; Bailey, Adam L.; Wahl-Jensen, Victoria; Nelson, Chase W.; Johnson, Joshua C.; Caì, Yíngyún; Goldberg, Tony L.; O'Connor, David H.; Jahrling, Peter B.

2016-01-01

ABSTRACT Simian arteriviruses are a diverse clade of viruses infecting captive and wild nonhuman primates. We recently reported that Kibale red colobus virus 1 (KRCV-1) causes a mild and self-limiting disease in experimentally infected crab-eating macaques, while simian hemorrhagic fever virus (SHFV) causes lethal viral hemorrhagic fever. Here we characterize how these viruses evolved during replication in cell culture and in experimentally infected macaques. During passage in cell culture, 68 substitutions that were localized in open reading frames (ORFs) likely associated with host cell entry and exit became fixed in the KRCV-1 genome. However, we did not detect any strong signatures of selection during replication in macaques. We uncovered patterns of evolution that were distinct from those observed in surveys of wild red colobus monkeys, suggesting that these species may exert different adaptive challenges for KRCV-1. During SHFV infection, we detected signatures of selection on ORF 5a and on a small subset of sites in the genome. Overall, our data suggest that patterns of evolution differ markedly among simian arteriviruses and among host species. IMPORTANCE Certain RNA viruses can cross species barriers and cause disease in new hosts. Simian arteriviruses are a diverse group of related viruses that infect captive and wild nonhuman primates, with associated disease severity ranging from apparently asymptomatic infections to severe, viral hemorrhagic fevers. We infected nonhuman primate cell cultures and then crab-eating macaques with either simian hemorrhagic fever virus (SHFV) or Kibale red colobus virus 1 (KRCV-1) and assessed within-host viral evolution. We found that KRCV-1 quickly acquired a large number of substitutions in its genome during replication in cell culture but that evolution in macaques was limited. In contrast, we detected selection focused on SHFV ORFs 5a and 5, which encode putative membrane proteins. These patterns suggest that in addition to diverse pathogenic phenotypes, these viruses may also exhibit distinct patterns of within-host evolution both in vitro and in vivo. PMID:27974564

Beneficial effect of hot spring bathing on stress levels in Japanese macaques.

PubMed

Takeshita, Rafaela S C; Bercovitch, Fred B; Kinoshita, Kodzue; Huffman, Michael A

2018-05-01

The ability of animals to survive dramatic climates depends on their physiology, morphology and behaviour, but is often influenced by the configuration of their habitat. Along with autonomic responses, thermoregulatory behaviours, including postural adjustments, social aggregation, and use of trees for shelter, help individuals maintain homeostasis across climate variations. Japanese macaques (Macaca fuscata) are the world's most northerly species of nonhuman primates and have adapted to extremely cold environments. Given that thermoregulatory stress can increase glucocorticoid concentrations in primates, we hypothesized that by using an available hot spring, Japanese macaques could gain protection against weather-induced cold stress during winter. We studied 12 adult female Japanese macaques living in Jigokudani Monkey Park, Japan, during the spring birth season (April to June) and winter mating season (October to December). We collected faecal samples for determination of faecal glucocorticoid (fGC) metabolite concentrations by enzyme immunoassay, as well as behavioural data to determine time spent in the hot springs, dominance rank, aggression rates, and affiliative behaviours. We used nonparametric statistics to examine seasonal changes in hot spring bathing, and the relationship between rank and air temperature on hot spring bathing. We used general linear mixed-effect models to examine factors impacting hormone concentrations. We found that Japanese macaques use hot spring bathing for thermoregulation during the winter. In the studied troop, the single hot spring is a restricted resource favoured by dominant females. High social rank had both costs and benefits: dominant females sustained high fGC levels, which were associated with high aggression rates in winter, but benefited by priority of access to the hot spring, which was associated with low fGC concentrations and therefore might help reduce energy expenditure and subsequent body heat loss. This unique habit of hot spring bathing by Japanese macaques illustrates how behavioural flexibility can help counter cold climate stress, with likely implications for reproduction and survival.

Distribution of simian immunodeficiency virus target cells in vaginal tissues of normal rhesus macaques: implications for virus transmission.

PubMed

Poonia, Bhawna; Wang, Xiaolei; Veazey, Ronald S

2006-12-01

Most new cases of HIV-1 infection occur as the result of vaginal transmission. Identifying the phenotype and distribution of potential viral target cells in the vagina is important for understanding events in viral transmission and for developing effective prevention strategies. For example, compounds that prevent CD4 or CCR5 binding have been demonstrated recently to prevent vaginal transmission in rhesus macaques, but the expression and distribution of CCR5 has not been examined in the macaque vagina. The objective of this study was to examine the distribution and phenotype of cells and molecules in the vagina of rhesus macaques that may be involved in HIV transmission, including CCR5, CD3, CD4, CD8, CD1a, CD28, CD95, CD123 and HLA-DR. Normal juvenile and adult female rhesus macaques were examined by multicolor immunohistochemistry and flow cytometry. Although both CD4 and CCR5 were observed in the lamina propria, essentially no CD4 or CCR5 expression was detected within the squamous or keratinized layers of the vaginal epithelium. CCR5 expression was higher in the vaginal lamina propria of mature macaques compared to 1-3-year-old juveniles. The vast majority of CD4(+)CCR5(+) lymphocytes in the vagina had a central memory (CD95(+)CD28(+)) phenotype. Numerous CCR5-expressing dendritic cells (CD123(+)) or macrophages (CD68(+)) were observed in the lamina propria, but no CCR5, CD4 or DC-SIGN expression was detectable in the epithelium. Thus, the multiple layers of squamous epithelium normally covering the vaginal mucosa may provide an effective barrier against vaginal HIV-1 transmission. Microbicides that block CD4 or CCR5 expression may act within the deeper layers of the vaginal epithelium rather than on the epithelial surface.

Effect of Chronic Social Stress on Prenatal Transfer of Antitetanus Immunity in Captive Breeding Rhesus Macaques (Macaca mulatta).

PubMed

Stammen, Rachelle L; Cohen, Joyce K; Meeker, Tracy L; Crane, Maria M; Amara, Rama R; Hicks, Sakeenah L; Meyer, Jerrold S; Ethun, Kelly F

2018-05-15

Because tetanus can cause significant morbidity and mortality in NHP, colonywide vaccination with tetanus toxoid is recommendedfor outdoor breeding colonies of rhesus macaques, with primary immunizations commonly given to infants at 6 mo of age followed by booster vaccines every 10 y. Maternal antibodies are thought to offer protective immunity to infants younger than 6 mo. However, historical colony data from the Yerkes National Primate Research Center show a higher incidence of tetanus among infants (≤ 6 mo old) born to subordinate dams. Whether this higher incidence of infantile tetanus is due to a higher incidence of trauma among subordinate animals or is a stress-induced impairment of maternal antibody protection is unknown. Studies in other NHP species suggest that chronic exposure to social stressors interferes with the receptor-mediated transplacental transfer of IgG. Therefore, the primary aim of this study was to determine whether chronic stress associated with social subordination impairs prenatal transfer of antitetanus immunity in breeding female rhesus macaques. Subjects included 26 high- and 26 low-ranking adult female rhesus macaques that were nearly 5 or 10 y after their initial immunization and their nonimmunized infants. We hypothesized that infants born to subordinate dams that were nearly 10 y after immunization would have the lowest infant-to-dam antibody ratios and thus would be at greatest risk for infection. Results revealed no significant intergroup differences in infant antitetanus IgG levels. However, infant-to-dam IgG ratios against tetanus were significantly lower among subordinate animals compared with dominant macaques, after accounting for the number of years since the dam's initial vaccination. In addition, higher maternal hair cortisol levels predicted lower infant-to-dam tetanus toxoid IgG ratios. Together, these findings suggest that chronic social stress in female rhesus macaques may hamper the prenatal transfer of antitetanus immunity to offspring.

Asian Elephant (Elephas maximus), Pig-Tailed Macaque (Macaca nemestrina) and Tiger (Panthera tigris) Populations at Tourism Venues in Thailand and Aspects of Their Welfare.

PubMed

Schmidt-Burbach, Jan; Ronfot, Delphine; Srisangiam, Rossukon

2015-01-01

This study focused on determining the size and welfare aspects of Asian elephant, pig-tailed macaque and tiger populations at facilities open to tourists in Thailand. Data were gathered from 118 venues through direct observations and interviews with staff. A score sheet-based welfare assessment was used to calculate scores between 1 and 10, indicating each venue's welfare situation. Factors such as freedom of movement for the animals, access to veterinary care, environmental noise quality, hygiene standards and work intensity were included in the score sheet. 1688 elephants, 371 macaques and 621 tigers were found at the venues. 89 venues exclusively kept elephants, 9 designated 'Monkey schools' offered macaque shows, 4 venues kept primarily tigers, mostly for petting and photo opportunities, and the remaining venues kept a mix of these animals. A strong imbalance in female to male gender ratios was recorded with about 4:1 for adult elephants and 1:4 for adult macaques. Severely inadequate welfare conditions were common, with 75% of macaques and 99% of tigers being kept at venues with scores less than 5. 86% of elephants were kept in inadequate conditions at venues with scores between 3 and 5, but a significant number of venues with scores above 5 were found. 4.6% of elephants were provided commendable conditions, reaching assessment scores of 8 and above. 71% of venues did not offer any sort of education about animals to visitors. This study is the first to assess welfare aspects of captive wild animals at tourism venues across Thailand. It concludes that significant concerns exist about the welfare of wild animals in the tourism sector of Thailand. Urgent attention needs to be given to address these concerns and prevent further suffering. But also to ensure the demand for wild animals doesn't have a negative impact on wild populations.

What Cortisol Can Tell us About the Costs of Sociality and Reproduction Among Free-Ranging Rhesus Macaque Females on Cayo Santiago

PubMed Central

Maestripieri, Dario; Georgiev, Alexander V.

2015-01-01

Research with the rhesus macaque population on Cayo Santiago can provide a unique perspective on the costs of sociality and reproduction in primates. Because the Cayo macaques live in unusually large groups and in a predator-free environment, in which their artificial food source lacks seasonal variation in abundance or quality, these monkeys constitute a semi-experimental study of the costs and benefits of group living. Here we review several long- and short-term studies that have focused on female life history and stress physiology. Long-term demographic data have shown that rhesus macaque females of middle- and low-ranking matrilines have lower adult survival probabilities than females of high-ranking matrilines. Costs of reproductive effort are also evident: adult females were more likely to die during the birth than during the mating season and they experienced higher cortisol levels when lactating. Lower-ranking females, in particular, experienced greater relative increase in cortisol production during lactation, in comparison to middle- and high-ranking females. Older high-ranking females had lower plasma cortisol levels than younger ones but cortisol levels were similarly high among young and old middle- and low-ranking females. Higher plasma cortisol levels and/or fecal glucocorticoid concentrations are associated with higher plasma concentrations of some proinflammatory cytokines. High cortisol, in turn, may be associated with chronic inflammation, and perhaps also with immunosuppression. In sum, the studies reviewed here provide multiple lines of evidence that sociality and reproductive effort impose measurable costs on female rhesus macaques. In line with socioecological theory, female dominance rank consistently emerges as an important modulator of variation in female life histories and physiology. The Cayo Santiago macaques are therefore a valuable model for elucidating the mechanisms by which within-group competition and reproduction impact health and survival in nonhuman primates and in humans. Am. J. Primatol. PMID:25643836

Infection of rhesus macaques with a pool of simian immunodeficiency virus with the envelope genes from acute HIV-1 infections.

PubMed

Krebs, Kendall C; Tian, Meijuan; Asmal, Mohammed; Ling, Binhua; Nelson, Kenneth; Henry, Kenneth; Gibson, Richard; Li, Yuejin; Han, Weining; Shattock, Robin J; Veazey, Ronald S; Letvin, Norman; Arts, Eric J; Gao, Yong

2016-11-25

New simian-human immunodeficiency chimeric viruses with an HIV-1 env (SHIVenv) are critical for studies on HIV pathogenesis, vaccine development, and microbicide testing. Macaques are typically exposed to single CCR5-using SHIVenv which in most instances does not reflect the conditions during acute/early HIV infection (AHI) in humans. Instead of individual and serial testing new SHIV constructs, a pool of SHIVenv_B derived from 16 acute HIV-1 infections were constructed using a novel yeast-based SHIV cloning approach and then used to infect macaques. Even though none of the 16 SHIVenvs contained the recently reported mutations in env genes that could significantly enhance their binding affinity to RhCD4, one SHIVenv (i.e. SHIVenv_B3-PRB926) established infection in macaques exposed to this pool. AHI SHIVenv_B viruses as well as their HIVenv_B counterparts were analyzed for viral protein content, function, and fitness to identify possible difference between SHIVenv_B3-PRB926 and the other 15 SHIVenvs in the pool. All of the constructs produced SHIV or HIV chimeric with wild type levels of capsid (p27 and p24) content, reverse transcriptase (RT) activity, and expressed envelope glycoproteins that could bind to cell receptors CD4/CCR5 and mediate virus entry. HIV-1env_B chimeric viruses were propagated in susceptible cell lines but the 16 SHIVenv_B variants showed only limited replication in macaque peripheral blood mononuclear cells (PBMCs) and 174×CEM.CCR5 cell line. AHI chimeric viruses including HIVenv_B3 showed only minor variations in cell entry efficiency and kinetics as well as replicative fitness in human PBMCs. Reduced number of N-link glycosylation sites and slightly greater CCR5 affinity/avidity was the only distinguishing feature of env_B3 versus other AHI env's in the pool, a feature also observed in the HIV establishing new infections in humans. Despite the inability to propagate in primary cells and cell lines, a pool of 16 SHIVenv viruses could establish infection but only one virus, SHIVenv_B3 was isolated in the macaque and then shown to repeatedly infected macaques. This SHIVenv_B3 virus did not show any distinct phenotypic property from the other 15 SHIVenv viruses but did have the fewest N-linked glycosylation sites.

Divergent Simian Arteriviruses Cause Simian Hemorrhagic Fever of Differing Severities in Macaques.

PubMed

Wahl-Jensen, Victoria; Johnson, Joshua C; Lauck, Michael; Weinfurter, Jason T; Moncla, Louise H; Weiler, Andrea M; Charlier, Olivia; Rojas, Oscar; Byrum, Russell; Ragland, Dan R; Huzella, Louis; Zommer, Erika; Cohen, Melanie; Bernbaum, John G; Caì, Yíngyún; Sanford, Hannah B; Mazur, Steven; Johnson, Reed F; Qin, Jing; Palacios, Gustavo F; Bailey, Adam L; Jahrling, Peter B; Goldberg, Tony L; O'Connor, David H; Friedrich, Thomas C; Kuhn, Jens H

2016-02-23

Simian hemorrhagic fever (SHF) is a highly lethal disease in captive macaques. Three distinct arteriviruses are known etiological agents of past SHF epizootics, but only one, simian hemorrhagic fever virus (SHFV), has been isolated in cell culture. The natural reservoir(s) of the three viruses have yet to be identified, but African nonhuman primates are suspected. Eleven additional divergent simian arteriviruses have been detected recently in diverse and apparently healthy African cercopithecid monkeys. Here, we report the successful isolation in MARC-145 cell culture of one of these viruses, Kibale red colobus virus 1 (KRCV-1), from serum of a naturally infected red colobus (Procolobus [Piliocolobus] rufomitratus tephrosceles) sampled in Kibale National Park, Uganda. Intramuscular (i.m.) injection of KRCV-1 into four cynomolgus macaques (Macaca fascicularis) resulted in a self-limiting nonlethal disease characterized by depressive behavioral changes, disturbance in coagulation parameters, and liver enzyme elevations. In contrast, i.m. injection of SHFV resulted in typical lethal SHF characterized by mild fever, lethargy, lymphoid depletion, lymphoid and hepatocellular necrosis, low platelet counts, increased liver enzyme concentrations, coagulation abnormalities, and increasing viral loads. As hypothesized based on the genetic and presumed antigenic distance between KRCV-1 and SHFV, all four macaques that had survived KRCV-1 injection died of SHF after subsequent SHFV injection, indicating a lack of protective heterotypic immunity. Our data indicate that SHF is a disease of macaques that in all likelihood can be caused by a number of distinct simian arteriviruses, although with different severity depending on the specific arterivirus involved. Consequently, we recommend that current screening procedures for SHFV in primate-holding facilities be modified to detect all known simian arteriviruses. Outbreaks of simian hemorrhagic fever (SHF) have devastated captive Asian macaque colonies in the past. SHF is caused by at least three viruses of the family Arteriviridae: simian hemorrhagic fever virus (SHFV), simian hemorrhagic encephalitis virus (SHEV), and Pebjah virus (PBJV). Nine additional distant relatives of these three viruses were recently discovered in apparently healthy African nonhuman primates. We hypothesized that all simian arteriviruses are potential causes of SHF. To test this hypothesis, we inoculated cynomolgus macaques with a highly divergent simian arterivirus (Kibale red colobus virus 1 [KRCV-1]) from a wild Ugandan red colobus. Despite being only distantly related to red colobuses, all of the macaques developed disease. In contrast to SHFV-infected animals, KRCV-1-infected animals survived after a mild disease presentation. Our study advances the understanding of an important primate disease. Furthermore, our data indicate a need to include the full diversity of simian arteriviruses in nonhuman primate SHF screening assays. Copyright © 2016 Wahl-Jensen et al.

Influenza virus A/Anhui/1/2013 (H7N9) replicates efficiently in the upper and lower respiratory tracts of cynomolgus macaques.

PubMed

de Wit, Emmie; Rasmussen, Angela L; Feldmann, Friederike; Bushmaker, Trenton; Martellaro, Cynthia; Haddock, Elaine; Okumura, Atsushi; Proll, Sean C; Chang, Jean; Gardner, Don; Katze, Michael G; Munster, Vincent J; Feldmann, Heinz

2014-08-12

In March 2013, three fatal human cases of infection with influenza A virus (H7N9) were reported in China. Since then, human cases have been accumulating. Given the public health importance of this virus, we performed a pathogenicity study of the H7N9 virus in the cynomolgus macaque model, focusing on clinical aspects of disease, radiographic, histological, and gene expression profile changes in the upper and lower respiratory tracts, and changes in systemic cytokine and chemokine profiles during infection. Cynomolgus macaques developed transient, mild to severe disease with radiographic evidence of pulmonary infiltration. Virus replicated in the upper as well as lower respiratory tract, with sustained replication in the upper respiratory tract until the end of the experiment at 6 days after inoculation. Virus shedding occurred mainly via the throat. Histopathological changes in the lungs were similar to those observed in humans, albeit less severe, with diffuse alveolar damage, infiltration of polymorphonuclear cells, formation of hyaline membranes, pneumocyte hyperplasia, and fibroproliferative changes. Analysis of gene expression profiles in lung lesions identified pathways involved in tissue damage during H7N9 infection as well as leads for development of therapeutics targeting host responses rather than virus replication. Overall, H7N9 infection was not as severe in cynomolgus macaques as in humans, supporting the possible role of underlying medical complications in disease severity as discussed for human H7N9 infection (H. N. Gao et al., N. Engl. J. Med. 368:2277-2285, 2013, doi:10.1056/NEJMoa1305584). Influenza A virus H7N9 emerged early in 2013, and human cases have continued to emerge since then. Although H7N9 virus-induced disease in humans is often very severe and even lethal, the majority of reported H7N9 cases occurred in older people and people with underlying medical conditions. To better understand the pathogenicity of this virus, healthy cynomolgus macaques were inoculated with influenza A virus H7N9. Cynomolgus macaques were used as a model because the receptor distribution for H7N9 virus in macaques was recently shown to be more similar to that in humans than that of other frequently used animal models. From comparison with previous studies, we conclude that the emerging H7N9 influenza virus was more pathogenic in cynomolgus macaques than seasonal influenza A viruses and most isolates of the pandemic H1N1 virus but less pathogenic than the 1918 Spanish influenza virus or highly pathogenic avian influenza (HPAI) H5N1 virus. Copyright © 2014 de Wit et al.

Repertoire comparison of the B-cell receptor encoding loci in humans and rhesus macaques by next generation sequencing

USDA-ARS?s Scientific Manuscript database

Rhesus macaques are a widely used model system for the study of vaccines, infectious diseases, and microbial pathogenesis. Their value as a model lies in their close evolutionary relationship to humans, which, in theory, allows them to serve as a close approximation of the human immune system. Howev...

Spatial Relational Memory in 9-Month-Old Macaque Monkeys

ERIC Educational Resources Information Center

Lavenex, Pierre; Lavenex, Pamela Banta

2006-01-01

This experiment assesses spatial and nonspatial relational memory in freely moving 9-mo-old and adult (11-13-yr-old) macaque monkeys ("Macaca mulatta"). We tested the use of proximal landmarks, two different objects placed at the center of an open-field arena, as conditional cues allowing monkeys to predict the location of food rewards hidden in…

Spontaneous Representations of Small Numbers of Objects by Rhesus Macaques: Examinations of Content and Format

ERIC Educational Resources Information Center

Hauser, Marc D.; Carey, Susan

2003-01-01

The project of comparative cognition benefits from common measures across species. We report here on five experiments using the violation of expectancy looking time measure with free-ranging rhesus macaques ("Macaca mulatta"), each designed to build on current knowledge concerning spontaneous representations of number. Each subject, tested in only…

Monkey vocal tracts are speech-ready.

PubMed

Fitch, W Tecumseh; de Boer, Bart; Mathur, Neil; Ghazanfar, Asif A

2016-12-01

For four decades, the inability of nonhuman primates to produce human speech sounds has been claimed to stem from limitations in their vocal tract anatomy, a conclusion based on plaster casts made from the vocal tract of a monkey cadaver. We used x-ray videos to quantify vocal tract dynamics in living macaques during vocalization, facial displays, and feeding. We demonstrate that the macaque vocal tract could easily produce an adequate range of speech sounds to support spoken language, showing that previous techniques based on postmortem samples drastically underestimated primate vocal capabilities. Our findings imply that the evolution of human speech capabilities required neural changes rather than modifications of vocal anatomy. Macaques have a speech-ready vocal tract but lack a speech-ready brain to control it.

Short Communication: Comparative Susceptibility of Rhesus Macaques of Indian and Chinese Origin to Vaginal Simian-Human Immunodeficiency Virus Transmission as Models for HIV Prevention Research.

PubMed

Veazey, Ronald S; Ling, Binhua

2017-12-01

Historically, Indian rhesus macaques (iRMs) have been preferred for simian immunodeficiency virus (SIV)/HIV prevention, pathogenesis, and treatment studies, yet their supply is limited. Chinese rhesus macaques (cRMs) are currently more available, yet little is known regarding the relative susceptibility of this subspecies to vaginal transmission of SIV or simian-human immunodeficiency virus (SHIV). In this study, we compared the susceptibility of 40 cRMs and 21 iRMs with a single vaginal challenge with SHIVsf162P. Our results showed that cRMs have comparable primary SHIV infection as iRMs, underscoring their equal importance in studies of HIV transmission and prevention.

Molecular and functional aspects of menstruation in the macaque.

PubMed

Brenner, Robert M; Slayden, Ov D

2012-12-01

Much of our understanding of the molecular control of menstruation arises from laboratory models that experimentally recapitulate some, but not all, aspects of uterine bleeding observed in women. These models include: in vitro culture of endometrial explants or isolated endometrial cells, transplantation of human endometrial tissue into immunodeficient mice and the induction of endometrial breakdown in appropriately pretreated mice. Each of these models has contributed to our understanding of molecular and cellular mechanisms of menstruation, but nonhuman primates, especially macaques, are the animal model of choice for evaluating therapies for menstrual disorders. In this chapter we review some basic aspects of menstruation, with special emphasis on the macaque model and its relevance to the clinical issues of irregular and heavy menstrual bleeding (HMB).

Otoacoustic Estimates of Cochlear Tuning: Testing Predictions in Macaque

NASA Astrophysics Data System (ADS)

Shera, Christopher A.; Bergevin, Christopher; Kalluri, Radha; Mc Laughlin, Myles; Michelet, Pascal; van der Heijden, Marcel; Joris, Philip X.

2011-11-01

Otoacoustic estimates of cochlear frequency selectivity suggest substantially sharper tuning in humans. However, the logic and methodology underlying these estimates remain untested by direct measurements in primates. We report measurements of frequency tuning in macaque monkeys, Old-World primates phylogenetically closer to humans than the small laboratory animals often taken as models of human hearing (e.g., cats, guinea pigs, and chinchillas). We find that measurements of tuning obtained directly from individual nerve fibers and indirectly using otoacoustic emissions both indicate that peripheral frequency selectivity in macaques is significantly sharper than in small laboratory animals, matching that inferred for humans at high frequencies. Our results validate the use of otoacoustic emissions for noninvasive measurement of cochlear tuning and corroborate the finding of sharper tuning in humans.

Viral kinetics are associated with changes in cytokines and chemokines in serum and target organs of SSM-CVB3-infected macaques.

PubMed

Han, Tiesuo; Zhao, Kui; Wu, Chenchen; Lu, Huijun; Song, Deguang; He, Wenqi; Gao, Feng

2013-02-01

To determine the relationship between viral kinetics and the expression patterns for different cytokines and chemokines in the serum and organs of coxsackievirus B3 (SSM-CVB3)-infected macaques over the course of infection. SSM-CVB3 levels in serum and organs were measured using the Spearman-Karber 50% tissue culture infectious dose (TCID(50)) method. Cytokine and chemokine levels in the serum and organs were measured by indirect-ELISA. Low viral titers were detected in the serum samples on the first day post-inoculation (p.i.) and peaked at 6 to 10 days p.i. in the serum samples from five macaques. Serum levels of IL-1β, IL-2, IL-6, IL-12p40, IL-17α, IFN-γ, TNF-α, MCP-1 and MIP-1β were detected each day and, similar to the viral titers, peaked at 6 to 10 days. IL-10 was only detected on days 10 to 14 p.i. Additionally, higher viral titers and relative viral mRNA levels were associated with higher cytokine and chemokine levels in selected tissues from infected macaques including heart, liver, spleen, lung, kidney and brain. The results indicate that patterns of cytokine and chemokine response are associated with viral kinetics in the serum and target organs of SSM-CVB3-infected macaques, suggesting that the changes in cytokines and chemokines could help further our understanding of the progress of CVB3 infections in clinical settings. Copyright © 2012 Elsevier Inc. All rights reserved.

Sex differences in the stone tool-use behavior of a wild population of burmese long-tailed macaques (Macaca fascicularis aurea).

PubMed

Gumert, Michael D; Hoong, Low Kuan; Malaivijitnond, Suchinda

2011-12-01

We investigated sex differences in how Burmese long-tailed macaques (Macaca fascicularis aurea) used stone tools to open shelled food items along the shores of two islands in Laemson National Park, Thailand. Over a 2-week period in December 2009, we collected scan and focal samples on macaques when they were visible along the shores and mangroves. We found females used stones more often while feeding and used smaller tools than males. Females also processed sessile oysters more than males, whereas males processed unattached foods more than females. It was unclear which sex was overall more proficient at stone tool use, but males did perform significantly better at opening unattached food items with large pounding stones. Females also struck food items more times during tool-use bouts and at a faster rate, but no significant difference was found in average tool-use bout duration. Males processed foods slightly faster within a tool-use bout, but we were unable to detect a significant difference in the rate of food processing while foraging with tools. In summary females chipped open sessile oysters with an axing technique more than males, while males used larger stones to pound open unattached shelled food more often than females. Despite using pounding more than females, males also regularly utilized the axing technique on sessile oysters. Our results are the first assessment of sex differences in macaque stone tool use, providing a basis for comparison with tool use in other primates, and to nonfunctional forms of stone use in other macaques. © 2011 Wiley Periodicals, Inc.

Distribution of glutamatergic, GABAergic, and glycinergic neurons in the auditory pathways of macaque monkeys.

PubMed

Ito, T; Inoue, K; Takada, M

2015-12-03

Macaque monkeys use complex communication calls and are regarded as a model for studying the coding and decoding of complex sound in the auditory system. However, little is known about the distribution of excitatory and inhibitory neurons in the auditory system of macaque monkeys. In this study, we examined the overall distribution of cell bodies that expressed mRNAs for VGLUT1, and VGLUT2 (markers for glutamatergic neurons), GAD67 (a marker for GABAergic neurons), and GLYT2 (a marker for glycinergic neurons) in the auditory system of the Japanese macaque. In addition, we performed immunohistochemistry for VGLUT1, VGLUT2, and GAD67 in order to compare the distribution of proteins and mRNAs. We found that most of the excitatory neurons in the auditory brainstem expressed VGLUT2. In contrast, the expression of VGLUT1 mRNA was restricted to the auditory cortex (AC), periolivary nuclei, and cochlear nuclei (CN). The co-expression of GAD67 and GLYT2 mRNAs was common in the ventral nucleus of the lateral lemniscus (VNLL), CN, and superior olivary complex except for the medial nucleus of the trapezoid body, which expressed GLYT2 alone. In contrast, the dorsal nucleus of the lateral lemniscus, inferior colliculus, thalamus, and AC expressed GAD67 alone. The absence of co-expression of VGLUT1 and VGLUT2 in the medial geniculate, medial superior olive, and VNLL suggests that synaptic responses in the target neurons of these nuclei may be different between rodents and macaque monkeys. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Minimally Invasive Lumbar Port System for the Collection of Cerebrospinal Fluid from Rhesus Macaques (Macaca mulatta)

PubMed Central

MacAllister, Rhonda Pung; Lester McCully, Cynthia M; Bacher, John; Thomas, Marvin L; Cruz, Rafael; Wangari, Solomon; Warren, Katherine E

2016-01-01

Biomedical translational research frequently incorporates collection of CSF from NHP, because CSF drug levels are used as a surrogate for CNS tissue penetration in pharmacokinetic and dynamic studies. Surgical placement of a CNS ventricular catheter reservoir for CSF collection is an intensive model to create and maintain and thus may not be feasible or practical for short-term studies. Furthermore, previous NHP lumbar port models require laminectomy for catheter placement. The new model uses a minimally invasive technique for percutaneous placement of a lumbar catheter to create a closed, subcutaneous system for effective, repeated CSF sample collection. None of the rhesus macaques (Macaca mulatta; n = 10) implanted with our minimally invasive lumbar port (MILP) system experienced neurologic deficits, postoperative infection of the surgical site, or skin erosion around the port throughout the 21.7-mo study. Functional MILP systems were maintained in 70% of the macaques, with multiple, high-quality, 0.5- to 1.0-mL samples of CSF collected for an average of 3 mo by using aspiration or gravitational flow. Among these macaques, 57% had continuous functionality for a mean of 19.2 mo; 50% of the cohort required surgical repair for port repositioning and replacement during the study. The MILP was unsuccessful in 2 macaques, at an average of 9.5 d after surgery. Nonpatency in these animals was attributed to the position of the lumbar catheter. The MILP system is an appropriate replacement for temporary catheterization and previous models requiring laminectomy and is a short-term alternative for ventricular CSF collection systems in NHP. PMID:27538866

Connectivity profiles reveal the relationship between brain areas for social cognition in human and monkey temporoparietal cortex

PubMed Central

Mars, Rogier B.; Sallet, Jérôme; Neubert, Franz-Xaver; Rushworth, Matthew F. S.

2013-01-01

The human ability to infer the thoughts and beliefs of others, often referred to as “theory of mind,” as well as the predisposition to even consider others, are associated with activity in the temporoparietal junction (TPJ) area. Unlike the case of most human brain areas, we have little sense of whether or how TPJ is related to brain areas in other nonhuman primates. It is not possible to address this question by looking for similar task-related activations in nonhuman primates because there is no evidence that nonhuman primates engage in theory-of-mind tasks in the same manner as humans. Here, instead, we explore the relationship by searching for areas in the macaque brain that interact with other macaque brain regions in the same manner as human TPJ interacts with other human brain regions. In other words, we look for brain regions with similar positions within a distributed neural circuit in the two species. We exploited the fact that human TPJ has a unique functional connectivity profile with cortical areas with known homologs in the macaque. For each voxel in the macaque temporal and parietal cortex we evaluated the similarity of its functional connectivity profile to that of human TPJ. We found that areas in the middle part of the superior temporal cortex, often associated with the processing of faces and other social stimuli, have the most similar connectivity profile. These results suggest that macaque face processing areas and human mentalizing areas might have a similar precursor. PMID:23754406

Recent advances in the development of vaccines against ricin.

PubMed

Brey, Robert N; Mantis, Nicholas J; Pincus, Seth H; Vitetta, Ellen S; Smith, Leonard A; Roy, Chad J

2016-05-03

Several promising subunit vaccines against ricin toxin (RT) have been developed during the last decade and are now being tested for safety and immunogenicity in humans and for efficacy in nonhuman primates. The incentive to develop a preventive vaccine as a countermeasure against RT use as a bioweapon is based on the high toxicity of RT after aerosol exposure, its environmental stability, abundance, and ease of purification. RT is the second most lethal biological toxin and is considered a "universal toxin" because it can kill all eukaryotic cells through binding to ubiquitous cell surface galactosyl residues. RT has two subunits conjoined by a single disulfide linkage: RTB, which binds galactosyl residues and RTA which enzymatically inactivates ribosomes intracellularly by cleavage ribosomal RNA. Attenuation of toxicity by elimination of the active site or introduction of other structural mutations of RTA has generated two similar clinical subunit vaccine candidates which induce antibodies in both humans and nonhuman primates. In rhesus macaques, inhaled RT causes rapid lung necrosis and fibrosis followed by death. After parenteral vaccination with RTA vaccine, macaques can be protected against aerosol RT exposure, suggesting that circulating antibodies can protect lung mucosa. Vaccination induces RT-neutralizing antibodies, the most likely correlate of protection. Macaques responded to conformational determinants in an RTA vaccine formulation, indicating preservation of RTA structure during initial manufacture. Comparative mapping studies have also demonstrated that macaques and humans recognize the same epitopes, significant in the study of macaques as a model during development of vaccines which cannot be tested for efficacy in humans.

The Organization of Dorsal Frontal Cortex in Humans and Macaques

PubMed Central

Mars, Rogier B.; Noonan, MaryAnn P.; Neubert, Franz-Xaver; Jbabdi, Saad; O'Reilly, Jill X.; Filippini, Nicola; Thomas, Adam G.; Rushworth, Matthew F.

2013-01-01

The human dorsal frontal cortex has been associated with the most sophisticated aspects of cognition, including those that are thought to be especially refined in humans. Here we used diffusion-weighted magnetic resonance imaging (DW-MRI) and functional MRI (fMRI) in humans and macaques to infer and compare the organization of dorsal frontal cortex in the two species. Using DW-MRI tractography-based parcellation, we identified 10 dorsal frontal regions lying between the human inferior frontal sulcus and cingulate cortex. Patterns of functional coupling between each area and the rest of the brain were then estimated with fMRI and compared with functional coupling patterns in macaques. Areas in human medial frontal cortex, including areas associated with high-level social cognitive processes such as theory of mind, showed a surprising degree of similarity in their functional coupling patterns with the frontal pole, medial prefrontal, and dorsal prefrontal convexity in the macaque. We failed to find evidence for “new” regions in human medial frontal cortex. On the lateral surface, comparison of functional coupling patterns suggested correspondences in anatomical organization distinct from those that are widely assumed. A human region sometimes referred to as lateral frontal pole more closely resembled area 46, rather than the frontal pole, of the macaque. Overall the pattern of results suggest important similarities in frontal cortex organization in humans and other primates, even in the case of regions thought to carry out uniquely human functions. The patterns of interspecies correspondences are not, however, always those that are widely assumed. PMID:23884933

Immunophenotypic Alterations in Resident Immune Cells and Myocardial Fibrosis in the Aging Rhesus Macaque (Macaca mulatta) Heart

PubMed Central

Macri, Sheila C.; Bailey, Charles C.; de Oca, Nicole Monts; Silva, Nilsa A.; Rosene, Douglas L.; Mansfield, Keith G.; Miller, Andrew D.

2012-01-01

The rhesus macaque (Macaca mulatta) is used extensively in translational biomedical research and drug development studies and is an important model of aging. Macaques often develop myocardial fibrosis with age which can result in the loss of normal cardiac architecture with the expansion of the extracellular matrix and deposition of collagen. The etiology and pathogenesis of this pernicious process is poorly understood. Cardiac fibrosis was assessed using histologic and immunohistochemical techniques in cardiac tissue sections from 34 rhesus macaques. Overall left ventricular and left ventricular mid-myocardial interstitial/perivascular fibrosis were positively correlated with age (r=0.6522, p<0.0001 and r=0.4704, p=0.005, respectively). When divided into young (mean=2.8 years), middle-aged (mean=17.5 years), and advanced age (mean=29.2 years) groups, immunophenotypic characterization of antigen presenting cells revealed differential expression of CD163 and DC-SIGN between the young and middle-aged groups compared to the advanced age group (p<0.0001). HAM-56 expression decreased significantly in the advanced age cohort (p=0.0021). The expression of CD8, CD163, and DCSIGN correlated positively with age (r=0.3999, p= 0.0191; r=0.5676, p=0.0005; r=0.5245, p=0.0014 respectively). These results show the importance of myocardial fibrosis as a common age-related pathology and additionally, alterations in T cell, macrophage, and dendritic cell phenotype in rhesus macaque myocardium are associated with age but unassociated with the fibrosis. PMID:22328408

Intergroup variation in robbing and bartering by long-tailed macaques at Uluwatu Temple (Bali, Indonesia).

PubMed

Brotcorne, Fany; Giraud, Gwennan; Gunst, Noëlle; Fuentes, Agustín; Wandia, I Nengah; Beudels-Jamar, Roseline C; Poncin, Pascal; Huynen, Marie-Claude; Leca, Jean-Baptiste

2017-10-01

Robbing and bartering (RB) is a behavioral practice anecdotally reported in free-ranging commensal macaques. It usually occurs in two steps: after taking inedible objects (e.g., glasses) from humans, the macaques appear to use them as tokens, returning them to humans in exchange for food. While extensively studied in captivity, our research is the first to investigate the object/food exchange between humans and primates in a natural setting. During a 4-month study in 2010, we used both focal and event sampling to record 201 RB events in a population of long-tailed macaques (Macaca fascicularis), including four neighboring groups ranging freely around Uluwatu Temple, Bali (Indonesia). In each group, we documented the RB frequency, prevalence and outcome, and tested the underpinning anthropogenic and demographic determinants. In line with the environmental opportunity hypothesis, we found a positive qualitative relation at the group level between time spent in tourist zones and RB frequency or prevalence. For two of the four groups, RB events were significantly more frequent when humans were more present in the environment. We also found qualitative partial support for the male-biased sex ratio hypothesis [i.e., RB was more frequent and prevalent in groups with higher ratios of (sub)adult males], whereas the group density hypothesis was not supported. This preliminary study showed that RB is a spontaneous, customary (in some groups), and enduring population-specific practice characterized by intergroup variation in Balinese macaques. As such, RB is a candidate for a new behavioral tradition in this species.

Discovery of novel MHC-class I alleles and haplotypes in Filipino cynomolgus macaques (Macaca fascicularis) by pyrosequencing and Sanger sequencing: Mafa-class I polymorphism.

PubMed

Shiina, Takashi; Yamada, Yukiho; Aarnink, Alice; Suzuki, Shingo; Masuya, Anri; Ito, Sayaka; Ido, Daisuke; Yamanaka, Hisashi; Iwatani, Chizuru; Tsuchiya, Hideaki; Ishigaki, Hirohito; Itoh, Yasushi; Ogasawara, Kazumasa; Kulski, Jerzy K; Blancher, Antoine

2015-10-01

Although the low polymorphism of the major histocompatibility complex (MHC) transplantation genes in the Filipino cynomolgus macaque (Macaca fascicularis) is expected to have important implications in the selection and breeding of animals for medical research, detailed polymorphism information is still lacking for many of the duplicated class I genes. To better elucidate the degree and types of MHC polymorphisms and haplotypes in the Filipino macaque population, we genotyped 127 unrelated animals by the Sanger sequencing method and high-resolution pyrosequencing and identified 112 different alleles, 28 at cynomolgus macaque MHC (Mafa)-A, 54 at Mafa-B, 12 at Mafa-I, 11 at Mafa-E, and seven at Mafa-F alleles, of which 56 were newly described. Of them, the newly discovered Mafa-A8*01:01 lineage allele had low nucleotide similarities (<86%) with primate MHC class I genes, and it was also conserved in the Vietnamese and Indonesian populations. In addition, haplotype estimations revealed 17 Mafa-A, 23 Mafa-B, and 12 Mafa-E haplotypes integrated with 84 Mafa-class I haplotypes and Mafa-F alleles. Of these, the two Mafa-class I haplotypes, F/A/E/B-Hp1 and F/A/E/B-Hp2, had the highest haplotype frequencies at 10.6 and 10.2%, respectively. This suggests that large scale genetic screening of the Filipino macaque population would identify these and other high-frequency Mafa-class I haplotypes that could be used as MHC control animals for the benefit of biomedical research.

Analysing Local Sparseness in the Macaque Brain Network

PubMed Central

Singh, Raghavendra; Nagar, Seema; Nanavati, Amit A.

2015-01-01

Understanding the network structure of long distance pathways in the brain is a necessary step towards developing an insight into the brain’s function, organization and evolution. Dense global subnetworks of these pathways have often been studied, primarily due to their functional implications. Instead we study sparse local subnetworks of the pathways to establish the role of a brain area in enabling shortest path communication between its non-adjacent topological neighbours. We propose a novel metric to measure the topological communication load on a vertex due to its immediate neighbourhood, and show that in terms of distribution of this local communication load, a network of Macaque long distance pathways is substantially different from other real world networks and random graph models. Macaque network contains the entire range of local subnetworks, from star-like networks to clique-like networks, while other networks tend to contain a relatively small range of subnetworks. Further, sparse local subnetworks in the Macaque network are not only found across topographical super-areas, e.g., lobes, but also within a super-area, arguing that there is conservation of even relatively short-distance pathways. To establish the communication role of a vertex we borrow the concept of brokerage from social science, and present the different types of brokerage roles that brain areas play, highlighting that not only the thalamus, but also cingulate gyrus and insula often act as “relays” for areas in the neocortex. These and other analysis of communication load and roles of the sparse subnetworks of the Macaque brain provide new insights into the organisation of its pathways. PMID:26437077

Effects of B Cell Depletion on Early Mycobacterium tuberculosis Infection in Cynomolgus Macaques.

PubMed

Phuah, Jiayao; Wong, Eileen A; Gideon, Hannah P; Maiello, Pauline; Coleman, M Teresa; Hendricks, Matthew R; Ruden, Rachel; Cirrincione, Lauren R; Chan, John; Lin, Philana Ling; Flynn, JoAnne L

2016-05-01

Although recent studies in mice have shown that components of B cell and humoral immunity can modulate the immune responses against Mycobacterium tuberculosis, the roles of these components in human and nonhuman primate infections are unknown. The cynomolgus macaque (Macaca fascicularis) model of M. tuberculosis infection closely mirrors the infection outcomes and pathology in human tuberculosis (TB). The present study used rituximab, an anti-CD20 antibody, to deplete B cells in M. tuberculosis-infected macaques to examine the contribution of B cells and humoral immunity to the control of TB in nonhuman primates during the acute phase of infection. While there was no difference in the overall pathology, disease profession, and clinical outcome between the rituximab-treated and untreated macaques in acute infection, analyzing individual granulomas revealed that B cell depletion resulted in altered local T cell and cytokine responses, increased bacterial burden, and lower levels of inflammation. There were elevated frequencies of T cells producing interleukin-2 (IL-2), IL-10, and IL-17 and decreased IL-6 and IL-10 levels within granulomas from B cell-depleted animals. The effects of B cell depletion varied among granulomas in an individual animal, as well as among animals, underscoring the previously reported heterogeneity of local immunologic characteristics of tuberculous granulomas in nonhuman primates. Taken together, our data clearly showed that B cells can modulate the local granulomatous response in M. tuberculosis-infected macaques during acute infection. The impact of these alterations on disease progression and outcome in the chronic phase remains to be determined. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

The Value of Extended Pedigrees for Next-Generation Analysis of Complex Disease in the Rhesus Macaque

PubMed Central

Vinson, Amanda; Prongay, Kamm; Ferguson, Betsy

2013-01-01

Complex diseases (e.g., cardiovascular disease and type 2 diabetes, among many others) pose the biggest threat to human health worldwide and are among the most challenging to investigate. Susceptibility to complex disease may be caused by multiple genetic variants (GVs) and their interaction, by environmental factors, and by interaction between GVs and environment, and large study cohorts with substantial analytical power are typically required to elucidate these individual contributions. Here, we discuss the advantages of both power and feasibility afforded by the use of extended pedigrees of rhesus macaques (Macaca mulatta) for genetic studies of complex human disease based on next-generation sequence data. We present these advantages in the context of previous research conducted in rhesus macaques for several representative complex diseases. We also describe a single, multigeneration pedigree of Indian-origin rhesus macaques and a sample biobank we have developed for genetic analysis of complex disease, including power of this pedigree to detect causal GVs using either genetic linkage or association methods in a variance decomposition approach. Finally, we summarize findings of significant heritability for a number of quantitative traits that demonstrate that genetic contributions to risk factors for complex disease can be detected and measured in this pedigree. We conclude that the development and application of an extended pedigree to analysis of complex disease traits in the rhesus macaque have shown promising early success and that genome-wide genetic and higher order -omics studies in this pedigree are likely to yield useful insights into the architecture of complex human disease. PMID:24174435

Human Immunodeficiency Virus Research Program

DTIC Science & Technology

1993-11-30

pluripotent hematopoietic stem cells ’- Description: This project exploits the proliferation and differentiation potential of hematopoietic stem cells and...if inactivated whole SIVme/elS generated in macaque cells when used as an immunogen in macaques induces a protective immunity following challenge with...antiviral strategies in hematopoeitic Mosca* stem cells (P) - Pending Protocol *Foundation Principal Investigator (PI) 95 OVERVIEW: The HIV Drugs and

Persistent babesiosis in a Rhesus macaque (Macaca mulatta) infected with a simian-human immunodeficiency virus

PubMed Central

Liu, David X.; Gill, Amy; Holman, Patricia J.; Didier, Peter J.; Blanchard, James L.; Veazey, Ronald S.; Lackner, Andrew A.

2014-01-01

A rhesus macaque developed persistent babesiosis following inoculation with a simian-human immunodeficiency virus. Blood smears demonstrated intraerythrocytic piroplasms and rare Maltese cross forms. Babesia microti-like protozoa were confirmed by PCR and gene sequence. With using nonhuman primates as models for human diseases, infection and complications from Babesia should be monitored. PMID:24517274

Pre-Historic and Recent Vicariance Events Shape Genetic Structure and Diversity in Endangered Lion-Tailed Macaque in the Western Ghats: Implications for Conservation

PubMed Central

Ram, Muthuvarmadam S.; Marne, Minal; Gaur, Ajay; Kumara, Honnavalli N.; Singh, Mewa; Kumar, Ajith; Umapathy, Govindhaswamy

2015-01-01

Genetic isolation of populations is a potent force that helps shape the course of evolution. However, small populations in isolation, especially in fragmented landscapes, are known to lose genetic variability, suffer from inbreeding depression and become genetically differentiated among themselves. In this study, we assessed the genetic diversity of lion-tailed macaques (Macaca silenus) inhabiting the fragmented landscape of Anamalai hills and examined the genetic structure of the species across its distributional range in the Western Ghats. We sequenced around 900 bases of DNA covering two mitochondrial regions–hypervariable region-I and partial mitochondrial cytochrome b–from individuals sampled both from wild and captivity, constructed and dated phylogenetic trees. We found that the lion-tailed macaque troops in the isolated forest patches in Anamalai hills have depleted mitochondrial DNA diversity compared to troops in larger and continuous forests. Our results also revealed an ancient divergence in the lion-tailed macaque into two distinct populations across the Palghat gap, dating to 2.11 million years ago. In light of our findings, we make a few suggestions on the management of wild and captive populations. PMID:26561307

Dopamine Innervation in the Thalamus: Monkey versus Rat

PubMed Central

García-Cabezas, Miguel Ángel; Martínez-Sánchez, Patricia; Sánchez-González, Miguel Ángel; Garzón, Miguel

2009-01-01

We recently identified the thalamic dopaminergic system in the human and macaque monkey brains, and, based on earlier reports on the paucity of dopamine in the rat thalamus, hypothesized that this dopaminergic system was particularly developed in primates. Here we test this hypothesis using immunohistochemistry against the dopamine transporter (DAT) in adult macaque and rat brains. The extent and density of DAT-immunoreactive (-ir) axons were remarkably greater in the macaque dorsal thalamus, where the mediodorsal association nucleus and the ventral motor nuclei held the densest immunolabeling. In contrast, sparse DAT immunolabeling was present in the rat dorsal thalamus; it was mainly located in the mediodorsal, paraventricular, ventral medial, and ventral lateral nuclei. The reticular nucleus, zona incerta, and lateral habenular nucleus held numerous DAT-ir axons in both species. Ultrastructural analysis in the macaque mediodorsal nucleus revealed that thalamic interneurons are a main postsynaptic target of DAT-ir axons; this suggests that the marked expansion of the dopamine innervation in the primate in comparison to the rodent thalamus may be related to the presence of a sizable interneuron population in primates. We remark that it is important to be aware of brain species differences when using animal models of human brain disease. PMID:18550594

Lymphocytic choriomeningitis virus (LCMV) infection of macaques: a model for Lassa fever

PubMed Central

Zapata, Juan C.; Pauza, C. David; Djavani, Mahmoud M.; Rodas, Juan D.; Moshkoff, Dmitry; Bryant, Joseph; Ateh, Eugene; Garcia, Cybele; Lukashevich, Igor S.; Salvato, Maria S.

2011-01-01

Arenaviruses such as Lassa fever virus (LASV) and lymphocytic choriomeningitis virus (LCMV) are benign in their natural reservoir hosts, and can occasionally cause severe viral hemorrhagic fever (VHF) in non-human primates and in human beings. LCMV is considerably more benign for human beings than Lassa virus, however certain strains, like the LCMV-WE strain, can cause severe disease when the virus is delivered as a high-dose inoculum. Here we describe a rhesus macaque model for Lassa fever that employs a virulent strain of LCMV. Since LASV must be studied within Biosafety Level-4 (BSL-4) facilities, the LCMV-infected macaque model has the advantage that it can be used at BSL-3. LCMV-induced disease is rarely as severe as other VHF, but it is similar in cases where vascular leakage leads to lethal systemic failure. The LCMV-infected macaque has been valuable for describing the course of disease with differing viral strains, doses and routes of infection. By monitoring system-wide changes in physiology and gene expression in a controlled experimental setting, it is possible to identify events that are pathognomonic for developing VHF and potential treatment targets. PMID:21820469

Female homosexual behavior and inter-sexual mate competition in Japanese macaques: possible implications for sexual selection theory.

PubMed

Vasey, Paul L; Leca, Jean-Baptiste; Gunst, Noëlle; VanderLaan, Doug P

2014-10-01

In this paper, we review research related to female homosexual behavior in Japanese macaques (Macaca fuscata), including our 20-year program of research on this species. Multiple lines of evidence indicate that female homosexual behavior in this species is sexually motivated. In contrast, many sociosexual hypotheses have been tested in relation to female homosexual behavior in Japanese macaques, but none have been supported. Female Japanese macaques sometimes engage in same-sex sexual activity even when motivated opposite-sex alternatives are available. Within this context of mate choice, males compete inter-sexually for opportunities to copulate with females above and beyond any intra-sexual competition that is required. Anecdotal evidence suggests that inter-sexual competition for female sexual partners has been observed in a number of other species, including humans. At present it is unclear whether inter-sexual competition for sexual partners influences patterns of reproduction. Our understanding of sexual selection and the evolution of mating systems may be improved by investigating whether inter-sexual mate competition influences the acquisition and maintenance of reproductive partners in those species in which such interactions occur. Copyright © 2014 Elsevier Ltd. All rights reserved.

Role of vocal tract characteristics in individual discrimination by Japanese macaques (Macaca fuscata).

PubMed

Furuyama, Takafumi; Kobayasi, Kohta I; Riquimaroux, Hiroshi

2016-08-23

The Japanese macaque (Macaca fuscata) exhibits a species-specific communication sound called the "coo call" to locate group members and maintain within-group contact. Monkeys have been demonstrated to be capable of discriminating between individuals based only on their voices, but there is still debate regarding how the fundamental frequencies (F0) and filter properties of the vocal tract characteristics (VTC) contribute to individual discrimination in nonhuman primates. This study was performed to investigate the acoustic keys used by Japanese macaques in individual discrimination. Two animals were trained with standard Go/NoGo operant conditioning to distinguish the coo calls of two unfamiliar monkeys. The subjects were required to continue depressing a lever until the stimulus changed from one monkey to the other. The test stimuli were synthesized by combining the F0s and VTC from each individual. Both subjects released the lever when the VTC changed, whereas they did not when the F0 changed. The reaction times to the test stimuli were not significantly different from that to the training stimuli that shared the same VTC. Our data suggest that vocal tract characteristics are important for the identification of individuals by Japanese macaques.

Intrauterine administration of CDB-2914 (Ulipristal) suppresses the endometrium of rhesus macaques

PubMed Central

Brenner, Robert M.; Slayden, Ov D.; Nath, Anita; Tsong, YY; Sitruk-Ware, Regine

2010-01-01

Background Ulipristal (CDB-2914; UPA) is a progesterone receptor modulator with contraceptive potential. To test its effects when delivered by an intrauterine system (IUS), we prepared control and UPA-filled IUS and evaluated their effects in rhesus macaques. Study Design Short lengths of Silastic tubing either empty (n=3), or containing UPA (n=5), were inserted into the uteri of 8 ovariectomized macaques. Animals were cycled by sequential treatment with estradiol and progesterone. After 3.5 cycles, the uterus was removed. Results During treatment, animals with an empty IUS menstruated for a mean total of 11.66 ± 0.88 days while UPA-IUS treated animals bled for only 1 ± 0.45 days. Indices of endometrial proliferation were significantly reduced by UPA-IUS treatment. The UPA exposed endometria were atrophied with some glandular cysts while the blank controls displayed a proliferative morphology without cysts. Androgen receptors were more intensely stained in the glands of the UPA-IUS treated endometria than in the blank-IUS treated controls. Conclusions In rhesus macaques, a UPA-IUS induced endometrial atrophy and amenorrhea. The work provides proof of principle that an IUS can deliver effective intrauterine concentrations of Ulipristal. PMID:20227552

Female orgasm rate increases with male dominance in Japanese macaques.

PubMed

Troisi; Carosi

1998-11-01

Under specific circumstances, nonhuman primate females may experience orgasm. The occurrence of female copulatory orgasm appears to be highly variable, however, and its proximate causation is poorly understood. We investigated the proximate mechanisms that control orgasmic response in female macaques. During 238 h of observation of sexual behaviour in a large captive group of Japanese macaques, Macaca fuscata, 240 copulations were recorded involving 68 different heterosexual pairs formed by 16 males and 26 females. Female orgasmic responses were observed in 80 of 240 copulations (33%). The frequency of orgasms was not correlated with female age or dominance rank, but it was higher for copulations lasting longer and involving a higher number of mounts and pelvic thrusts. When the level of physical stimulation experienced by females during copulation was statistically controlled, the highest frequency of female orgasms was found among pairs formed by high-ranking males and low-ranking females and the lowest frequency among pairs formed by low-ranking males and high-ranking females. These findings suggest that the proximate mechanisms that control orgasmic threshold in female macaques are more responsive to social stimuli and less constrained by physiological limitations than previously thought. Copyright 1998 The Association for the Study of Animal Behaviour.

Evaluation of Infrared Thermometry in Cynomolgus Macaques (Macaca fascicularis).

PubMed

Laffins, Michael M; Mellal, Nacera; Almlie, Cynthia L; Regalia, Douglas E

2017-01-01

Recording an accurate body temperature is important to assess an animal's health status. We compared temperature data from sedated cynomolgus macaques (Macaca fascicularis) to evaluate differences between rectal, infrared (inguinal and chest), and implanted telemetry techniques with the objective of demonstrating the diagnostic equivalence of the infrared device with other approaches. Infrared thermometer readings are instantaneous and require no contact with the animal. Body temperature data were obtained from 205 (137 male, 68 female) cynomolgus macaques under ketamine (10 mg/kg IM) sedation over a 3-mo period during scheduled physical examinations. Infrared measurements were taken 5 cm from the chest and inguinal areas. We evaluated 10 (9 functional devices) sedated cynomolgus macaques (5 male, 5 female) implanted with telemetry units in a muscular pouch between the internal and external abdominal oblique muscles. We determined that the mean body temperature acquired by using telemetry did not differ from either the mean of inguinal and chest infrared measurements but did differ from the mean of temperature obtained rectally. In addition, the mean rectal temperature differed from the mean of the inguinal reading but not the mean of the chest temperature. The results confirm our hypothesis that the infrared thermometer can be used to replace standard rectal thermometry.

Prevention of SIV Rectal Transmission and Priming of T Cell Responses in Macaques after Local Pre-exposure Application of Tenofovir Gel

PubMed Central

Cranage, Martin; Sharpe, Sally; Herrera, Carolina; Cope, Alethea; Dennis, Mike; Berry, Neil; Ham, Claire; Heeney, Jonathan; Rezk, Naser; Kashuba, Angela; Anton, Peter; McGowan, Ian; Shattock, Robin

2008-01-01

Background The rectum is particularly vulnerable to HIV transmission having only a single protective layer of columnar epithelium overlying tissue rich in activated lymphoid cells; thus, unprotected anal intercourse in both women and men carries a higher risk of infection than other sexual routes. In the absence of effective prophylactic vaccines, increasing attention is being given to the use of microbicides and preventative antiretroviral (ARV) drugs. To prevent mucosal transmission of HIV, a microbicide/ARV should ideally act locally at and near the virus portal of entry. As part of an integrated rectal microbicide development programme, we have evaluated rectal application of the nucleotide reverse transcriptase (RT) inhibitor tenofovir (PMPA, 9-[(R)-2-(phosphonomethoxy) propyl] adenine monohydrate), a drug licensed for therapeutic use, for protective efficacy against rectal challenge with simian immunodeficiency virus (SIV) in a well-established and standardised macaque model. Methods and Findings A total of 20 purpose-bred Indian rhesus macaques were used to evaluate the protective efficacy of topical tenofovir. Nine animals received 1% tenofovir gel per rectum up to 2 h prior to virus challenge, four macaques received placebo gel, and four macaques remained untreated. In addition, three macaques were given tenofovir gel 2 h after virus challenge. Following intrarectal instillation of 20 median rectal infectious doses (MID50) of a noncloned, virulent stock of SIVmac251/32H, all animals were analysed for virus infection, by virus isolation from peripheral blood mononuclear cells (PBMC), quantitative proviral DNA load in PBMC, plasma viral RNA (vRNA) load by sensitive quantitative competitive (qc) RT-PCR, and presence of SIV-specific serum antibodies by ELISA. We report here a significant protective effect (p = 0.003; Fisher exact probability test) wherein eight of nine macaques given tenofovir per rectum up to 2 h prior to virus challenge were protected from infection (n = 6) or had modified virus outcomes (n = 2), while all untreated macaques and three of four macaques given placebo gel were infected, as were two of three animals receiving tenofovir gel after challenge. Moreover, analysis of lymphoid tissues post mortem failed to reveal sequestration of SIV in the protected animals. We found a strong positive association between the concentration of tenofovir in the plasma 15 min after rectal application of gel and the degree of protection in the six animals challenged with virus at this time point. Moreover, colorectal explants from non-SIV challenged tenofovir-treated macaques were resistant to infection ex vivo, whereas no inhibition was seen in explants from the small intestine. Tissue-specific inhibition of infection was associated with the intracellular detection of tenofovir. Intriguingly, in the absence of seroconversion, Gag-specific gamma interferon (IFN-γ)-secreting T cells were detected in the blood of four of seven protected animals tested, with frequencies ranging from 144 spot forming cells (SFC)/106 PBMC to 261 spot forming cells (SFC)/106 PBMC. Conclusions These results indicate that colorectal pretreatment with ARV drugs, such as tenofovir, has potential as a clinically relevant strategy for the prevention of HIV transmission. We conclude that plasma tenofovir concentration measured 15 min after rectal administration may serve as a surrogate indicator of protective efficacy. This may prove to be useful in the design of clinical studies. Furthermore, in vitro intestinal explants served as a model for drug distribution in vivo and susceptibility to virus infection. The finding of T cell priming following exposure to virus in the absence of overt infection is provocative. Further studies would reveal if a combined modality microbicide and vaccination strategy is feasible by determining the full extent of local immune responses induced and their protective potential. PMID:18684007

Computed tomography or necropsy diagnosis of multiple bullae and the treatment of pneumothorax in rhesus macaques (Macaca mulatta).

PubMed

Kim, Jong-Min; Han, Sungyoung; Shin, Jun-Seop; Min, Byoung-Hoon; Jeong, Won Young; Lee, Ga Eul; Kim, Min Sun; Kim, Ju Eun; Chung, Hyunwoo; Park, Chung-Gyu

2017-10-01

Pulmonary bullae and pneumothorax have various etiologies in veterinary medicine. We diagnosed multiple pulmonary bullae combined with or without pneumothorax by computed tomography (CT) or necropsy in seven rhesus macaques (Macaca mulatta) imported from China. Two of seven rhesus macaques accompanied by pneumothorax were cured by fixation of ruptured lung through left or right 3rd intercostal thoracotomy. Pneumonyssus simicola, one of the etiologies of pulmonary bullae, was not detected from tracheobronchiolar lavage. To the best of our knowledge, this is the first case report on the CT-aided diagnosis of pulmonary bullae and the successful treatment of combined pneumothorax by thoracotomy in non-human primates (NHPs). © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Do infant Japanese macaques ( Macaca fuscata) categorize objects without specific training?

PubMed

Murai, Chizuko; Tomonaga, Masaki; Kamegai, Kimi; Terazawa, Naoko; Yamaguchi, Masami K

2004-01-01

In the present study, we examined whether infant Japanese macaques categorize objects without any training, using a similar technique also used with human infants (the paired-preference method). During the familiarization phase, subjects were presented twice with two pairs of different objects from one global-level category. During the test phase, they were presented twice with a pair consisting of a novel familiar-category object and a novel global-level category object. The subjects were tested with three global-level categories (animal, furniture, and vehicle). It was found that they showed significant novelty preferences as a whole, indicating that they processed similarities between familiarization objects and novel familiar-category objects. These results suggest that subjects responded distinctively to objects without training, indicating the possibility that infant macaques possess the capacity for categorization.

HIV-2 and its role in conglutinated approach towards Acquired Immunodeficiency Syndrome (AIDS) Vaccine Development.

PubMed

Diwan, Batul; Saxena, Rupali; Tiwari, Archana

2013-12-01

Acquired Immunodeficiency Syndrome (AIDS) is one of the most critically acclaimed endemic diseases, caused by two lentiviruses HIV-1 and 2. HIV-2 displays intimate serological and antigenic resemblance to Simian Immunodeficiency Virus (SIV) along with less pathogenicity, lower infectivity and appreciable cross reactivity with HIV-1 antigens. The present era is confronted with the challenge to fabricate a vaccine effective against all clades of both the species of HIV. But vaccine development against HIV-1 has proven highly intricate, moreover the laborious and deficient conventional approaches has slackened the pace regarding the development of new vaccines. These concerns may be tackled with the development of HIV-2 vaccine as a natural control of HIV-1 that has been found in ancestors of HIV-2 i.e. African monkeys, mangabeys and macaques. Thereby, suggesting the notion of cross protection among HIV-2 and HIV-1. Assistance of bioinformatics along with vaccinomics strategy can bring about a quantum leap in this direction for surpassing the bottleneck in conventional approaches. These specifics together can add to our conception that HIV-2 vaccine design by in silico strategy will surely be a constructive approach for HIV-1 targeting.

Report on primate supply for biomedical scientific work in the UK. EUPREN UK Working Party.

PubMed

Owen, S; Thomas, C; West, P; Wolfensohn, S; Wood, M

1997-10-01

A Working Party of the UK group of European Primate Resources Network (EUPREN) considered primate supply for scientific work in the UK. Through a questionnaire, which achieved a very good response, it obtained details of primate use, sources and breeding in the UK and it put forward options to ensure that animal welfare is the best possible whilst ensuring continued supply. The questionnaire showed that contract research laboratories and pharmaceutical companies use about 80% of the 4233 primates used annually at the moment, with the rest accounted for by academic establishments and public sector laboratories. Fifty-four per cent are cynomolgus macaques (Macaca fascicularis), of which nearly 90% are captive-bred outside the European Union (EU), the remainder being bred in the UK. Nearly 90% of cynomolgus macaques are used by only five institutions. Thirty-seven per cent of primates used are marmosets (Callithrix jacchus jacchus), all of which are bred in the UK. Most of the rest are rhesus macaques (Macaca mulatta), about half of which are captive-bred outside the EU, the other half being bred in the UK. Overall primate use has increased from about 3000 per year in 1990 and users predict that requirements for all species except baboons (Papio sp.) will be maintained or increase. Marmoset breeding in the UK is already closely matched to use, and it could be increased reasonably easily if necessary. Some of the existing breeding centres of macaques in the UK would be prepared to consider expanding to supply others, although investment and imported breeding stock would be needed and it is likely that a large investment would be needed to breed a significant fraction of the macaque use in the UK. A further problem is that the users of only about 10% of the cynomolgus macaques said that they could replace this species by rhesus macaques, which are easier to breed in the UK. The questionnaire showed that much of the use of macaques would be transferred to other countries equally remote from the natural source countries of the animals, if constraints on primate use became more severe in the UK. Users felt that it is unlikely that much of the work could be transferred to the natural source countries themselves. A review of the literature revealed a paucity of information on the effects of transport on primate welfare. The importance of obtaining this information before making decisions about alternative means of supply is stressed. Current schemes for the accreditation of primate breeders were reviewed. A list of options is presented for discussion. Users vary so much in their requirements that it is unlikely that one means of supply will be applicable to all. Animal welfare will benefit and supply will be more certain if cooperation between those concerned (preferably through the UK group of EUPREN) is maintained.

Measles Vaccination of Nonhuman Primates Provides Partial Protection against Infection with Canine Distemper Virus

PubMed Central

de Vries, Rory D.; Ludlow, Martin; Verburgh, R. Joyce; van Amerongen, Geert; Yüksel, Selma; Nguyen, D. Tien; McQuaid, Stephen; Osterhaus, Albert D. M. E.; Duprex, W. Paul

2014-01-01

ABSTRACT Measles virus (MV) is being considered for global eradication, which would likely reduce compliance with MV vaccination. As a result, children will grow up without MV-specific immunity, creating a potential niche for closely related animal morbilliviruses such as canine distemper virus (CDV). Natural CDV infection causing clinical signs has never been reported in humans, but recent outbreaks in captive macaques have shown that CDV can cause disease in primates. We studied the virulence and tropism of recombinant CDV expressing enhanced green fluorescent protein in naive and measles-vaccinated cynomolgus macaques. In naive animals CDV caused viremia and fever and predominantly infected CD150+ lymphocytes and dendritic cells. Virus was reisolated from the upper and lower respiratory tracts, but infection of epithelial or neuronal cells was not detectable at the time points examined, and the infections were self-limiting. This demonstrates that CDV readily infects nonhuman primates but suggests that additional mutations are necessary to achieve full virulence in nonnatural hosts. Partial protection against CDV was observed in measles-vaccinated macaques, as demonstrated by accelerated control of virus replication and limited shedding from the upper respiratory tract. While neither CDV infection nor MV vaccination induced detectable cross-reactive neutralizing antibodies, MV-specific neutralizing antibody levels of MV-vaccinated macaques were boosted by CDV challenge infection, suggesting that cross-reactive VN epitopes exist. Rapid increases in white blood cell counts in MV-vaccinated macaques following CDV challenge suggested that cross-reactive cellular immune responses were also present. This study demonstrates that zoonotic morbillivirus infections can be controlled by measles vaccination. IMPORTANCE Throughout history viral zoonoses have had a substantial impact on human health. Given the drive toward global eradication of measles, it is essential to understand the zoonotic potential of animal morbilliviruses. Morbilliviruses are thought to have evolved from a common ancestral virus that jumped species and adapted to new hosts. Recently, canine distemper virus (CDV), a morbillivirus normally restricted to carnivores, caused disease outbreaks in nonhuman primates. Here, we report that experimental CDV infection of monkeys resulted in fever and leukopenia. The virus replicated to high levels in lymphocytes but did not spread to epithelial cells or the central nervous system. Importantly, like measles virus in macaques, the infections were self-limiting. In measles-vaccinated macaques CDV was cleared more rapidly, resulting in limited virus shedding from the upper respiratory tract. These studies demonstrate that although CDV can readily infect primates, measles immunity is protective, and CDV infection is self-limiting. PMID:24501402

Measles vaccination of nonhuman primates provides partial protection against infection with canine distemper virus.

PubMed

de Vries, Rory D; Ludlow, Martin; Verburgh, R Joyce; van Amerongen, Geert; Yüksel, Selma; Nguyen, D Tien; McQuaid, Stephen; Osterhaus, Albert D M E; Duprex, W Paul; de Swart, Rik L

2014-04-01

Measles virus (MV) is being considered for global eradication, which would likely reduce compliance with MV vaccination. As a result, children will grow up without MV-specific immunity, creating a potential niche for closely related animal morbilliviruses such as canine distemper virus (CDV). Natural CDV infection causing clinical signs has never been reported in humans, but recent outbreaks in captive macaques have shown that CDV can cause disease in primates. We studied the virulence and tropism of recombinant CDV expressing enhanced green fluorescent protein in naive and measles-vaccinated cynomolgus macaques. In naive animals CDV caused viremia and fever and predominantly infected CD150(+) lymphocytes and dendritic cells. Virus was reisolated from the upper and lower respiratory tracts, but infection of epithelial or neuronal cells was not detectable at the time points examined, and the infections were self-limiting. This demonstrates that CDV readily infects nonhuman primates but suggests that additional mutations are necessary to achieve full virulence in nonnatural hosts. Partial protection against CDV was observed in measles-vaccinated macaques, as demonstrated by accelerated control of virus replication and limited shedding from the upper respiratory tract. While neither CDV infection nor MV vaccination induced detectable cross-reactive neutralizing antibodies, MV-specific neutralizing antibody levels of MV-vaccinated macaques were boosted by CDV challenge infection, suggesting that cross-reactive VN epitopes exist. Rapid increases in white blood cell counts in MV-vaccinated macaques following CDV challenge suggested that cross-reactive cellular immune responses were also present. This study demonstrates that zoonotic morbillivirus infections can be controlled by measles vaccination. Throughout history viral zoonoses have had a substantial impact on human health. Given the drive toward global eradication of measles, it is essential to understand the zoonotic potential of animal morbilliviruses. Morbilliviruses are thought to have evolved from a common ancestral virus that jumped species and adapted to new hosts. Recently, canine distemper virus (CDV), a morbillivirus normally restricted to carnivores, caused disease outbreaks in nonhuman primates. Here, we report that experimental CDV infection of monkeys resulted in fever and leukopenia. The virus replicated to high levels in lymphocytes but did not spread to epithelial cells or the central nervous system. Importantly, like measles virus in macaques, the infections were self-limiting. In measles-vaccinated macaques CDV was cleared more rapidly, resulting in limited virus shedding from the upper respiratory tract. These studies demonstrate that although CDV can readily infect primates, measles immunity is protective, and CDV infection is self-limiting.

Glaucoma Progression Detection by Retinal Nerve Fiber Layer Measurement Using Scanning Laser Polarimetry: Event and Trend Analysis

PubMed Central

Moon, Byung Gil; Cho, Jung Woo; Kang, Sung Yong; Yun, Sung-Cheol; Na, Jung Hwa; Lee, Youngrok; Kook, Michael S.

2012-01-01

Purpose To evaluate the use of scanning laser polarimetry (SLP, GDx VCC) to measure the retinal nerve fiber layer (RNFL) thickness in order to evaluate the progression of glaucoma. Methods Test-retest measurement variability was determined in 47 glaucomatous eyes. One eye each from 152 glaucomatous patients with at least 4 years of follow-up was enrolled. Visual field (VF) loss progression was determined by both event analysis (EA, Humphrey guided progression analysis) and trend analysis (TA, linear regression analysis of the visual field index). SLP progression was defined as a reduction of RNFL exceeding the predetermined repeatability coefficient in three consecutive exams, as compared to the baseline measure (EA). The slope of RNFL thickness change over time was determined by linear regression analysis (TA). Results Twenty-two eyes (14.5%) progressed according to the VF EA, 16 (10.5%) by VF TA, 37 (24.3%) by SLP EA and 19 (12.5%) by SLP TA. Agreement between VF and SLP progression was poor in both EA and TA (VF EA vs. SLP EA, k = 0.110; VF TA vs. SLP TA, k = 0.129). The mean (±standard deviation) progression rate of RNFL thickness as measured by SLP TA did not significantly differ between VF EA progressors and non-progressors (-0.224 ± 0.148 µm/yr vs. -0.218 ± 0.151 µm/yr, p = 0.874). SLP TA and EA showed similar levels of sensitivity when VF progression was considered as the reference standard. Conclusions RNFL thickness as measurement by SLP was shown to be capable of detecting glaucoma progression. Both EA and TA of SLP showed poor agreement with VF outcomes in detecting glaucoma progression. PMID:22670073

Glaucoma progression detection by retinal nerve fiber layer measurement using scanning laser polarimetry: event and trend analysis.

PubMed

Moon, Byung Gil; Sung, Kyung Rim; Cho, Jung Woo; Kang, Sung Yong; Yun, Sung-Cheol; Na, Jung Hwa; Lee, Youngrok; Kook, Michael S

2012-06-01

To evaluate the use of scanning laser polarimetry (SLP, GDx VCC) to measure the retinal nerve fiber layer (RNFL) thickness in order to evaluate the progression of glaucoma. Test-retest measurement variability was determined in 47 glaucomatous eyes. One eye each from 152 glaucomatous patients with at least 4 years of follow-up was enrolled. Visual field (VF) loss progression was determined by both event analysis (EA, Humphrey guided progression analysis) and trend analysis (TA, linear regression analysis of the visual field index). SLP progression was defined as a reduction of RNFL exceeding the predetermined repeatability coefficient in three consecutive exams, as compared to the baseline measure (EA). The slope of RNFL thickness change over time was determined by linear regression analysis (TA). Twenty-two eyes (14.5%) progressed according to the VF EA, 16 (10.5%) by VF TA, 37 (24.3%) by SLP EA and 19 (12.5%) by SLP TA. Agreement between VF and SLP progression was poor in both EA and TA (VF EA vs. SLP EA, k = 0.110; VF TA vs. SLP TA, k = 0.129). The mean (±standard deviation) progression rate of RNFL thickness as measured by SLP TA did not significantly differ between VF EA progressors and non-progressors (-0.224 ± 0.148 µm/yr vs. -0.218 ± 0.151 µm/yr, p = 0.874). SLP TA and EA showed similar levels of sensitivity when VF progression was considered as the reference standard. RNFL thickness as measurement by SLP was shown to be capable of detecting glaucoma progression. Both EA and TA of SLP showed poor agreement with VF outcomes in detecting glaucoma progression.

Expression levels of the innate response gene RIG-I and its regulators RNF125 and TRIM25 in HIV-1-infected adult and pediatric individuals.

PubMed

Britto, Alan M A; Amoedo, Nívea D; Pezzuto, Paula; Afonso, Adriana O; Martínez, Ana M B; Silveira, Jussara; Sion, Fernando S; Machado, Elizabeth S; Soares, Marcelo A; Giannini, Ana L M

2013-07-31

TLRs (Toll-like receptors) and RLRs (RIG-I-like receptors) mediate innate immune responses by detecting microorganism invasion. RIG-I activation results in the production of interferon (IFN) type 1 and IFN responsive genes (ISGs). As the ubiquitin ligases RNF125 and TRIM25 are involved in regulating RIG-I function, our aim was to assess whether the levels of these three genes vary between healthy and HIV-infected individuals and whether these levels are related to disease progression. Gene expression analyses for RIG-I, RNF125, and TRIM25 were performed for HIV-infected adults and the children's peripheral blood mononuclear cells (PBMCs). Reverse transcription-quantitative PCRs (RT-qPCRs) were performed in order to quantify the expression levels of RIG-I, RNF125 and TRIM25 from PBMCs purified from control or HIV-infected individuals. Controls express higher levels of the three genes when compared to HIV-infected patients. These expressions are clearly distinct between healthy and progressors, and are reproduced in adults and children. In controls, RNF125 is the highest expressed gene, whereas in progressors, RIG-I is either the highest expressed gene or is expressed similarly to RNF125 and TRIM25. A pattern of expression of RIG-I, RNF125, and TRIM25 genes in HIV patients is evident. The high expression of RNF125 in healthy individuals reflects the importance of keeping RIG-I function off, inhibiting unnecessary IFN production. Consistent with this assumption, RNF125 levels are lower in HIV patients and importantly, the RNF125/RIG-I ratio is lower in patients who progress to AIDS. Our results might help to predict disease progression and unveil the role of poorly characterized host genes during HIV infection.

Effects of low calcium dialysate on the progression of coronary artery calcification in hemodialysis patients: An open-label 12-month randomized clinical trial.

PubMed

Kim, Soo Jin; Lee, Young-Ki; Oh, Jieun; Cho, AJin; Noh, Jung Woo

2017-09-15

The association between the dialysate calcium level and coronary artery calcification (CAC) has not yet been evaluated in hemodialysis patients. The objective of this study was to determine whether lowering the dialysate calcium levels would decrease the progression of coronary artery calcification (CAC) compared to using standard calcium dialysate. We conducted an open-label randomized trial with parallel groups. The patients were randomly assigned to either 12-month treatment with low calcium dialysate (LCD; 1.25mmol/L, n=36) or standard calcium dialysate (SCD; 1.5mmol/L, n=40). The primary outcome was the change in the CAC scores assessed by 64-slice multidetector computed tomography after 12months. During the treatment period, CAC scores increased in both groups, especially significant in LCD group (402.5±776.8, 580.5±1011.9, P=0.004). When we defined progressors as patients at second and third tertiles of CAC changes, progressor group had a higher proportion of LCD-treated patients than SCD-treated patients (P=0.0229). In multivariate analysis, LCD treatment is a significant risk factor for increase in CAC scores (odds ratio=5.720, 95% CI: 1.219-26.843, P=0.027). Use of LCD may accelerate the progression of CAC in patients with chronic hemodialysis over a 12-month period. Clinical Research Information Service [Internet]; Osong (Chungcheongbuk-do): Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea), 2010: KCT0000942. Available from: https://cris.nih.go.kr/cris/search/search_result_st01_kren.jsp?seq=3572&sLeft=2&type=my. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study

PubMed Central

Herrick, Ariane L; Peytrignet, Sebastien; Lunt, Mark; Pan, Xiaoyan; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan J; Dinsdale, Graham; Brown, Edith; Czirják, László; Distler, Jörg H W; Distler, Oliver; Fligelstone, Kim; Gregory, William J; Ochiel, Rachel; Vonk, Madelon C; Ancuţa, Codrina; Ong, Voon H; Farge, Dominique; Hudson, Marie; Matucci-Cerinic, Marco; Balbir-Gurman, Alexandra; Midtvedt, Øyvind; Jobanputra, Paresh; Jordan, Alison C; Stevens, Wendy; Moinzadeh, Pia; Hall, Frances C; Agard, Christian; Anderson, Marina E; Diot, Elisabeth; Madhok, Rajan; Akil, Mohammed; Buch, Maya H; Chung, Lorinda; Damjanov, Nemanja S; Gunawardena, Harsha; Lanyon, Peter; Ahmad, Yasmeen; Chakravarty, Kuntal; Jacobsen, Søren; MacGregor, Alexander J; McHugh, Neil; Müller-Ladner, Ulf; Riemekasten, Gabriela; Becker, Michael; Roddy, Janet; Carreira, Patricia E; Fauchais, Anne Laure; Hachulla, Eric; Hamilton, Jennifer; İnanç, Murat; McLaren, John S; van Laar, Jacob M; Pathare, Sanjay; Proudman, Susanna M; Rudin, Anna; Sahhar, Joanne; Coppere, Brigitte; Serratrice, Christine; Sheeran, Tom; Veale, Douglas J; Grange, Claire; Trad, Georges-Selim; Denton, Christopher P

2018-01-01

Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. ‘Progressors’ were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441. PMID:29306872

Novel genetic association of TNF-α-238 and PDCD1-7209 polymorphisms with long-term non-progressive HIV-1 infection.

PubMed

Nasi, Milena; Riva, Agostino; Borghi, Vanni; D'Amico, Roberto; Del Giovane, Cinzia; Casoli, Claudio; Galli, Massimo; Vicenzi, Elisa; Gibellini, Lara; De Biasi, Sara; Clerici, Mario; Mussini, Cristina; Cossarizza, Andrea; Pinti, Marcello

2013-10-01

About 2-5% of HIV-1-infected subjects, defined as long-term non-progressors (LTNPs), remain immunologically stable for a long time without treatment. The factors governing this condition are known only in part, and include genetic factors. Thus, we studied 20 polymorphisms of 15 genes encoding proinflammatory and immunoregulatory cytokines, chemokines and their receptors, genes involved in apoptosis, and the gene HCP5. We analyzed 47 Caucasian LTNPs infected for >9 years, compared with 131 HIV-1-infected Caucasian patients defined as 'usual progressors'. The genotypes were determined by methods based upon PCR, and the statistical analysis was performed by univariate logistic regression. The well-known CCR5Δ32 del32 allele, the cell death-related TNF-α-238 A and PDCD1-7209 T alleles, and HCP5 rs2395029 G, a non-coding protein associated with the HLA-B*5701, were found positively associated with the LTNP condition. No association was observed for other single nucleotide polymorphisms (SDF-1-801, IL-10-592, MCP-1-2518, CX3CR1 V249I, CCR2V64I, RANTES-403, IL-2-330, IL-1β-511, IL-4-590, FASL IVS3nt-169, FAS-670, FAS-1377, FASL IVS2nt-124, PDCD1-7146, MMP-7-181, and MMP7-153). The novel genetic associations between allelic variants of genes TNF-α-238 and PDCD1-7209 with the LTNP condition underline the importance of host genetic factors in the progression of HIV-1 infection and in immunological preservation. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes.

PubMed

Sims, Emily K; Chaudhry, Zunaira; Watkins, Renecia; Syed, Farooq; Blum, Janice; Ouyang, Fangqian; Perkins, Susan M; Mirmira, Raghavendra G; Sosenko, Jay; DiMeglio, Linda A; Evans-Molina, Carmella

2016-09-01

We tested whether an elevation in the serum proinsulin-to-C-peptide ratio (PI:C), a biomarker of β-cell endoplasmic reticulum (ER) dysfunction, was associated with progression to type 1 diabetes. Fasting total PI and C levels were measured in banked serum samples obtained from TrialNet Pathway to Prevention (PTP) participants, a cohort of autoantibody-positive relatives without diabetes of individuals with type 1 diabetes. Samples were obtained ∼12 months before diabetes onset from PTP progressors in whom diabetes developed (n = 60), and were compared with age-, sex-, and BMI-matched nonprogressors who remained normoglycemic (n = 58). PI:C ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels. Although absolute PI levels did not differ between groups, PI:C ratios were significantly increased in antibody-positive subjects in whom there was progression to diabetes compared with nonprogressors (median 1.81% vs. 1.17%, P = 0.03). The difference between groups was most pronounced in subjects who were ≤10 years old, where the median progressor PI:C ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PI:C quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PI:C ratio values (odds ratio 1.44, 95% CI 1.02, 2.05). These data suggest that β-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PI:C ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase. © 2016 by the American Diabetes Association.

Elevations in the Fasting Serum Proinsulin–to–C-Peptide Ratio Precede the Onset of Type 1 Diabetes

PubMed Central

Sims, Emily K.; Chaudhry, Zunaira; Watkins, Renecia; Syed, Farooq; Blum, Janice; Ouyang, Fangqian; Perkins, Susan M.; Mirmira, Raghavendra G.; Sosenko, Jay; DiMeglio, Linda A.

2016-01-01

OBJECTIVE We tested whether an elevation in the serum proinsulin–to–C-peptide ratio (PI:C), a biomarker of β-cell endoplasmic reticulum (ER) dysfunction, was associated with progression to type 1 diabetes. RESEARCH DESIGN AND METHODS Fasting total PI and C levels were measured in banked serum samples obtained from TrialNet Pathway to Prevention (PTP) participants, a cohort of autoantibody-positive relatives without diabetes of individuals with type 1 diabetes. Samples were obtained ∼12 months before diabetes onset from PTP progressors in whom diabetes developed (n = 60), and were compared with age-, sex-, and BMI-matched nonprogressors who remained normoglycemic (n = 58). PI:C ratios were calculated as molar ratios and were multiplied by 100% to obtain PI levels as a percentage of C levels. RESULTS Although absolute PI levels did not differ between groups, PI:C ratios were significantly increased in antibody-positive subjects in whom there was progression to diabetes compared with nonprogressors (median 1.81% vs. 1.17%, P = 0.03). The difference between groups was most pronounced in subjects who were ≤10 years old, where the median progressor PI:C ratio was nearly triple that of nonprogressors; 90.0% of subjects in this age group within the upper PI:C quartile progressed to the development of diabetes. Logistic regression analysis, adjusted for age and BMI, demonstrated increased odds of progression for higher natural log PI:C ratio values (odds ratio 1.44, 95% CI 1.02, 2.05). CONCLUSIONS These data suggest that β-cell ER dysfunction precedes type 1 diabetes onset, especially in younger children. Elevations in the serum PI:C ratio may have utility in predicting the onset of type 1 diabetes in the presymptomatic phase. PMID:27385327

Gene expression profile in long-term non progressor HIV infected patients: in search of potential resistance factors.

PubMed

Luque, Maria Carolina; Santos, Camila C; Mairena, Eliane C; Wilkinson, Peter; Boucher, Genèvieve; Segurado, Aluisio C; Fonseca, Luiz A; Sabino, Ester; Kalil, Jorge E; Cunha-Neto, Edecio

2014-11-01

Long-term non-progressors (LTNP) represent a minority (1-5%) of HIV-infected individuals characterized by documented infection for more than 7-10 years, a stable CD4+ T cell count over 500/mm(3) and low viremia in the absence of antiretroviral treatment. Protective factors described so far such as the CCR5delta32 deletion, protective HLA alleles, or defective viruses fail to fully explain the partial protection phenotype. The existence of additional host resistance mechanisms in LTNP patients was investigated here using a whole human genome microarray study comparing gene expression profiles of unstimulated peripheral blood mononuclear cells from LTNP patients, HIV-1 infected patients under antiretroviral therapy with CD4+ T cell levels above 500/mm(3) (ST), as well as healthy individuals. Genes that were up- or downregulated exclusively in LTNP, ST or in both groups in comparison to controls were identified and classified in functional categories using Ingenuity Pathway Analysis. ST and LTNP patient groups revealed distinct genetic profiles, regarding gene number in each category and up- or downregulation of specific genes, which could have a bearing on the outcome of each group. We selected some relevant genes to validate the differential expression using quantitative real-time qRT-PCR. Among others, we found several genes related to the canonical Wnt/beta-catenin signaling pathway. Our results identify new possible host genes and molecules that could be involved in the mechanisms leading to the slower progression to AIDS and sustained CD4+ T cell counts that is peculiar to LTNP patients. Copyright © 2014. Published by Elsevier Ltd.

Functional avidity and IL-2/perforin production is linked to the emergence of mutations within HLA-B*5701-restricted epitopes and HIV-1 disease progression

PubMed Central

Buggert, Marcus; Norström, Melissa M; Salemi, Marco; Hecht, Frederick M; Karlsson, Annika C

2014-01-01

Viral escape from HIV-1-specific CD8+ T cells has been demonstrated in numerous studies previously. However, the qualitative features driving the emergence of mutations within epitopes are still unclear. In this study, we aimed to distinguish whether specific functional characteristics of HLA-B*5701-restricted CD8+ T cells influence the emergence of mutations in high-risk progressors (HRPs) versus low-risk progressors (LRPs). Single genome sequencing was performed to detect viral mutations (variants) within seven HLA-B*5701-restricted epitopes in Gag (n = 4) and Nef (n = 3) in six untreated HLA-B*5701 subjects followed from early infection up to seven years. Several well-characterized effector markers (IFN-γ, IL-2, MIP-1β, TNF, CD107a and perforin) were identified by flow cytometry following autologous (initial and emerging variant/s) epitope stimulations. This study demonstrates that specific functional attributes may facilitate the outgrowth of mutations within HLA-B*5701-restricted epitopes. A significantly lower fraction of IL-2 producing cells and a decrease in functional avidity and polyfunctional sensitivity were evident in emerging epitope variants compared to the initial autologous epitopes. Interestingly, the HRPs mainly drove these differences, while the LRPs maintained a directed and maintained functional response against emerging epitope variants. In addition, LRPs induced improved cell cycle progression and perforin up-regulation after autologous and emerging epitope variant stimulations in contrast to HRPs. The maintained quantitative and qualitative features of the CD8+ T cell responses in LRPs toward emerging epitope variants provide insights into why HLA-B*5701 subjects have different risks of HIV-1 disease progression. PMID:24740510

Biomarkers of Progression after HIV Acute/Early Infection: Nothing Compares to CD4⁺ T-cell Count?

PubMed

Turk, Gabriela; Ghiglione, Yanina; Hormanstorfer, Macarena; Laufer, Natalia; Coloccini, Romina; Salido, Jimena; Trifone, César; Ruiz, María Julia; Falivene, Juliana; Holgado, María Pía; Caruso, María Paula; Figueroa, María Inés; Salomón, Horacio; Giavedoni, Luis D; Pando, María de Los Ángeles; Gherardi, María Magdalena; Rabinovich, Roberto Daniel; Pury, Pedro A; Sued, Omar

2018-01-13

Progression of HIV infection is variable among individuals, and definition disease progression biomarkers is still needed. Here, we aimed to categorize the predictive potential of several variables using feature selection methods and decision trees. A total of seventy-five treatment-naïve subjects were enrolled during acute/early HIV infection. CD4⁺ T-cell counts (CD4TC) and viral load (VL) levels were determined at enrollment and for one year. Immune activation, HIV-specific immune response, Human Leukocyte Antigen (HLA) and C-C chemokine receptor type 5 (CCR5) genotypes, and plasma levels of 39 cytokines were determined. Data were analyzed by machine learning and non-parametric methods. Variable hierarchization was performed by Weka correlation-based feature selection and J48 decision tree. Plasma interleukin (IL)-10, interferon gamma-induced protein (IP)-10, soluble IL-2 receptor alpha (sIL-2Rα) and tumor necrosis factor alpha (TNF-α) levels correlated directly with baseline VL, whereas IL-2, TNF-α, fibroblast growth factor (FGF)-2 and macrophage inflammatory protein (MIP)-1β correlated directly with CD4⁺ T-cell activation ( p < 0.05). However, none of these cytokines had good predictive values to distinguish "progressors" from "non-progressors". Similarly, immune activation, HIV-specific immune responses and HLA/CCR5 genotypes had low discrimination power. Baseline CD4TC was the most potent discerning variable with a cut-off of 438 cells/μL (accuracy = 0.93, κ-Cohen = 0.85). Limited discerning power of the other factors might be related to frequency, variability and/or sampling time. Future studies based on decision trees to identify biomarkers of post-treatment control are warrantied.

Temporary hindlimb paresis following dystocia due to foetal macrosomia in a Celebes crested macaque (Macaca nigra).

PubMed

Debenham, John James; Bettembourg, Vanessa; Østevik, Liv; Modig, Michaela; Jâderlund, Karin Hultin; Lervik, Andreas

2017-04-01

A multiparous Celebes crested macaque presented with dystocia due to foetal macrosomia, causing foetal mortality and hindlimb paresis. After emergency caesarean section, recovery of motor function took 1 month before hindlimbs were weight bearing and 2 months before re-integration with the troop. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Changes in the primate trade in indonesian wildlife markets over a 25-year period: Fewer apes and langurs, more macaques, and slow lorises.

PubMed

Nijman, Vincent; Spaan, Denise; Rode-Margono, Eva Johanna; Wirdateti; Nekaris, K A I

2017-11-01

Indonesia has amongst the highest primate species richness, and many species are included on the country's protected species list, partially to prevent over-exploitation. Nevertheless traders continue to sell primates in open wildlife markets especially on the islands of Java and Bali. We surveyed 13 wildlife markets in 2012-2014 and combined our results with previous surveys from 1990-2009 into a 122-survey dataset with 2,424 records of 17 species. These data showed that the diversity of species in trade decreased over time, shifting from rare rainforest-dwelling primates traded alongside more widespread species that are not confined to forest to the latter type only. In the 1990s and early 2000s orangutans, gibbons and langurs were commonly traded alongside macaques and slow lorises but in the last decade macaques and slow lorises comprised the bulk of the trade. In 2012-2014 we monitored six wildlife markets in Jakarta, Bandung and Garut (all on Java), and Denpasar (Bali). During 51 surveys we recorded 1,272 primates of eight species. Traders offered long-tailed macaque (total 1,007 individuals) and three species of slow loris (228 individuals) in five of the six markets, whereas they traded ebony langurs (18 individuals), and pig-tailed macaques (14 individuals) mostly in Jakarta. Pramuka and Jatinegara markets, both in Jakarta, stood out as important hubs for the primate trade, with a clear shift in importance over time from the former to the latter. Slow lorises, orangutans, gibbons and some langurs are protected under Indonesian law, which prohibits all trade in them; of these protected species, only the slow lorises remained common in trade throughout the 25-year period. Trade in non-protected macaques and langurs is subject to strict regulations-which market traders did not follow-making all the market trade in primates that we observed illegal. Trade poses a substantial threat to Indonesian primates, and without enforcement, the sheer volume of trade may mean that species of Least Concern or Near Threatened may rapidly decline. Am. J. Primatol. 79:e22517, 2017. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Identification of unique B virus (Macacine Herpesvirus 1) epitopes of zoonotic and macaque isolates using monoclonal antibodies

PubMed Central

Vasireddi, Mugdha; Patrusheva, Irina; Seoh, Hyuk-Kyu; Filfili, Chadi N.; Wildes, Martin J.; Oh, Jay

2017-01-01

Our overall aim is to develop epitope-based assays for accurate differential diagnosis of B virus zoonotic infections in humans. Antibodies to cross-reacting epitopes on human-simplexviruses continue to confound the interpretation of current assays where abundant antibodies exist from previous infections with HSV types 1 and 2. To find B virus-specific epitopes we cloned ten monoclonal antibodies (mAbs) from the hybridomas we produced. Our unique collection of rare human sera from symptomatic and asymptomatic patients infected with B virus was key to the evaluation and identification of the mAbs as reagents in competition ELISAs (mAb-CE). The analysis of the ten mAbs revealed that the target proteins for six mAbs was glycoprotein B of which two are reactive to simian simplexviruses and not to human simplexviruses. Two mAbs reacted specifically with B virus glycoprotein D, and two other mAbs were specific to VP13/14 and gE-gI complex respectively. The mAbs specific to VP13/14 and gE-gI are strain specific reacting with B virus isolates from rhesus and Japanese macaques and not with isolates from cynomolgus and pigtail macaques. The mAb-CE revealed that a high proportion of naturally B virus infected rhesus macaques and two symptomatic humans possess antibodies to epitopes of VP13/14 protein and on the gE-gI complex. The majority of sera from B virus infected macaques and simplexvirus-infected humans competed with the less specific mAbs. These experiments produced a novel panel of mAbs that enabled B virus strain identification and confirmation of B virus infected macaques by the mAb-CE. For human sera the mAb-CE could be used only for selected cases due to the selective B virus strain-specificity of the mAbs against VP13/14 and gE/gI. To fully accomplish our aim to provide reagents for unequivocal differential diagnosis of zoonotic B virus infections, additional mAbs with a broader range of specificities is critical. PMID:28783746

Social network community structure and the contact-mediated sharing of commensal E. coli among captive rhesus macaques (Macaca mulatta).

PubMed

Balasubramaniam, Krishna; Beisner, Brianne; Guan, Jiahui; Vandeleest, Jessica; Fushing, Hsieh; Atwill, Edward; McCowan, Brenda

2018-01-01

In group-living animals, heterogeneity in individuals' social connections may mediate the sharing of microbial infectious agents. In this regard, the genetic relatedness of individuals' commensal gut bacterium Escherichia coli may be ideal to assess the potential for pathogen transmission through animal social networks. Here we use microbial phylogenetics and population genetics approaches, as well as host social network reconstruction, to assess evidence for the contact-mediated sharing of E. coli among three groups of captively housed rhesus macaques ( Macaca mulatta ), at multiple organizational scales. For each group, behavioral data on grooming, huddling, and aggressive interactions collected for a six-week period were used to reconstruct social network communities via the Data Cloud Geometry (DCG) clustering algorithm. Further, an E. coli isolate was biochemically confirmed and genotypically fingerprinted from fecal swabs collected from each macaque. Population genetics approaches revealed that Group Membership, in comparison to intrinsic attributes like age, sex, and/or matriline membership of individuals, accounted for the highest proportion of variance in E. coli genotypic similarity. Social network approaches revealed that such sharing was evident at the community-level rather than the dyadic level. Specifically, although we found no links between dyadic E. coli similarity and social contact frequencies, similarity was significantly greater among macaques within the same social network communities compared to those across different communities. Moreover, tests for one of our study-groups confirmed that E. coli isolated from macaque rectal swabs were more genotypically similar to each other than they were to isolates from environmentally deposited feces. In summary, our results suggest that among frequently interacting, spatially constrained macaques with complex social relationships, microbial sharing via fecal-oral, social contact-mediated routes may depend on both individuals' direct connections and on secondary network pathways that define community structure. They lend support to the hypothesis that social network communities may act as bottlenecks to contain the spread of infectious agents, thereby encouraging disease control strategies to focus on multiple organizational scales. Future directions includeincreasing microbial sampling effort per individual to better-detect dyadic transmission events, and assessments of the co-evolutionary links between sociality, infectious agent risk, and host immune function.

Improved quality of cartilage repair by bone marrow mesenchymal stem cells for treatment of an osteochondral defect in a cynomolgus macaque model

PubMed Central

Araki, Susumu; Imai, Shinji; Ishigaki, Hirohito; Mimura, Tomohiro; Nishizawa, Kazuya; Ueba, Hiroaki; Kumagai, Kousuke; Kubo, Mitsuhiko; Mori, Kanji; Ogasawara, Kazumasa; Matsusue, Yoshitaka

2015-01-01

Background and purpose Integration of repaired cartilage with surrounding native cartilage is a major challenge for successful tissue-engineering strategies of cartilage repair. We investigated whether incorporation of mesenchymal stem cells (MSCs) into the collagen scaffold improves integration and repair of cartilage defects in a cynomolgus macaque model. Methods Cynomolgus macaque bone marrow-derived MSCs were isolated and incorporated into type-I collagen gel. Full-thickness osteochondral defects (3 mm in diameter, 5 mm in depth) were created in the patellar groove of 36 knees of 18 macaques and were either left untreated (null group, n = 12), had collagen gel alone inserted (gel group, n = 12), or had collagen gel incorporating MSCs inserted (MSC group, n = 12). After 6, 12, and 24 weeks, the cartilage integration and tissue response were evaluated macroscopically and histologically (4 null, 4 gel, and 4 MSC knees at each time point). Results The gel group showed most cartilage-rich reparative tissue covering the defect, owing to formation of excessive cartilage extruding though the insufficient subchondral bone. Despite the fact that a lower amount of new cartilage was produced, the MSC group had better-quality cartilage with regular surface, seamless integration with neighboring naïve cartilage, and reconstruction of trabecular subchondral bone. Interpretation Even with intensive investigation, MSC-based cell therapy has not yet been established in experimental cartilage repair. Our model using cynomolgus macaques had optimized conditions, and the method using MSCs is superior to other experimental settings, allowing the possibility that the procedure might be introduced to future clinical practice. PMID:25175660

Longitudinal analysis reveals characteristically high proportions of bacterial vaginosis-associated bacteria and temporal variability of vaginal microbiota in northern pig-tailed macaques (Macaca leonina).

PubMed

Zhu, Lin; Lei, Ai-Hua; Zheng, Hong-Yi; Lyu, Long-Bao; Zhang, Zhi-Gang; Zheng, Yong-Tang

2015-09-18

The complex and dynamic vaginal microbial ecosystem is critical to both health and disease of the host. Studies focusing on how vaginal microbiota influences HIV-1 infection may face limitations in selecting proper animal models. Given that northern pig-tailed macaques (Macaca leonina) are susceptible to HIV-1 infection, they may be an optimal animal model for elucidating the mechanisms by which vaginal microbiota contributes to resistance and susceptibility to HIV-1 infection. However, little is known about the composition and temporal variability of vaginal microbiota of the northern pig-tailed macaque. Here, we present a comprehensive catalog of the composition and temporal dynamics of vaginal microbiota of two healthy northern pig-tailed macaques over 19 weeks using 454-pyrosequencing of 16S rRNA genes. We found remarkably high proportions of a diverse array of anaerobic bacteria associated with bacterial vaginosis. Atopobium and Sneathia were dominant genera, and interestingly, we demonstrated the presence of Lactobacillus-dominated vaginal microbiota. Moreover, longitudinal analysis demonstrated that the temporal dynamics of the vaginal microbiota were considerably individualized. Finally, network analysis revealed that vaginal pH may influence the temporal dynamics of the vaginal microbiota, suggesting that inter-subject variability of vaginal bacterial communities could be mirrored in inter-subject variation in correlation profiles of species with each other and with vaginal pH over time. Our results suggest that the northern pig-tailed macaque could be an ideal animal model for prospective investigation of the mechanisms by which vaginal microbiota influence susceptibility and resistance to HIV-1 infection in the context of highly polymicrobial and Lactobacillus-dominated states.

Testing for links between face color and age, dominance status, parity, weight, and intestinal nematode infection in a sample of female Japanese macaques.

PubMed

Rigaill, Lucie; MacIntosh, Andrew J J; Higham, James P; Winters, Sandra; Shimizu, Keiko; Mouri, Keiko; Suzumura, Takafumi; Furuichi, Takeshi; Garcia, Cécile

2017-01-01

Studies of the role of secondary sexual ornaments in mate choice tend to focus on colorful traits in males, but females of many animal species express colorful ornamentation too. Among non-human primates, investigations into the role of female secondary sexual traits as indicators of life history characteristics, reproductive success, and health status have mostly focused on sexual swellings, whereas only few studies have been conducted on the role of facial color. Recent studies on rhesus macaques and mandrills suggested that female ornamentation might provide information about female life history characteristics, but not on disease resistance factors and parasite infection, which have been shown to affect male ornamentation in some non-primate species. In Japanese macaques (Macaca fuscata), females have brightly colored faces that are indicative of their reproductive status. Here, we aimed to determine whether female facial color might also convey information about age, dominance rank, parity, weight, and intestinal nematode infection in free-ranging individuals. We analyzed whether female facial parameters (luminance and redness) were linked to these individual characteristics, using digital photography and data on intestinal parasite infection collected systematically during 1 month for each of seven free-ranging females. We found no evidence to suggest that female facial color is an indicator of any of these measures in Japanese macaques. Considering our small data set, it is still preliminary to draft any clear conclusions. Future studies combining digital, hormonal, parasitological and behavioral data are needed to assess the possible role of female face color on male preferences and mating choice in Japanese macaques.

Retinal, functional, and morphological comparisons of two different macaque species, Macaca mulatta and Macaca fasicularis, for models of laser eye injury

NASA Astrophysics Data System (ADS)

DiCarlo, Cheryl D.; Hacker, Henry D.; Brown, Araceli; Cheramie, Rachael; Martinsen, Gary L.; Rockwell, Benjamin; Stuck, Bruce E.

2005-04-01

The past several years has seen a severe shortage of pathogen-free Indian origin rhesus macaques due to the increased requirement for this model in retroviral research. With greater than 30 years of research data accumulated using the Rhesus macaque as the model for laser eye injury there exists a need to bridge to a more readily available nonhuman primate model. Much of the data previously collected from the Rhesus monkey (Macaca mulatta) provided the basis for the American National Standards Institute (ANSI) standards for laser safety. Currently a Tri-service effort is underway to utilize the Cynomolgus monkey (Macaca fasicularis) as a replacement for the Rhesus macaque. Preliminary functional and morphological baseline data collected from multifocal electroretinography (mfERG), optical coherence tomography (OCT) and retinal cell counts were compared from a small group of monkeys and tissues to determine if significant differences existed between the species. Initial functional findings rom mfERG yielded only one difference for the n2 amplitude value which was greater in the Cynomolgus monkey. No significant differences were seen in retinal and foveal thickness, as determined by OCT scans and no significant differences were seen in ganglion cell and inner nuclear cell nuclei counts. A highly significant difference was seen in the numbers of photoreceptor nuclei with greater numbers in the Rhesus macaque. This indicates more studies should be performed to determine the impact that a model change would have on the laser bioeffects community and their ability to continue to provide minimal visible lesion data for laser safety standards. The continued goal of this project will be to provide that necessary baseline information for a seamless transition to a more readily available animal model.

Speech-like orofacial oscillations in stump-tailed macaque (Macaca arctoides) facial and vocal signals.

PubMed

Toyoda, Aru; Maruhashi, Tamaki; Malaivijitnond, Suchinda; Koda, Hiroki

2017-10-01

Speech is unique to humans and characterized by facial actions of ∼5 Hz oscillations of lip, mouth or jaw movements. Lip-smacking, a facial display of primates characterized by oscillatory actions involving the vertical opening and closing of the jaw and lips, exhibits stable 5-Hz oscillation patterns, matching that of speech, suggesting that lip-smacking is a precursor of speech. We tested if facial or vocal actions exhibiting the same rate of oscillation are found in wide forms of facial or vocal displays in various social contexts, exhibiting diversity among species. We observed facial and vocal actions of wild stump-tailed macaques (Macaca arctoides), and selected video clips including facial displays (teeth chattering; TC), panting calls, and feeding. Ten open-to-open mouth durations during TC and feeding and five amplitude peak-to-peak durations in panting were analyzed. Facial display (TC) and vocalization (panting) oscillated within 5.74 ± 1.19 and 6.71 ± 2.91 Hz, respectively, similar to the reported lip-smacking of long-tailed macaques and the speech of humans. These results indicated a common mechanism for the central pattern generator underlying orofacial movements, which would evolve to speech. Similar oscillations in panting, which evolved from different muscular control than the orofacial action, suggested the sensory foundations for perceptual saliency particular to 5-Hz rhythms in macaques. This supports the pre-adaptation hypothesis of speech evolution, which states a central pattern generator for 5-Hz facial oscillation and perceptual background tuned to 5-Hz actions existed in common ancestors of macaques and humans, before the emergence of speech. © 2017 Wiley Periodicals, Inc.

Predictive Value of Parkinsonian Primates in Pharmacologic Studies: A Comparison between the Macaque, Marmoset, and Squirrel Monkey.

PubMed

Veyres, Nicolas; Hamadjida, Adjia; Huot, Philippe

2018-05-01

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate is the gold-standard animal model of Parkinson disease (PD) and has been used to assess the effectiveness of experimental drugs on dyskinesia, parkinsonism, and psychosis. Three species have been used in most studies-the macaque, marmoset, and squirrel monkey-the last much less so than the first two species; however, the predictive value of each species at forecasting clinical efficacy, or lack thereof, is poorly documented. Here, we have reviewed all the published literature detailing pharmacologic studies that assessed the effects of experimental drugs on dyskinesia, parkinsonism, and psychosis in each of these species and have calculated their predictive value of success and failure at the clinical level. We found that, for dyskinesia, the macaque has a positive predictive value of 87.5% and a false-positive rate of 38.1%, whereas the marmoset has a positive predictive value of 76.9% and a false-positive rate of 15.6%. For parkinsonism, the macaque has a positive predictive value of 68.2% and a false-positive rate of 44.4%, whereas the marmoset has a positive predictive value of 86.9% and a false-positive rate of 41.7%. No drug that alleviates psychosis in the clinic has shown efficacy at doing so in the macaque, whereas the marmoset has 100% positive predictive value. The small number of studies conducted in the squirrel monkey precluded us from calculating its predictive efficacy. We hope our results will help in the design of pharmacologic experiments and will facilitate the drug discovery and development process in PD. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Progesterone Accelerates the Completion of Sperm Capacitation and Activates CatSper Channel in Spermatozoa from the Rhesus Macaque1

PubMed Central

Sumigama, Shiho; Mansell, Steven; Miller, Melissa; Lishko, Polina V.; Cherr, Gary N.; Meyers, Stuart A.; Tollner, Theodore

2015-01-01

During transit through the female reproductive tract, mammalian spermatozoa are exposed to increasing concentrations of progesterone (P4) released by the cumulus oophorus. P4 triggers massive calcium influx into human sperm through activation of the sperm-specific calcium channel CatSper. These properties of human spermatozoa are thought to be unique since CatSper is not progesterone sensitive in rodent sperm. Here, by performing patch clamp recording from spermatozoa from rhesus macaque for the first time, we report that they express P4-sensitive CatSper channel identically to human sperm and react to P4 by inducing responsiveness to zona pellucida, unlike human sperm, which respond directly to P4. We have also determined the physiologic levels of P4 capable of inducing capacitation-associated changes in macaque sperm. Progesterone (1 μM) induced up to a 3-fold increase in the percentage of sperm undergoing the zona pellucida-induced acrosome reaction with the lowest threshold as low as 10 nM of P4. Submicromolar levels of P4 induced a dose-dependent increase in curvilinear velocity and lateral head displacement, while sperm protein tyrosine phosphorylation was not altered. Macaque spermatozoa exposed to 10 μM of P4 developed fully hyperactivated motility. Similar to human sperm, on approaching cumulus mass and binding to zona pellucida, macaque spermatozoa display hyperactivation and undergo an acrosome reaction that coincides with the rise in the sperm intracellular calcium. Taken together, these data indicate that P4 accelerates the completion of capacitation and provides evidence of spermatozoa “priming” as they move into a gradient of progesterone in search for the oocyte. PMID:26490839

Expression of m1-type muscarinic acetylcholine receptors by parvalbumin-immunoreactive neurons in the primary visual cortex: a comparative study of rat, guinea pig, ferret, macaque, and human.

PubMed

Disney, Anita A; Reynolds, John H

2014-04-01

Cholinergic neuromodulation is a candidate mechanism for aspects of arousal and attention in mammals. We have reported previously that cholinergic modulation in the primary visual cortex (V1) of the macaque monkey is strongly targeted toward GABAergic interneurons, and in particular that the vast majority of parvalbumin-immunoreactive (PV) neurons in macaque V1 express the m1-type (pirenzepine-sensitive, Gq-coupled) muscarinic ACh receptor (m1AChR). In contrast, previous physiological data indicates that PV neurons in rats rarely express pirenzepine-sensitive muscarinic AChRs. To examine further this apparent species difference in the cholinergic effectors for the primary visual cortex, we have conducted a comparative study of the expression of m1AChRs by PV neurons in V1 of rats, guinea pigs, ferrets, macaques, and humans. We visualize PV- and mAChR-immunoreactive somata by dual-immunofluorescence confocal microscopy and find that the species differences are profound; the vast majority (>75%) of PV-ir neurons in macaques, humans, and guinea pigs express m1AChRs. In contrast, in rats only ∼25% of the PV population is immunoreactive for m1AChRs. Our data reveal that while they do so much less frequently than in primates, PV neurons in rats do express Gq-coupled muscarinic AChRs, which appear to have gone undetected in the previous in vitro studies. Data such as these are critical in determining the species that represent adequate models for the capacity of the cholinergic system to modulate inhibition in the primate cortex. Copyright © 2013 Wiley Periodicals, Inc.

Aged Chinese-origin rhesus macaques infected with SIV develop marked viremia in absence of clinical disease, inflammation or cognitive impairment.

PubMed

Bissel, Stephanie J; Gurnsey, Kate; Jedema, Hank P; Smith, Nicholas F; Wang, Guoji; Bradberry, Charles W; Wiley, Clayton A

2018-02-01

Damage to the central nervous system during HIV infection can lead to variable neurobehavioral dysfunction termed HIV-associated neurocognitive disorders (HAND). There is no clear consensus regarding the neuropathological or cellular basis of HAND. We sought to study the potential contribution of aging to the pathogenesis of HAND. Aged (range = 14.7-24.8 year) rhesus macaques of Chinese origin (RM-Ch) (n = 23) were trained to perform cognitive tasks. Macaques were then divided into four groups to assess the impact of SIVmac251 infection (n = 12) and combined antiretroviral therapy (CART) (5 infected; 5 mock-infected) on the execution of these tasks. Aged SIV-infected RM-Ch demonstrated significant plasma viremia and modest CSF viral loads but showed few clinical signs, no elevations of systemic temperature, and no changes in activity levels, platelet counts or weight. Concentrations of biomarkers of acute and chronic inflammation such as soluble CD14, CXCL10, IL-6 and TNF-α are known to be elevated following SIV infection of young adult macaques of several species, but concentrations of these biomarkers did not shift after SIV infection in aged RM-Ch and remained similar to mock-infected macaques. Neither acute nor chronic SIV infection or CART had a significant impact on accuracy, speed or percent completion in a sensorimotor test. Viremia in the absence of a chronic elevated inflammatory response seen in some aged RM-Ch is reminiscent of SIV infection in natural disease resistant hosts. The absence of cognitive impairment during SIV infection in aged RM-Ch might be in part attributed to diminishment of some facets of the immunological response. Additional study encompassing species and age differences is necessary to substantiate this hypothesis.

Effect of ovarian aging on androgen biosynthesis in a cynomolgus macaque model

PubMed Central

Ethun, K. F.; Wood, C. E.; Parker, C. R.; Kaplan, J. R.; Chen, H.; Appt, S. E.

2013-01-01

Objective The role of androgens in chronic disease pathogenesis, cognitive function and libido during menopause is of increasing interest. The aim of this study was to characterize the distribution and expression of androgenic proteins in the macaque ovary and to investigate the relationship between serum androgen concentrations, follicle number, and the persistence of androgenesis in the aging macaque ovary. Methods The subjects were 26 adult female cynomolgus macaques. Ovaries were immunostained for cytochrome P450 17α-hydroxylase/17–20 lyase (P450c17), 3β-hydroxysteroid dehydrogenase (3βHSD), and cytochrome b5 (cytb5). Based on primordial follicle counts, animals were divided into tertiles (low (≤200), intermediate (226–1232), and high (2372–4356)) to evaluate differences in androgen staining and changes in serum androgen concentrations following ovariectomy. Results Positive immunostaining for P450c17 and cytb5 within the theca interna layer of growing follicles persisted in advanced atretic follicles and secondary interstitial cells (residual stromal cells). Ovaries with low follicle numbers had less staining for all androgenic proteins compared to ovaries with higher numbers of growing follicles. Immunostaining for cytb5 was the most reliable marker for persistent androgenesis in ovaries with minimal primordial follicle numbers (<100) and residual stromal cells. Following ovariectomy, a significant decrease in testosterone (−27.7%, −30.8%, −27.5%; p < 0.01) and androstenedione (−33.4%, −35.7%, −46.0%; p < 0.01) was observed in monkeys with low, intermediate, and high primordial follicle counts, respectively. Conclusions Despite low follicle numbers, the aging macaque ovary retains the necessary proteins for androgenesis within residual stromal cells and contributes to peripheral androgen concentrations. PMID:21864136

Social object play among young Japanese macaques (Macaca fuscata) in Arashiyama, Japan.

PubMed

Shimada, Masaki

2006-10-01

Social object play (SOP), i.e., social play using portable object(s), among young Japanese macaques (Macaca fuscata; 0-4 years old) in the Arashiyama E troop was studied using a modified sequence sampling method from July to October 2000. SOP was a relatively common activity for most of the young macaques and often continued for long periods. Participants used many kinds of object, including edible natural objects and artificial objects, such as plastic bottles, but they never used provisioned food or wild fruit in SOP bouts. An analysis of long bouts (>/=0.5 min) revealed the following interactive SOP features: (1) at any given time, participants used only one object, and only one participant held the object; (2) during SOP play-chasing, the object holder was likely to be chased by others; (3) during long bouts, the object changed hands frequently; and (4) agonistic competition for an object among young macaques was rare. Combinations of sexes, ages, relative ranks, or matrilines of the object holder and non-holder did not affect the tendency that the holder was chased by non-holder(s) during play-chasing. Even when there was a change in object holders, the repetitiveness of this interactive pattern, i.e., that the holder would be chased during SOP bouts, distinguished the SOP structure from that of other types of social play without object(s). General proximate social play mechanisms, such as self-handicapping or role taking, were associated with SOP. Other mechanisms that affected SOP included the following: (1) young macaques treated an object as a target in play competition, and (2) 'being the holder of a target object' was associated with the 'role of the chasee.'

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

PubMed Central

Jensen, Kara; dela Pena-Ponce, Myra Grace; Piatak, Michael; Shoemaker, Rebecca; Oswald, Kelli; Jacobs, William R.; Fennelly, Glenn; Lucero, Carissa; Mollan, Katie R.; Hudgens, Michael G.; Amedee, Angela; Kozlowski, Pamela A.; Estes, Jacob D.; Lifson, Jeffrey D.; Van Rompay, Koen K. A.; Larsen, Michelle

2016-01-01

ABSTRACT Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (SIV) vaccine is immunogenic, and although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4+ T cells were concurrently activated, and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG-vaccinated infant macaques than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants. PMID:27655885

Next-Generation Sequence Analysis of the Genome of RFHVMn, the Macaque Homolog of Kaposi's Sarcoma (KS)-Associated Herpesvirus, from a KS-Like Tumor of a Pig-Tailed Macaque

PubMed Central

Bruce, A. Gregory; Ryan, Jonathan T.; Thomas, Mathew J.; Peng, Xinxia; Grundhoff, Adam; Tsai, Che-Chung

2013-01-01

The complete sequence of retroperitoneal fibromatosis-associated herpesvirus Macaca nemestrina (RFHVMn), the pig-tailed macaque homolog of Kaposi's sarcoma-associated herpesvirus (KSHV), was determined by next-generation sequence analysis of a Kaposi's sarcoma (KS)-like macaque tumor. Colinearity of genes was observed with the KSHV genome, and the core herpesvirus genes had strong sequence homology to the corresponding KSHV genes. RFHVMn lacked homologs of open reading frame 11 (ORF11) and KSHV ORFs K5 and K6, which appear to have been generated by duplication of ORFs K3 and K4 after the divergence of KSHV and RFHV. RFHVMn contained positional homologs of all other unique KSHV genes, although some showed limited sequence similarity. RFHVMn contained a number of candidate microRNA genes. Although there was little sequence similarity with KSHV microRNAs, one candidate contained the same seed sequence as the positional homolog, kshv-miR-K12-10a, suggesting functional overlap. RNA transcript splicing was highly conserved between RFHVMn and KSHV, and strong sequence conservation was noted in specific promoters and putative origins of replication, predicting important functional similarities. Sequence comparisons indicated that RFHVMn and KSHV developed in long-term synchrony with the evolution of their hosts, and both viruses phylogenetically group within the RV1 lineage of Old World primate rhadinoviruses. RFHVMn is the closest homolog of KSHV to be completely sequenced and the first sequenced RV1 rhadinovirus homolog of KSHV from a nonhuman Old World primate. The strong genetic and sequence similarity between RFHVMn and KSHV, coupled with similarities in biology and pathology, demonstrate that RFHVMn infection in macaques offers an important and relevant model for the study of KSHV in humans. PMID:24109218

Chronic Δ9-Tetrahydrocannabinol Administration May Not Attenuate Simian Immunodeficiency Virus Disease Progression in Female Rhesus Macaques

PubMed Central

Amedee, Angela M.; Nichols, Whitney A.; LeCapitaine, Nicole J.; Stouwe, Curtis Vande; Birke, Leslie L.; Lacour, Nedra; Winsauer, Peter J.

2014-01-01

Abstract Persons living with HIV/AIDS (PLWHA) frequently use cannabinoids, either recreationally by smoking marijuana or therapeutically (delta-9-tetrahydrocannabinol; Δ9-THC dronabinol). Previously, we demonstrated that chronic Δ9-THC administration decreases early mortality in male simian immunodeficiency virus (SIV)-infected macaques. In this study, we sought to examine whether similar protective effects resulted from chronic cannabinoid administration in SIV-infected female rhesus macaques. Clinical and viral parameters were evaluated in eight female rhesus macaques that received either Δ9-THC (0.18–0.32 mg/kg, intramuscularly, twice daily) or vehicle (VEH) starting 28 days prior to intravenous inoculation with SIVmac251. SIV disease progression was assessed by changes in body weight, mortality, viral levels in plasma and mucosal sites, and lymphocyte subsets. In contrast to our results in male animals, chronic Δ9-THC did not protect SIV-infected female rhesus macaques from early mortality. Markers of SIV disease, including viral load and CD4+/CD8+ ratio, were not altered by Δ9-THC compared to control females; however, females that received chronic Δ9-THC did not gain as much weight as control animals. In addition, Δ9-THC administration increased total CXCR4 expression in both peripheral and duodenal CD4+ and CD8+ T lymphocytes prior to SIV inoculation. Although protection from early mortality was not evident, chronic Δ9-THC did not affect clinical markers of SIV disease progression. The contrasting effects of chronic Δ9-THC in males versus females remain to be explained, but highlight the need for further studies to explore the sex-dependent effects of Δ9-THC and other cannabinoids on the HIV disease course and their implications for virus transmission. PMID:25113915

The Organization of Collective Group Movements in Wild Barbary Macaques (Macaca sylvanus): Social Structure Drives Processes of Group Coordination in Macaques

PubMed Central

Seltmann, Anne; Majolo, Bonaventura

2013-01-01

Social animals have to coordinate activities and collective movements to benefit from the advantages of group living. Animals in large groups maintain cohesion by self-organization processes whereas in smaller groups consensus decisions can be reached. Where consensus decisions are relevant leadership may emerge. Variation in the organization of collective movements has been linked to variation in female social tolerance among macaque species ranging from despotic to egalitarian. Here we investigated the processes underlying group movements in a wild macaque species characterized by a degree of social tolerance intermediate to previously studied congeneric species. We focused on processes before, during and after the departure of the first individual. To this end, we observed one group of wild Barbary macaques (Macaca sylvanus) in the Middle Atlas, Morocco using all-occurrence behaviour sampling of 199 collective movements. We found that initiators of a collective movement usually chose the direction in which more individuals displayed pre-departure behavior. Dominant individuals contributed to group movements more than subordinates, especially juveniles, measured as frequencies of successful initiations and pre-departure behaviour. Joining was determined by affiliative relationships and the number of individuals that already joined the movement (mimetism). Thus, in our study group partially shared consensus decisions mediated by selective mimetism seemed to be prevalent, overall supporting the suggestion that a species’ social style affects the organization of group movements. As only the most tolerant species show equally shared consensus decisions whereas in others the decision is partially shared with a bias to dominant individuals the type of consensus decisions seems to follow a stepwise relation. Joining order may also follow a stepwise, however opposite, relationship, because dominance only determined joining in highly despotic, but not in intermediate and tolerant species. PMID:23805305

Immunogenicity of NYVAC Prime-Protein Boost Human Immunodeficiency Virus Type 1 Envelope Vaccination and Simian-Human Immunodeficiency Virus Challenge of Nonhuman Primates.

PubMed

Saunders, Kevin O; Santra, Sampa; Parks, Robert; Yates, Nicole L; Sutherland, Laura L; Scearce, Richard M; Balachandran, Harikrishnan; Bradley, Todd; Goodman, Derrick; Eaton, Amanda; Stanfield-Oakley, Sherry A; Tartaglia, James; Phogat, Sanjay; Pantaleo, Giuseppe; Esteban, Mariano; Gomez, Carmen E; Perdiguero, Beatriz; Jacobs, Bertram; Kibler, Karen; Korber, Bette; Montefiori, David C; Ferrari, Guido; Vandergrift, Nathan; Liao, Hua-Xin; Tomaras, Georgia D; Haynes, Barton F

2018-04-15

A preventive human immunodeficiency virus type 1 (HIV-1) vaccine is an essential part of the strategy to eradicate AIDS. A critical question is whether antibodies that do not neutralize primary isolate (tier 2) HIV-1 strains can protect from infection. In this study, we investigated the ability of an attenuated poxvirus vector (NYVAC) prime-envelope gp120 boost to elicit potentially protective antibody responses in a rhesus macaque model of mucosal simian-human immunodeficiency virus (SHIV) infection. NYVAC vector delivery of a group M consensus envelope, trivalent mosaic envelopes, or a natural clade B isolate B.1059 envelope elicited antibodies that mediated neutralization of tier 1 viruses, cellular cytotoxicity, and phagocytosis. None of the macaques made neutralizing antibodies against the tier 2 SHIV SF162P3 used for mucosal challenge. Significant protection from infection was not observed for the three groups of vaccinated macaques compared to unvaccinated macaques, although binding antibody to HIV-1 Env correlated with decreased viremia after challenge. Thus, NYVAC Env prime-gp120 boost vaccination elicited polyfunctional, nonneutralizing antibody responses with minimal protective activity against tier 2 SHIV mucosal challenge. IMPORTANCE The antibody responses that confer protection against HIV-1 infection remain unknown. Polyfunctional antibody responses correlated with time to infection in previous macaque studies. Determining the ability of vaccines to induce these types of responses is critical for understanding how to improve upon the one efficacious human HIV-1 vaccine trial completed thus far. We characterized the antibody responses induced by a NYVAC-protein vaccine and determined the protective capacity of polyfunctional antibody responses in an R5, tier 2 mucosal SHIV infection model. Copyright © 2018 American Society for Microbiology.

SIV/Macaque Model of HIV Infection in Cocaine Users: Minimal Effects of Cocaine on Behavior, Virus Replication, and CNS Inflammation

PubMed Central

Weed, Michael; Adams, Robert J.; Hienz, Robert D.; Meulendyke, Kelly A.; Linde, Michael E.; Clements, Janice E.; Mankowski, Joseph L.; Zink, M. Christine

2011-01-01

Studies of the effects of drugs of abuse on HIV immune status, disease progression, and neuroAIDS have produced conflicting data and have not definitively shown whether this combination promotes cognitive impairment or disease progression. Using a consistent SIV–macaque model, we investigated the effects of cocaine on behavior, virologic parameters, and CNS inflammation. Macaques received either vehicle or chronic administration of behaviorally active doses of cocaine (1.7 or 3.2 mg/kg/day). Chronic cocaine administration reduced CD8+ T cell counts during acute and late stage infection but had no effect on CD4+ T cell counts. Low-dose cocaine-treated animals had lower CSF vRNA levels late in infection, but cocaine did not alter plasma viral load or vRNA or protein in brain. There were no differences in CSF CCL-2 or interleukin (IL)-6 levels or severity of encephalitis in cocaine-treated as compared to vehicle-treated macaques. There were no differences in brain inflammation or neurodegeneration markers, as determined by interferon (IFN)-β, MxA, CCL2, IL-6, TNFα, IFNγ, and indolamine 2,3-deoxygenase mRNA levels. APP levels also were not altered. The executive function of inhibitory control was not impaired in cocaine-treated or control animals following SIV infection. However, animals receiving 3.2 mg/kg/day cocaine performed more slowly in a bimanual motor test. Thus, chronic administration of cocaine produced only minor changes in behavior, encephalitis severity, CNS inflammation/neurodegeneration, and virus replication in SIV-infected pigtailed macaques, suggesting that cocaine would have only modest effects on the progression of neuroAIDS in HIV-infected individuals. PMID:21626125

Of stones and monkeys: testing ecological constraints on stone handling, a behavioral tradition in Japanese macaques.

PubMed

Leca, Jean-Baptiste; Gunst, Noëlle; Huffman, Michael A

2008-02-01

Japanese macaques are known to manipulate stones by displaying various seemingly functionless behavioral patterns, including carrying a stone, rubbing two stones together, or gathering several stones into a pile. This form of solitary object play called stone handling (SH) is a behavioral tradition in Japanese macaques, showing striking intertroop differences in frequency and form. Here, we evaluated two ecologically based hypotheses invoked to account for these differences. We hypothesized that the occurrence and form of SH would be affected by stone availability and the degree of terrestriality. We used standardized sampling methods to assess differences in SH and terrestriality among four captive and six free-ranging troops of Japanese macaques, and determine site-specific stone availability. Although we demonstrated that SH is almost exclusively a terrestrial activity, our comparative analyses showed that the number of stones readily available and the relative amount of time spent on the ground by the macaques were not associated with the intertroop differences in the occurrence of SH. Failure to accept the terrestriality and stone availability hypotheses suggests that the performance of SH and the motivation to engage in this activity are both more diverse and more complex than the direct links to time spent on the ground or the number of stones locally available. Other environmental influences and sociodemographic factors should be jointly considered to identify the sources of variation in SH, as a beginning to better understand the constraints on the appearance and subsequent diffusion of stone-use traditions in nonhuman primates. Am J Phys Anthropol, 2008. (c) 2007 Wiley-Liss, Inc. Copyright 2007 Wiley-Liss, Inc.

Type 3 innate lymphoid cell depletion is mediated by TLRs in lymphoid tissues of simian immunodeficiency virus–infected macaques

PubMed Central

Xu, Huanbin; Wang, Xiaolei; Lackner, Andrew A.; Veazey, Ronald S.

2015-01-01

Innate lymphoid cells (ILCs) type 3, also known as lymphoid tissue inducer cells, plays a major role in both the development and remodeling of organized lymphoid tissues and the maintenance of adaptive immune responses. HIV/simian immunodeficiency virus (SIV) infection causes breakdown of intestinal barriers resulting in microbial translocation, leading to systemic immune activation and disease progression. However, the effects of HIV/SIV infection on ILC3 are unknown. Here, we analyzed ILC3 from mucosal and systemic lymphoid tissues in chronically SIV-infected macaques and uninfected controls. ILC3 cells were defined and identified in macaque lymphoid tissues as non-T, non-B (lineage-negative), c-Kit+IL-7Rα+ (CD117+CD127+) cells. These ILC3 cells highly expressed CD90 (∼63%) and aryl hydrocarbon receptor and produced IL-17 (∼63%), IL-22 (∼36%), and TNF-α (∼72%) but did not coexpress CD4 or NK cell markers. The intestinal ILC3 cell loss correlated with the reduction of total CD4+ T cells and T helper (Th)17 and Th22 cells in the gut during SIV infection (P < 0.001). Notably, ILC3 could be induced to undergo apoptosis by microbial products through the TLR2 (lipoteichoic acid) and/or TLR4 (LPS) pathway. These findings indicated that persistent microbial translocation may result in loss of ILC3 in lymphoid tissues in SIV-infected macaques, further contributing to the HIV-induced impairment of gut-associated lymphoid tissue structure and function, especially in mucosal tissues.—Xu, H., Wang, X., Lackner, A. A., Veazey, R. S. Type 3 innate lymphoid cell depletion is mediated by TLRs in lymphoid tissues of simian immunodeficiency virus–infected macaques. PMID:26283536

Novel full-length major histocompatibility complex class I allele discovery and haplotype definition in pig-tailed macaques.

PubMed

Semler, Matthew R; Wiseman, Roger W; Karl, Julie A; Graham, Michael E; Gieger, Samantha M; O'Connor, David H

2018-06-01

Pig-tailed macaques (Macaca nemestrina, Mane) are important models for human immunodeficiency virus (HIV) studies. Their infectability with minimally modified HIV makes them a uniquely valuable animal model to mimic human infection with HIV and progression to acquired immunodeficiency syndrome (AIDS). However, variation in the pig-tailed macaque major histocompatibility complex (MHC) and the impact of individual transcripts on the pathogenesis of HIV and other infectious diseases is understudied compared to that of rhesus and cynomolgus macaques. In this study, we used Pacific Biosciences single-molecule real-time circular consensus sequencing to describe full-length MHC class I (MHC-I) transcripts for 194 pig-tailed macaques from three breeding centers. We then used the full-length sequences to infer Mane-A and Mane-B haplotypes containing groups of MHC-I transcripts that co-segregate due to physical linkage. In total, we characterized full-length open reading frames (ORFs) for 313 Mane-A, Mane-B, and Mane-I sequences that defined 86 Mane-A and 106 Mane-B MHC-I haplotypes. Pacific Biosciences technology allows us to resolve these Mane-A and Mane-B haplotypes to the level of synonymous allelic variants. The newly defined haplotypes and transcript sequences containing full-length ORFs provide an important resource for infectious disease researchers as certain MHC haplotypes have been shown to provide exceptional control of simian immunodeficiency virus (SIV) replication and prevention of AIDS-like disease in nonhuman primates. The increased allelic resolution provided by Pacific Biosciences sequencing also benefits transplant research by allowing researchers to more specifically match haplotypes between donors and recipients to the level of nonsynonymous allelic variation, thus reducing the risk of graft-versus-host disease.

Expression and localization of p-glycoprotein, multidrug resistance protein 4, and breast cancer resistance protein in the female lower genital tract of human and pigtailed macaque.

PubMed

Zhou, Tian; Hu, Minlu; Pearlman, Andrew; Patton, Dorothy; Rohan, Lisa

2014-11-01

Antiretroviral drug absorption and disposition in cervicovaginal tissue is important for the effectiveness of vaginally or orally administered drug products in preexposure prophylaxis (PrEP) of HIV-1 sexual transmission to women. Therefore, it is imperative to understand critical determinants of cervicovaginal tissue pharmacokinetics. This study aimed to examine the mRNA expression and protein localization of three efflux transporters, P-glycoprotein (P-gp), multidrug resistance-associated protein 4 (MRP4), and breast cancer resistance protein (BCRP), in the lower genital tract of premenopausal women and pigtailed macaques. Along the human lower genital tract, the three transporters were moderately to highly expressed compared to colorectal tissue and liver, as revealed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). In a given genital tract segment, the transporter with the highest expression level was either BCRP or P-gp, while MRP4 was always expressed at the lowest level among the three transporters tested. The immunohistochemical staining showed that P-gp and MRP4 were localized in multiple cell types including epithelial cells and vascular endothelial cells. BCRP was predominantly localized in the vascular endothelial cells. Differences in transporter mRNA level and localization were observed among endocervix, ectocervix, and vagina. Compared to human tissues, the macaque cervicovaginal tissues displayed comparable expression and localization patterns of the three transporters, although subtle differences were observed between the two species. The role of these cervicovaginal transporters in drug absorption and disposition warrants further studies. The resemblance between human and pigtailed macaque in transporter expression and localization suggests the utility of the macaque model in the studies of human cervicovaginal transporters.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Na, Lei; Tang, Yan-Dong; Biotechnology Institute of Southern Medical University, Guangzhou 510515

Highlights: • TRIMe7-CypA expresses in rhesus and pig-tailed, but not long-tailed macaques. • TRIMe7-CypA does not show the restriction to a HIV-GFP report virus in vitro. • It acts as a negative modulator to TRIM5α likely by competitive inhibition. - Abstract: The existence of innate, host-specific restriction factors is a major obstacle to the development of nonhuman primate models for AIDS studies, and TRIM5α is one of the most important of these restriction factors. In recent years, a TRIM5 chimeric gene that was retrotransposed by a cyclophilin A (CypA) cDNA was identified in certain macaque species. The TRIM5α-CypA fusion protein,more » TRIMCyp, which was expressed in these monkeys, had lost its restriction ability toward HIV-1. We previously found that TRIMe7-CypA, an alternative splicing isoform of the TRIMCyp transcripts, was expressed in pig-tailed and rhesus macaques but absent in long-tailed macaques. In this study, the anti-HIV-1 activity of TRIMe7-CypA in the rhesus macaque (RhTRIMe7-CypA) was investigated. The over-expression of RhTRIMe7-CypA in CrFK, HeLa and HEK293T cells did not restrict the infection or replication of an HIV-1-GFP reporter virus in these cells. As a positive control, rhesus (rh)TRIM5α strongly inhibited the reporter virus. Intriguingly, the anti-HIV-1 activity of RhTRIM5α was significantly reduced in a dose-dependent manner by the co-repression of RhTRIMe7-CypA. Our data indicate that although the RhTRIMe7-CypA isoform does not appear to restrict HIV-1, it may act as a negative modulator of TRIM family proteins, presumably by competitive inhibition.« less

Comparison of human and rhesus macaque T-cell responses elicited by boosting with NYVAC encoding human immunodeficiency virus type 1 clade C immunogens.

PubMed

Mooij, Petra; Balla-Jhagjhoorsingh, Sunita S; Beenhakker, Niels; van Haaften, Patricia; Baak, Ilona; Nieuwenhuis, Ivonne G; Heidari, Shirin; Wolf, Hans; Frachette, Marie-Joelle; Bieler, Kurt; Sheppard, Neil; Harari, Alexandre; Bart, Pierre-Alexandre; Liljeström, Peter; Wagner, Ralf; Pantaleo, Giuseppe; Heeney, Jonathan L

2009-06-01

Rhesus macaques (Macaca mulatta) have played a valuable role in the development of human immunodeficiency virus (HIV) vaccine candidates prior to human clinical trials. However, changes and/or improvements in immunogen quality in the good manufacturing practice (GMP) process or changes in adjuvants, schedule, route, dose, or readouts have compromised the direct comparison of T-cell responses between species. Here we report a comparative study in which T-cell responses from humans and macaques to HIV type 1 antigens (Gag, Pol, Nef, and Env) were induced by the same vaccine batches prepared under GMP and administered according to the same schedules in the absence and presence of priming. Priming with DNA (humans and macaques) or alphavirus (macaques) and boosting with NYVAC induced robust and broad antigen-specific responses, with highly similar Env-specific gamma interferon (IFN-gamma) enzyme-linked immunospot assay responses in rhesus monkeys and human volunteers. Persistent cytokine responses of antigen-specific CD4(+) and CD8(+) T cells of the central memory as well as the effector memory phenotype, capable of simultaneously eliciting multiple cytokines (IFN-gamma, interleukin 2, and tumor necrosis factor alpha), were induced. Responses were highly similar in humans and primates, confirming earlier data indicating that priming is essential for inducing robust NYVAC-boosted IFN-gamma T-cell responses. While significant similarities were observed in Env-specific responses in both species, differences were also observed with respect to responses to other HIV antigens. Future studies with other vaccines using identical lots, immunization schedules, and readouts will establish a broader data set of species similarities and differences with which increased confidence in predicting human responses may be achieved.

Comparison of Human and Rhesus Macaque T-Cell Responses Elicited by Boosting with NYVAC Encoding Human Immunodeficiency Virus Type 1 Clade C Immunogens▿

PubMed Central

Mooij, Petra; Balla-Jhagjhoorsingh, Sunita S.; Beenhakker, Niels; van Haaften, Patricia; Baak, Ilona; Nieuwenhuis, Ivonne G.; Heidari, Shirin; Wolf, Hans; Frachette, Marie-Joelle; Bieler, Kurt; Sheppard, Neil; Harari, Alexandre; Bart, Pierre-Alexandre; Liljeström, Peter; Wagner, Ralf; Pantaleo, Giuseppe; Heeney, Jonathan L.

2009-01-01

Rhesus macaques (Macaca mulatta) have played a valuable role in the development of human immunodeficiency virus (HIV) vaccine candidates prior to human clinical trials. However, changes and/or improvements in immunogen quality in the good manufacturing practice (GMP) process or changes in adjuvants, schedule, route, dose, or readouts have compromised the direct comparison of T-cell responses between species. Here we report a comparative study in which T-cell responses from humans and macaques to HIV type 1 antigens (Gag, Pol, Nef, and Env) were induced by the same vaccine batches prepared under GMP and administered according to the same schedules in the absence and presence of priming. Priming with DNA (humans and macaques) or alphavirus (macaques) and boosting with NYVAC induced robust and broad antigen-specific responses, with highly similar Env-specific gamma interferon (IFN-γ) enzyme-linked immunospot assay responses in rhesus monkeys and human volunteers. Persistent cytokine responses of antigen-specific CD4+ and CD8+ T cells of the central memory as well as the effector memory phenotype, capable of simultaneously eliciting multiple cytokines (IFN-γ, interleukin 2, and tumor necrosis factor alpha), were induced. Responses were highly similar in humans and primates, confirming earlier data indicating that priming is essential for inducing robust NYVAC-boosted IFN-γ T-cell responses. While significant similarities were observed in Env-specific responses in both species, differences were also observed with respect to responses to other HIV antigens. Future studies with other vaccines using identical lots, immunization schedules, and readouts will establish a broader data set of species similarities and differences with which increased confidence in predicting human responses may be achieved. PMID:19321612

Protection of rhesus macaques against inhalational anthrax with a Bacillus anthracis capsule conjugate vaccine.

PubMed

Chabot, Donald J; Ribot, Wilson J; Joyce, Joseph; Cook, James; Hepler, Robert; Nahas, Debbie; Chua, Jennifer; Friedlander, Arthur M

2016-07-25

The efficacy of currently licensed anthrax vaccines is largely attributable to a single Bacillus anthracis immunogen, protective antigen. To broaden protection against possible strains resistant to protective antigen-based vaccines, we previously developed a vaccine in which the anthrax polyglutamic acid capsule was covalently conjugated to the outer membrane protein complex of Neisseria meningitidis serotype B and demonstrated that two doses of 2.5μg of this vaccine conferred partial protection of rhesus macaques against inhalational anthrax . Here, we demonstrate complete protection of rhesus macaques against inhalational anthrax with a higher 50μg dose of the same capsule conjugate vaccine. These results indicate that B. anthracis capsule is a highly effective vaccine component that should be considered for incorporation in future generation anthrax vaccines. Published by Elsevier Ltd.

Retrovirus Studies in Nonhuman Primates at Four Regional Primate Research Centers.

DTIC Science & Technology

1989-12-31

inoculation of the vaginal mucosa with SIV-infected splenocytes. The Heterosexual Transmission of AIDS: A Simian Model. The overall objective of this...female rhesus macagues. We have previously reported that SIV can be transmitted across the vaginal mucosa of female rhesus macaques (Miller, et. al... vaginal vault of female rhesus macaques immobilized with Ketamine HCl. After each inoculation, the animals remained immobile for 15 minutes. To determine

Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques

DTIC Science & Technology

2003-12-01

Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques Evidence that Dendritic Cells Are Early and Sustained Targets of Infection Thomas W...is known about the development of EBOV hemorrhagic fever . In the present study, 21 cynomol- gus monkeys were experimentally infected with EBOV and...Am J Pathol 2003, 163:2347–2370) Among viruses causing hemorrhagic fever (HF), and among emerging infectious diseases with global impact in general

Therapeutic Remyelination Strategies in a Novel Model of Multiple Sclerosis: Japanese Macaque Encephalomyelitis

DTIC Science & Technology

2010-05-01

viruses, especially gama- herpesviruses , may act as a trigger of multiple sclerosis (MS; Ascherio and Munger, 2010). Furthermore, there is growing...than others, suggesting a genetic pre-disposition to JME. Furthermore, we have cloned a gamma- herpesvirus (called Japanese macaque rhadovirus; JMRV...models in non-human primates and rodents. We aim to use this model to better understand how gamma- herpesviruses trigger MS; whether polymorphisms in

Gravity orientation tuning in macaque anterior thalamus.

PubMed

Laurens, Jean; Kim, Byounghoon; Dickman, J David; Angelaki, Dora E

2016-12-01

Gravity may provide a ubiquitous allocentric reference to the brain's spatial orientation circuits. Here we describe neurons in the macaque anterior thalamus tuned to pitch and roll orientation relative to gravity, independently of visual landmarks. We show that individual cells exhibit two-dimensional tuning curves, with peak firing rates at a preferred vertical orientation. These results identify a thalamic pathway for gravity cues to influence perception, action and spatial cognition.

Natural and cross-inducible anti-SIV antibodies in Mauritian cynomolgus macaques

PubMed Central

Li, Hongzhao; Nykoluk, Mikaela; Li, Lin; Liu, Lewis R.; Omange, Robert W.; Soule, Geoff; Schroeder, Lukas T.; Toledo, Nikki; Kashem, Mohammad Abul; Correia-Pinto, Jorge F.; Liang, Binhua; Schultz-Darken, Nancy; Alonso, Maria J.; Whitney, James B.; Plummer, Francis A.

2017-01-01

Cynomolgus macaques are an increasingly important nonhuman primate model for HIV vaccine research. SIV-free animals without pre-existing anti-SIV immune responses are generally needed to evaluate the effect of vaccine-induced immune responses against the vaccine epitopes. Here, in order to select such animals for vaccine studies, we screened 108 naïve female Mauritian cynomolgus macaques for natural (baseline) antibodies to SIV antigens using a Bio-Plex multiplex system. The antigens included twelve 20mer peptides overlapping the twelve SIV protease cleavage sites (-10/+10), respectively (PCS peptides), and three non-PCS Gag or Env peptides. Natural antibodies to SIV antigens were detected in subsets of monkeys. The antibody reactivity to SIV was further confirmed by Western blot using purified recombinant SIV Gag and Env proteins. As expected, the immunization of monkeys with PCS antigens elicited anti-PCS antibodies. However, unexpectedly, antibodies to non-PCS peptides were also induced, as shown by both Bio-Plex and Western blot analyses, while the non-PCS peptides do not share sequence homology with PCS peptides. The presence of natural and vaccine cross-inducible SIV antibodies in Mauritian cynomolgus macaques should be considered in animal selection, experimental design and result interpretation, for their best use in HIV vaccine research. PMID:28982126

Species-Associated Differences in the Inhibition of Propofol Glucuronidation by Magnolol

PubMed Central

Yang, Lu; Zhu, Liangliang; Ge, Guangbo; Xiao, Ling; Wu, Yan; Liang, Sicheng; Cao, Yunfeng; Yang, Ling; Wang, Dong

2014-01-01

Magnolol, a major active constituent in herbal medicine, potently inhibits propofol glucuronidation in human liver microsomes, with inhibition constants in the nanomolar range. This study was conducted to investigate magnolol-induced inhibition of propofol glucuronidation in liver microsomes from Swiss–Hauschka mice, Sprague–Dawley rats, Chinese Bama pigs, and cynomolgus macaques. Results indicated that magnolol (10 μM) inhibited propofol glucuronidation in liver microsomes from Bama pigs and cynomolgus macaques but not in those from mice or rats. Data from liver microsomes from Bama pigs indicated a competitive inhibition mechanism, with a Ki of 1.7 μM. In contrast to that of pig liver microsomes, the inhibition of microsomes from cynomolgus macaques followed a noncompetitive mechanism, with a Ki of 3.4 μM. In summary, this study indicates that magnolol-induced inhibition of propofol glucuronidation varies substantially among species, and the Ki values determined by using liver microsomes from various experimental animal species far exceed that for human liver microsomes. The inhibition of propofol glucuronidation by magnolol in liver microsomes from all animal species tested was significantly lower than the inhibition previously demonstrated in human liver microsomes. Hepatic microsomes from Swiss–Hauschka mice, Sprague–Dawley rats, Chinese Bama pigs, and cynomolgus macaques are not effective models of the inhibition of glucuronidation induced by magnolol in humans. PMID:25199099

Species-associated differences in the inhibition of propofol glucuronidation by magnolol.

PubMed

Yang, Lu; Zhu, Liangliang; Ge, Guangbo; Xiao, Ling; Wu, Yan; Liang, Sicheng; Cao, Yunfeng; Yang, Ling; Wang, Dong

2014-07-01

Magnolol, a major active constituent in herbal medicine, potently inhibits propofol glucuronidation in human liver microsomes, with inhibition constants in the nanomolar range. This study was conducted to investigate magnolol-induced inhibition of propofol glucuronidation in liver microsomes from Swiss-Hauschka mice, Sprague-Dawley rats, Chinese Bama pigs, and cynomolgus macaques. Results indicated that magnolol (10 μM) inhibited propofol glucuronidation in liver microsomes from Bama pigs and cynomolgus macaques but not in those from mice or rats. Data from liver microsomes from Bama pigs indicated a competitive inhibition mechanism, with a Ki of 1.7 μM. In contrast to that of pig liver microsomes, the inhibition of microsomes from cynomolgus macaques followed a noncompetitive mechanism, with a Ki of 3.4 μM. In summary, this study indicates that magnolol-induced inhibition of propofol glucuronidation varies substantially among species, and the Ki values determined by using liver microsomes from various experimental animal species far exceed that for human liver microsomes. The inhibition of propofol glucuronidation by magnolol in liver microsomes from all animal species tested was significantly lower than the inhibition previously demonstrated in human liver microsomes. Hepatic microsomes from Swiss-Hauschka mice, Sprague-Dawley rats, Chinese Bama pigs, and cynomolgus macaques are not effective models of the inhibition of glucuronidation induced by magnolol in humans.

Are non-human primates capable of rhythmic entrainment? Evidence for the gradual audiomotor evolution hypothesis.

PubMed

Merchant, Hugo; Honing, Henkjan

2013-01-01

We propose a decomposition of the neurocognitive mechanisms that might underlie interval-based timing and rhythmic entrainment. Next to reviewing the concepts central to the definition of rhythmic entrainment, we discuss recent studies that suggest rhythmic entrainment to be specific to humans and a selected group of bird species, but, surprisingly, is not obvious in non-human primates. On the basis of these studies we propose the gradual audiomotor evolution hypothesis that suggests that humans fully share interval-based timing with other primates, but only partially share the ability of rhythmic entrainment (or beat-based timing). This hypothesis accommodates the fact that non-human primates (i.e., macaques) performance is comparable to humans in single interval tasks (such as interval reproduction, categorization, and interception), but show differences in multiple interval tasks (such as rhythmic entrainment, synchronization, and continuation). Furthermore, it is in line with the observation that macaques can, apparently, synchronize in the visual domain, but show less sensitivity in the auditory domain. And finally, while macaques are sensitive to interval-based timing and rhythmic grouping, the absence of a strong coupling between the auditory and motor system of non-human primates might be the reason why macaques cannot rhythmically entrain in the way humans do.

Comparison of the effects of pathogenic simian human immunodeficiency virus strains SHIV-89.6P and SHIV-KU2 in cynomolgus macaques.

PubMed

Pawar, Santosh N; Mattila, Joshua T; Sturgeon, Timothy J; Lin, Philana Ling; Narayan, Opendra; Montelaro, Ronald C; Flynn, Joanne L

2008-04-01

Factors explaining why human immunodeficiency virus (HIV) enhances the risk of reactivated tuberculosis (TB) are poorly understood. Unfortunately, experimental models of HIV-induced reactivated TB are lacking. We examined whether cynomolgus macaques, which accurately model latent TB in humans, could be used to model pathogenesis of HIV infection in the lungs and associated lymph nodes. These experiments precede studies modeling the effects of HIV infection on latent TB. We infected two groups of macaques with chimeric simian-human immunodeficiency viruses (SHIV-89.6P and SHIV-KU2) and followed viral titers and immunologic parameters including lymphocytes numbers and phenotype in the blood, bronchoalveolar lavage cells, and lymph nodes over the course of infection. Tissues from the lungs, liver, kidney, spleen, and lymph nodes were similarly examined at necropsy. Both strains produced dramatic CD4(+) T cell depletion. Plasma titers were not different between viruses, but we found more SHIV-89.6P in the lungs. Both viruses induced similar patterns of cell activation markers. SHIV-89.6P induced more IFN-gamma expression than SHIV-KU2. These results indicate SHIV-89.6P and SHIV-KU2 infect cynomolgus macaques and may be used to accurately model effects of HIV infection on latent TB.

Individual and social learning processes involved in the acquisition and generalization of tool use in macaques

PubMed Central

Macellini, S.; Maranesi, M.; Bonini, L.; Simone, L.; Rozzi, S.; Ferrari, P. F.; Fogassi, L.

2012-01-01

Macaques can efficiently use several tools, but their capacity to discriminate the relevant physical features of a tool and the social factors contributing to their acquisition are still poorly explored. In a series of studies, we investigated macaques' ability to generalize the use of a stick as a tool to new objects having different physical features (study 1), or to new contexts, requiring them to adapt the previously learned motor strategy (study 2). We then assessed whether the observation of a skilled model might facilitate tool-use learning by naive observer monkeys (study 3). Results of study 1 and study 2 showed that monkeys trained to use a tool generalize this ability to tools of different shape and length, and learn to adapt their motor strategy to a new task. Study 3 demonstrated that observing a skilled model increases the observers' manipulations of a stick, thus facilitating the individual discovery of the relevant properties of this object as a tool. These findings support the view that in macaques, the motor system can be modified through tool use and that it has a limited capacity to adjust the learnt motor skills to a new context. Social factors, although important to facilitate the interaction with tools, are not crucial for tool-use learning. PMID:22106424

Evaluation of Infrared Thermometry in Cynomolgus Macaques (Macaca fascicularis)

PubMed Central

Laffins, Michael M; Mellal, Nacera; Almlie, Cynthia L; Regalia, Douglas E

2017-01-01

Recording an accurate body temperature is important to assess an animal's health status. We compared temperature data from sedated cynomolgus macaques (Macaca fascicularis) to evaluate differences between rectal, infrared (inguinal and chest), and implanted telemetry techniques with the objective of demonstrating the diagnostic equivalence of the infrared device with other approaches. Infrared thermometer readings are instantaneous and require no contact with the animal. Body temperature data were obtained from 205 (137 male, 68 female) cynomolgus macaques under ketamine (10 mg/kg IM) sedation over a 3-mo period during scheduled physical examinations. Infrared measurements were taken 5 cm from the chest and inguinal areas. We evaluated 10 (9 functional devices) sedated cynomolgus macaques (5 male, 5 female) implanted with telemetry units in a muscular pouch between the internal and external abdominal oblique muscles. We determined that the mean body temperature acquired by using telemetry did not differ from either the mean of inguinal and chest infrared measurements but did differ from the mean of temperature obtained rectally. In addition, the mean rectal temperature differed from the mean of the inguinal reading but not the mean of the chest temperature. The results confirm our hypothesis that the infrared thermometer can be used to replace standard rectal thermometry. PMID:28905720

Auditory properties in the parabelt regions of the superior temporal gyrus in the awake macaque monkey: an initial survey.

PubMed

Kajikawa, Yoshinao; Frey, Stephen; Ross, Deborah; Falchier, Arnaud; Hackett, Troy A; Schroeder, Charles E

2015-03-11

The superior temporal gyrus (STG) is on the inferior-lateral brain surface near the external ear. In macaques, 2/3 of the STG is occupied by an auditory cortical region, the "parabelt," which is part of a network of inferior temporal areas subserving communication and social cognition as well as object recognition and other functions. However, due to its location beneath the squamous temporal bone and temporalis muscle, the STG, like other inferior temporal regions, has been a challenging target for physiological studies in awake-behaving macaques. We designed a new procedure for implanting recording chambers to provide direct access to the STG, allowing us to evaluate neuronal properties and their topography across the full extent of the STG in awake-behaving macaques. Initial surveys of the STG have yielded several new findings. Unexpectedly, STG sites in monkeys that were listening passively responded to tones with magnitudes comparable to those of responses to 1/3 octave band-pass noise. Mapping results showed longer response latencies in more rostral sites and possible tonotopic patterns parallel to core and belt areas, suggesting the reversal of gradients between caudal and rostral parabelt areas. These results will help further exploration of parabelt areas. Copyright © 2015 the authors 0270-6474/15/354140-11$15.00/0.

Specific CD8+ T Cell Responses Correlate with Control of Simian Immunodeficiency Virus Replication in Mauritian Cynomolgus Macaques

PubMed Central

Budde, Melisa L.; Greene, Justin M.; Chin, Emily N.; Ericsen, Adam J.; Scarlotta, Matthew; Cain, Brian T.; Pham, Ngoc H.; Becker, Ericka A.; Harris, Max; Weinfurter, Jason T.; O'Connor, Shelby L.; Piatak, Michael; Lifson, Jeffrey D.; Gostick, Emma; Price, David A.; Friedrich, Thomas C.

2012-01-01

Specific major histocompatibility complex (MHC) class I alleles are associated with an increased frequency of spontaneous control of human and simian immunodeficiency viruses (HIV and SIV). The mechanism of control is thought to involve MHC class I-restricted CD8+ T cells, but it is not clear whether particular CD8+ T cell responses or a broad repertoire of epitope-specific CD8+ T cell populations (termed T cell breadth) are principally responsible for mediating immunologic control. To test the hypothesis that heterozygous macaques control SIV replication as a function of superior T cell breadth, we infected MHC-homozygous and MHC-heterozygous cynomolgus macaques with the pathogenic virus SIVmac239. As measured by a gamma interferon enzyme-linked immunosorbent spot assay (IFN-γ ELISPOT) using blood, T cell breadth did not differ significantly between homozygotes and heterozygotes. Surprisingly, macaques that controlled SIV replication, regardless of their MHC zygosity, shared durable T cell responses against similar regions of Nef. While the limited genetic variability in these animals prevents us from making generalizations about the importance of Nef-specific T cell responses in controlling HIV, these results suggest that the T cell-mediated control of virus replication that we observed is more likely the consequence of targeting specificity rather than T cell breadth. PMID:22573864

Comparison of the vaginal environment of Macaca mulatta and Macaca nemestrina throughout the menstrual cycle

PubMed Central

Hadzic, Sarah V.; Wang, Xiaolei; Dufour, Jason; Doyle, Lara; Marx, Preston A.; Lackner, Andrew A.; Paulsen, Daniel B.; Veazey, Ronald S.

2014-01-01

Problem Pigtail macaques, Macaca nemestrina (PT) are more susceptible to vaginal transmission of simian immunodeficiency virus (SIV) and other sexually transmitted diseases (STD) than rhesus macaques (RM). However, comparative studies to explore the reasons for these differences are lacking. Method of Study Here we compared differences in hormone levels and vaginal mucosal anatomy and thickness of RM and PT through different stages of the menstrual cycle. Concentrations of plasma estradiol (E2) and progesterone (P4) were determined weekly, and vaginal biopsies examined at day 0 and 14 of the menstrual cycle. Results Consistent changes in vaginal epithelial thickness occurred at different stages of the menstrual cycle. In both species, the vaginal epithelium was significantly thicker in the follicular than in luteal phase. Keratinized epithelium was strikingly much more prominent in RM, especially during the luteal phase. Further, the vaginal epithelium was significantly thinner and the P4:E2 ratio was higher in PT during luteal phase than RM. Conclusions Striking anatomical differences in the vaginal epithelium between rhesus and pigtail macaques combined with differences in P4:E2 ratio support the hypothesis that thinning and less keratinization of the vaginal epithelium may be involved in the greater susceptibility of pigtail macaques to vaginal transmission of SIV or other STD. PMID:24521395

Thyroid cancer in a long-term nonprogressor HIV-1 infection

PubMed Central

Phatak, Uday A.; Chitale, P. V.; Jagdale, Rakhi V.

2015-01-01

Long-term non-progressor HIV infection (LTNP-HIV) is seen in <1 percent of HIV-afflicted population. There are definite criteria for the diagnosis of LTNP-HIV. Malignancies either solid tumors or haematological cancers have not been reported in such population. We report here a rare case of follicular thyroid carcinoma in LTNP-HIV infection. She never had any opportunistic infections. She did not receive anti-retroviral therapy in the entire course of illness and continued to have good quality of life. Treatment of follicular thyroid cancer was similar to other patients without HIV infection. This could be the first case study from India. PMID:26692617

A novel role for visual perspective cues in the neural computation of depth.

PubMed

Kim, HyungGoo R; Angelaki, Dora E; DeAngelis, Gregory C

2015-01-01

As we explore a scene, our eye movements add global patterns of motion to the retinal image, complicating visual motion produced by self-motion or moving objects. Conventionally, it has been assumed that extraretinal signals, such as efference copy of smooth pursuit commands, are required to compensate for the visual consequences of eye rotations. We consider an alternative possibility: namely, that the visual system can infer eye rotations from global patterns of image motion. We visually simulated combinations of eye translation and rotation, including perspective distortions that change dynamically over time. We found that incorporating these 'dynamic perspective' cues allowed the visual system to generate selectivity for depth sign from motion parallax in macaque cortical area MT, a computation that was previously thought to require extraretinal signals regarding eye velocity. Our findings suggest neural mechanisms that analyze global patterns of visual motion to perform computations that require knowledge of eye rotations.

Guiding intramuscular diaphragm injections using real-time ultrasound and electromyography.

PubMed

Sarwal, Aarti; Cartwright, Michael S; Mitchell, Erin; Williams, Koudy; Walker, Francis O; Childers, Martin K

2015-02-01

We describe a unique method that combines ultrasound and electromyography to guide intramuscular diaphragm injections in anesthetized large animals. Ultrasound was used to visualize the diaphragm on each side of spontaneously breathing, anesthetized beagle dogs and cynomolgus macaques. An electromyography (EMG) needle was introduced and directed by ultrasound to confirm that the needle entered the muscular portion of the diaphragm, and methylene blue was injected. Injection accuracy was confirmed upon necropsy by tracking the spread of methylene blue. All methylene blue injections were confirmed to have been placed appropriately into the diaphragm. This study demonstrates the feasibility and accuracy of using ultrasound and EMG to guide injections and to reduce complications associated with conventional blind techniques. Ultrasound guidance can be used for clinical EMG of the diaphragm. Future applications may include targeted diaphragm injections with gene replacement therapy in neuromuscular diseases. © 2014 Wiley Periodicals, Inc.

Guiding Intramuscular Diaphragm Injections Using Real-time Ultrasound & Electromyography

PubMed Central

Sarwal, Aarti; Cartwright, Michael S.; Mitchell, Erin; Williams, Koudy; Walker, Francis O.; Childers, Martin K.

2014-01-01

Introduction We describe a unique method that combines ultrasound and electromyography to guide intramuscular diaphragm injections in anesthetized large animals. Methods Ultrasound was used to visualize the diaphragm on each side of spontaneously breathing, anesthetized beagle dogs and cynomolgus macaques. An electromyography needle was introduced and directed by ultrasound to confirm that the needle entered the muscular portion of the diaphragm, and methylene blue was injected. Injection accuracy was confirmed upon necropsy by tracking the spread of methylene blue. Results All methylene blue injections were confirmed to have been placed appropriately into the diaphragm. Conclusions This study demonstrates the feasibility and accuracy of using ultrasound and EMG to guide injections and to reduce complications associated with conventional blind techniques. Ultrasound guidance can be used for clinical electromyography of the diaphragm. Future applications may include targeted diaphragm injections with gene replacement therapy in neuromuscular diseases. PMID:25354257

Toxicokinetic Model Development for the Insensitive Munitions Component 3-Nitro-1,2,4-Triazol-5-One.

PubMed

Sweeney, Lisa M; Phillips, Elizabeth A; Goodwin, Michelle R; Bannon, Desmond I

2015-01-01

3-Nitro-1,2,4-triazol-5-one (NTO) is a component of insensitive munitions that are potential replacements for conventional explosives. Toxicokinetic data can aid in the interpretation of toxicity studies and interspecies extrapolation, but only limited data on the toxicokinetics and metabolism of NTO are available. To supplement these limited data, further in vivo studies of NTO in rats were conducted and blood concentrations were measured, tissue distribution of NTO was estimated using an in silico method, and physiologically based pharmacokinetic models of the disposition of NTO in rats and macaques were developed and extrapolated to humans. The model predictions can be used to extrapolate from designated points of departure identified from rat toxicology studies to provide a scientific basis for estimates of acceptable human exposure levels for NTO. © The Author(s) 2015.

AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges

PubMed Central

Gardner, Matthew R.; Kattenhorn, Lisa M.; Kondur, Hema R.; von Schaewen, Markus; Dorfman, Tatyana; Chiang, Jessica J.; Haworth, Kevin G.; Decker, Julie M.; Alpert, Michael D.; Bailey, Charles C.; Neale, Ernest S.; Fellinger, Christoph H.; Joshi, Vinita R.; Fuchs, Sebastian P.; Martinez-Navio, Jose M.; Quinlan, Brian D.; Yao, Annie Y.; Mouquet, Hugo; Gorman, Jason; Zhang, Baoshan; Poignard, Pascal; Nussenzweig, Michel C.; Burton, Dennis R.; Kwong, Peter D.; Piatak, Michael; Lifson, Jeffrey D.; Gao, Guangping; Desrosiers, Ronald C.; Evans, David T.; Hahn, Beatrice H.; Ploss, Alexander; Cannon, Paula M.; Seaman, Michael S.; Farzan, Michael

2015-01-01

Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs)1,2. However even the best bNAbs neutralize 10–50% of HIV-1 isolates inefficiently (IC80 > 5 μg/ml), suggesting that high concentrations of these antibodies would be necessary to achieve general protection3–6. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean IC50 < 0.05 μg/ml). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2, and SIV isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46, and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17 to 77 μg/ml of fully functional rhesus eCD4-Ig for 40 weeks, and these macaques were protected from multiple infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine. PMID:25707797

A Novel Assay for Antibody-Dependent Cell-Mediated Cytotoxicity against HIV-1- or SIV-Infected Cells Reveals Incomplete Overlap with Antibodies Measured by Neutralization and Binding Assays

PubMed Central

Alpert, Michael D.; Heyer, Lisa N.; Williams, David E. J.; Harvey, Jackson D.; Greenough, Thomas; Allhorn, Maria

2012-01-01

The resistance of human immunodeficiency virus type 1 (HIV-1) to antibody-mediated immunity often prevents the detection of antibodies that neutralize primary isolates of HIV-1. However, conventional assays for antibody functions other than neutralization are suboptimal. Current methods for measuring the killing of virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC) are limited by the number of natural killer (NK) cells obtainable from individual donors, donor-to-donor variation, and the use of nonphysiological targets. We therefore developed an ADCC assay based on NK cell lines that express human or macaque CD16 and a CD4+ T-cell line that expresses luciferase from a Tat-inducible promoter upon HIV-1 or simian immunodeficiency virus (SIV) infection. NK cells and virus-infected targets are mixed in the presence of serial plasma dilutions, and ADCC is measured as the dose-dependent loss of luciferase activity. Using this approach, ADCC titers were measured in plasma samples from HIV-infected human donors and SIV-infected macaques. For the same plasma samples paired with the same test viruses, this assay was approximately 2 orders of magnitude more sensitive than optimized assays for neutralizing antibodies—frequently allowing the measurement of ADCC in the absence of detectable neutralization. Although ADCC correlated with other measures of Env-specific antibodies, neutralizing and gp120 binding titers did not consistently predict ADCC activity. Hence, this assay affords a sensitive method for measuring antibodies capable of directing ADCC against HIV- or SIV-infected cells expressing native conformations of the viral envelope glycoprotein and reveals incomplete overlap of the antibodies that direct ADCC and those measured in neutralization and binding assays. PMID:22933282

Retrovirus Studies in Nonhuman Primates at Four Regional Primate Research Centers.

DTIC Science & Technology

1990-09-30

inoculation of the vaginal mucosa with SIV-infected splenocytes. The Heterosexual Transmission of AIDS: A Simian Model. The overall objective of this...rhesus macaques. We have previously reported that SIV can be transmitted across the vaginal mucosa of female rhesus macaques (Miller, et. al., 1990). To...infused through a 2.5mm outer diameter (8 French) soft, plastic, pediatric nasogastric feeding tube (American Pharmaseal, Valencia, Ca.) into the 3 vaginal

Selectivity of Local Field Potentials in Macaque Inferior Temporal Cortex

DTIC Science & Technology

2004-09-01

Selectivity of Local Field Potentials in Macaque Inferior Temporal Cortex Gabriel Kreiman , Chou Hung, Tomaso Poggio and James DiCarlo AI Memo 2004...IT. Note: Gabriel Kreiman and Chou Hung contributed equally to this work This report describes research done within the Center for Biological...separate the neuronal components of the MUA by using spike sorting algorithms (Quiroga et al., 2004; Yu and Kreiman , 1999). It will be interesting to

Vaginal Stone in a Cynomolgus Macaque (Macaca fascicularis).

PubMed

Colagross-Schouten, Angela M; Canfield, Don R

2015-12-01

A 20-y-old female cynomolgus macaque (Macaca fascicularis) housed in an indoor primate facility presented for poor appetite and acute weakness after several years of no adverse health events. Physical examination revealed a firm, ovoid mass in the caudal abdomen. Further evaluation revealed the mass to be a vaginal calculus composed of calcium carbonate, apatite, and struvite. To our knowledge, this case is the first reported description of a vaginal stone in an NHP.

Complete Genome Sequence of a Naturally Occurring Simian Foamy Virus Isolate from Rhesus Macaque (SFVmmu_K3T).

PubMed

Nandakumar, Subhiksha; Bae, Eunhae H; Khan, Arifa S

2017-08-17

The full-length genome sequence of a simian foamy virus (SFVmmu_K3T), isolated from a rhesus macaque ( Macaca mulatta ), was obtained using high-throughput sequencing. SFVmmu_K3T consisted of 12,983 bp and had a genomic organization similar to that of other SFVs, with long terminal repeats (LTRs) and open reading frames for Gag, Pol, Env, Tas, and Bet.

Establishment and characterization of Macaca fascicularis lymphoblastoid cell lines.

PubMed

Manning, C H; Heise, E R

1992-01-01

A panel of cynomolgus macaque lymphoblastoid cell lines (LCL) was established by transforming peripheral blood mononuclear cells (PBMC) with Herpesvirus papio (HVP), and selected lines were examined by flow cytometry. Results indicate that HVP-transformed macaque LCL are phenotypically heterogeneous and resemble human Epstein-Barr virus (EBV)-transformed LCL in the abundant expression of major histocompatibility complex (MHC) class I and class II molecules. At least some lines are of B cell origin.

Responses of juvenile bonnet macaques to social stimuli presented through color videotapes.

PubMed

Plimpton, E H; Swartz, K B; Rosenblum, L A

1981-03-01

Twelve juvenile bonnet macaques (Macaca radiata), 6 males and 6 females, were presented with color videotape recordings of 3 types of social stimuli. The stimulus animals, all unfamiliar adult conspecifics, consisted of a passive female, a passive male, and a threatening male. Subjects were observed in the presence of their mother and 1 other juvenile-mother dyad. The juveniles showed the highest scores for contact with mother when presented with the threatening male stimulus. Similarly, subjects lipsmacked significantly more to the male threatening male stimulus than to either the passive male or female. The female stimulus was approached significantly more than either the passive or threatening male. Results suggest that juvenile macaques will respond to social stimuli presented through color video recordings in a socially appropriate manner. This technique provides a new tool in the investigation of social perception in nonhuman primates.

A seroprevalence study of primate workers for asymptomatic rhesus cytomegalovirus infection

PubMed Central

Bowman, J. Jason; Burbelo, Peter D.; Gill, Rachel B.; Sauri, Michael A.; Schmitt, James M.; Cohen, Jeffrey I.

2014-01-01

Background Human cytomegalovirus (HCMV) infection can cause severe disease in neonates and immunocompromised persons, and infectious mononucleosis in healthy adults. While, rhesus CMV (RhCMV) infects human cells in culture, it is unknown whether the virus can infect humans. Objectives We sought to determine whether primate workers, including those with injuries from animals, might be infected asymptomatically with RhCMV. Study design We developed serologic assays that distinguish RhCMV from HCMV antibodies. We tested two groups of primate workers: those with documented injuries or mucosal splashes associated with rhesus macaques, and those with no documented exposure who worked with these animals. Results None of over 200 primate workers, including 119 with injuries or mucosal splashes associated with exposures to macaques, were seropositive for RhCMV. Conclusions The frequency of asymptomatic RhCMV infection in persons who work with rhesus macaques was <0.5% (<1/200 primate workers). PMID:24890818

Vocal tract length and formant frequency dispersion correlate with body size in rhesus macaques.

PubMed

Fitch, W T

1997-08-01

Body weight, length, and vocal tract length were measured for 23 rhesus macaques (Macaca mulatta) of various sizes using radiographs and computer graphic techniques. linear predictive coding analysis of tape-recorded threat vocalizations were used to determine vocal tract resonance frequencies ("formants") for the same animals. A new acoustic variable is proposed, "formant dispersion," which should theoretically depend upon vocal tract length. Formant dispersion is the averaged difference between successive formant frequencies, and was found to be closely tied to both vocal tract length and body size. Despite the common claim that voice fundamental frequency (F0) provides an acoustic indication of body size, repeated investigations have failed to support such a relationship in many vertebrate species including humans. Formant dispersion, unlike voice pitch, is proposed to be a reliable predictor of body size in macaques, and probably many other species.