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1

Comprehensive Cross-Clade Neutralization Analysis of a Panel of Anti-Human Immunodeficiency Virus Type 1 Monoclonal Antibodies  

PubMed Central

Broadly neutralizing monoclonal antibodies (MAbs) are potentially important tools in human immunodeficiency virus type 1 (HIV-1) vaccine design. A few rare MAbs have been intensively studied, but we still have a limited appreciation of their neutralization breadth. Using a pseudovirus assay, we evaluated MAbs from clade B-infected donors and a clade B HIV+ plasma against 93 viruses from diverse backgrounds. Anti-gp120 MAbs exhibited greater activity against clade B than non-B viruses, whereas anti-gp41 MAbs exhibited broad interclade activity. Unexpectedly, MAb 4E10 (directed against the C terminus of the gp41 ectodomain) neutralized all 90 viruses with moderate potency. MAb 2F5 (directed against an epitope adjacent to that of 4E10) neutralized 67% of isolates, but none from clade C. Anti-gp120 MAb b12 (directed against an epitope overlapping the CD4 binding site) neutralized 50% of viruses, including some from almost every clade. 2G12 (directed against a high-mannose epitope on gp120) neutralized 41% of the viruses, but none from clades C or E. MAbs to the gp120 V3 loop, including 447-52D, neutralized a subset of clade B viruses (up to 45%) but infrequently neutralized other clades (?7%). MAbs b6 (directed against the CD4 binding site) and X5 (directed against a CD4-induced epitope of gp120) neutralized only sensitive primary clade B viruses. The HIV+ plasma neutralized 70% of the viruses, including some from all major clades. Further analysis revealed five neutralizing immunotypes that were somewhat associated with clades. As well as the significance for vaccine design, our data have implications for passive-immunization studies in countries where clade C viruses are common, given that only MAbs b12 and 4E10 were effective against viruses from this clade.

Binley, James M.; Wrin, Terri; Korber, Bette; Zwick, Michael B.; Wang, Meng; Chappey, Colombe; Stiegler, Gabriela; Kunert, Renate; Zolla-Pazner, Susan; Katinger, Hermann; Petropoulos, Christos J.; Burton, Dennis R.

2004-01-01

2

Variables influencing anti-human immunodeficiency virus type 1 neutralizing human monoclonal antibody (NhMAb) production among infected Thais.  

PubMed

We conducted this study to determine the clinical variables associated with the production of human immunodeficiency virus type 1 (HIV-1) circulating recombinant form (CRF) 01_AE neutralizing human monoclonal antibodies (NhMAbs) using a hybridoma technique. This cross sectional study was performed in 20 asymptomatic HIV-1-infected Thais. Peripheral blood mononuclear cells (PBMCs) were obtained from each study participant and fused with SPYMEG cells. Culture supernatant collected from growing hybridomas was tested for neutralizing activity against HIV-1 CRF01_AE Env-recombinant viruses. Fifty hybridomas expressing anti-HIV-1 NhMAbs with strong neutralizing activity against at least 1 CRF01_AE Env-recombinant virus were found. A positive association between the numbers of hybridomas produced and the CD4 counts of study participants (p = 0.019) was observed. NhMAb-producing hybridomas with strong neutralizing activity were mostly found in participans diagnosed with HIV-1 infection within the previous 1 year. The HIV-1 viral load was not significantly correlated with the numbers of either established hybridomas or clones expressing anti-HIV-1 NhMAbs with strong neutralizing activity. To our knowledge, this is the first study of NhMAb-producing hybridomas obtained from HIV-1 CRF01_AE-infected populations identified by antibody binding to HIV-1 V3 loop peptide enzyme-linked immunosorbent assay (ELISA) or TRUGENE HIV-1 Genotyping Assay (HIV-1 pol sequence). It provides important criterion to slect study participants with high CD4 counts who produce large numbers of hybridoma clones. The results are valuable for further studies related to nurtalizing antibodies production and HIV-1 vaccine development. PMID:24437318

Akapirat, Siriwat; Avihingsanon, Anchalee; Ananworanich, Jintanat; Schuetz, Alexandra; Ramasoota, Pongrama; Luplertlop, Natthanej; Ono, Ken-Ichiro; Ikuta, Kazuyoshi; Utachee, Piraporn; Kameoka, Masanori; Leaungwutiwong, Pornsawan

2013-09-01

3

Identification and Characterization of a Peptide That Specifically Binds the Human, Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 Antibody b12  

PubMed Central

Human monoclonal antibody (MAb) b12 recognizes a conformational epitope that overlaps the CD-4-binding site of the human immunodeficiency virus type 1 (HIV-1) envelope. MAb b12 neutralizes a broad range of HIV-1 primary isolates and protects against primary virus challenge in animal models. We report here the discovery and characterization of B2.1, a peptide that binds specifically to MAb b12. B2.1 was selected from a phage-displayed peptide library by using immunoglobulin G1 b12 as the selecting agent. The peptide is a homodimer whose activity depends on an intact disulfide bridge joining its polypeptide chains. Competition studies with gp120 indicate that B2.1 occupies the b12 antigen-binding site. The affinity of b12 for B2.1 depends on the form in which the peptide is presented; b12 binds best to the homodimer as a recombinant polypeptide fused to the phage coat. Originally, b12 was isolated from a phage-displayed Fab library constructed from the bone marrow of an HIV-1-infected donor. The B2.1 peptide is highly specific for b12 since it selected only phage bearing b12 Fab from this large and diverse antibody library.

Zwick, Michael B.; Bonnycastle, Lori L. C.; Menendez, Alfredo; Irving, Melita B.; Barbas, Carlos F.; Parren, Paul W. H. I.; Burton, Dennis R.; Scott, Jamie K.

2001-01-01

4

Naphthalene sulfonate polymers with CD4-blocking and anti-human immunodeficiency virus type 1 activities.  

PubMed Central

PIC 024-4 and PRO 2000 are naphthalene sulfonate polymers that bind to CD4 with nanomolar affinity and block binding of gp120. Both have activity against human immunodeficiency virus type 1 in H9 cells, peripheral blood mononuclear cells, and primary monocyte/macrophages, are synergistic with zidovudine, and do not inhibit tetanus toxoid-stimulated T-cell proliferation at anti-human immunodeficiency virus type 1 concentrations.

Rusconi, S; Moonis, M; Merrill, D P; Pallai, P V; Neidhardt, E A; Singh, S K; Willis, K J; Osburne, M S; Profy, A T; Jenson, J C; Hirsch, M S

1996-01-01

5

Polysulfated sialic acid derivatives as anti-human immunodeficiency virus.  

PubMed

We report the synthesis of a novel alkyl polysulfated sialic acid derivative denoted as NMSO3. NMSO3 exhibited potent inhibition against both laboratory and clinical human immunodeficiency virus type 1 (HIV-1). The anti-viral activity of this compound (1 uM) was compared to dextran sulfate (3 uM), and was found to be more potent against HIV-1IIIb than AZT (10 uM). The anti-coagulation time was more than 15-fold shorter than that of dextran sulfate. An in vivo anti-viral study of NMSO3 in NOD-SCID-PBL mice HIV model showed complete protection of the animals from virus challenge at the concentration of 10 mg/kg. This suggests that NMSO3 can be effective in the treatment of HIV-infected individuals. PMID:16143490

Terada, Masaki; Fujita, Shuji; Suda, Isao; Mastico, Robert

2005-09-01

6

The Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 Antibody 2G12 Recognizes a Cluster of ?1->2 Mannose Residues on the Outer Face of gp120  

PubMed Central

2G12 is a broadly neutralizing human monoclonal antibody against human immunodeficiency virus type-1 (HIV-1) that has previously been shown to bind to a carbohydrate-dependent epitope on gp120. Here, site-directed mutagenesis and carbohydrate analysis were used to define further the 2G12 epitope. Extensive alanine scanning mutagenesis showed that elimination of the N-linked carbohydrate attachment sequences associated with residues N295, N332, N339, N386, and N392 by N?A substitution produced significant decreases in 2G12 binding affinity to gp120JR-CSF. Further mutagenesis suggested that the glycans at N339 and N386 were not critical for 2G12 binding to gp120JR-CSF. Comparison of the sequences of isolates neutralized by 2G12 was also consistent with a lesser role for glycans attached at these positions. The mutagenesis studies provided no convincing evidence for the involvement of gp120 amino acid side chains in 2G12 binding. Antibody binding was inhibited when gp120 was treated with Aspergillus saitoi mannosidase, Jack Bean mannosidase, or endoglycosidase H, indicating that Man?1?2Man-linked sugars of oligomannose glycans on gp120 are required for 2G12 binding. Consistent with this finding, the binding of 2G12 to gp120 could be inhibited by monomeric mannose but not by galactose, glucose, or N-acetylglucosamine. The inability of 2G12 to bind to gp120 produced in the presence of the glucose analogue N-butyl-deoxynojirimycin similarly implicated Man?1?2Man-linked sugars in 2G12 binding. Competition experiments between 2G12 and the lectin cyanovirin for binding to gp120 showed that 2G12 only interacts with a subset of available Man?1?2Man-linked sugars. Consideration of all the data, together with inspection of a molecular model of gp120, suggests that the most likely epitope for 2G12 is formed from mannose residues contributed by the glycans attached to N295 and N332, with the other glycans playing an indirect role in maintaining epitope conformation.

Scanlan, Christopher N.; Pantophlet, Ralph; Wormald, Mark R.; Ollmann Saphire, Erica; Stanfield, Robyn; Wilson, Ian A.; Katinger, Hermann; Dwek, Raymond A.; Rudd, Pauline M.; Burton, Dennis R.

2002-01-01

7

Generation and characterization of human anti-human IL-21 neutralizing monoclonal antibodies  

PubMed Central

Interleukin 21 (IL-21) is a type I four-helical bundle cytokine that exerts a variety of significant effects on many hematopoietic cells, including T and B lymphocytes and natural killer cells. IL-21 is produced predominantly by CD4+ T cells and natural killer T cells and, when aberrantly overexpressed, appears to play important roles in a wide variety of autoimmune disorders. To generate potential therapeutic reagents capable of inhibiting IL-21 for clinical use, we immunized human immunoglobulin transgenic mice with IL-21 and then identified and cloned a panel of human anti-human IL-21 binding monoclonal antibodies. IL-21 neutralizing and IL-21-binding, non-neutralizing antibodies were assigned to distinct epitope “bins” based on surface plasmon resonance competition studies. The most potent neutralizing antibodies had extremely high (sub pM) affinity for IL-21 and were able to block IL-21 activity in various biological assays using either an IL-21R-transfected pre-B-cell line or primary human B cells, and their neutralizing activity was, in some cases, superior to that of a soluble form of the high affinity heterodimeric IL-21 receptor. Characterization of this panel of IL-21 antibodies provided the basis for the selection of a therapeutic candidate antibody capable of inhibiting IL-21 activity for the treatment of autoimmune and inflammatory diseases.

Jaspers, Stephen R; Meengs, Brent; Rixon, Mark W; Stevens, Brenda L; Lewis, Kenneth B; Julien, Susan H; Bukowski, Thomas R; Wolf, Anitra C; Hamacher, Nels B; Snavely, Mark

2012-01-01

8

Sophorolipids, microbial glycolipids with anti-human immunodeficiency virus and sperm-immobilizing activities.  

PubMed

The increased incidence of human immunodeficiency virus (HIV)/AIDS disease in women aged 15 to 49 years has identified the urgent need for a female-controlled, efficacious, and safe vaginal topical microbicide. To meet this challenge, sophorolipid (SL) produced by Candida bombicola and its structural analogs have been studied in this report for their spermicidal, anti-HIV, and cytotoxic activities. The sophorolipid diacetate ethyl ester derivative is the most potent spermicidal and virucidal agent of the series of SLs studied. Its virucidal activity against HIV and sperm-immobilizing activity against human semen are similar to those of nonoxynol-9. However, it also induced enough vaginal cell toxicity to raise concerns about its applicability for long-term microbicidal contraception. Its structure-activity relationship has been established for creating new analogs with less cytotoxicity and higher activity. PMID:16189085

Shah, Vishal; Doncel, Gustavo F; Seyoum, Theodoros; Eaton, Kristin M; Zalenskaya, Irina; Hagver, Rena; Azim, Abul; Gross, Richard

2005-10-01

9

Sophorolipids, Microbial Glycolipids with Anti-Human Immunodeficiency Virus and Sperm-Immobilizing Activities  

PubMed Central

The increased incidence of human immunodeficiency virus (HIV)/AIDS disease in women aged 15 to 49 years has identified the urgent need for a female-controlled, efficacious, and safe vaginal topical microbicide. To meet this challenge, sophorolipid (SL) produced by Candida bombicola and its structural analogs have been studied in this report for their spermicidal, anti-HIV, and cytotoxic activities. The sophorolipid diacetate ethyl ester derivative is the most potent spermicidal and virucidal agent of the series of SLs studied. Its virucidal activity against HIV and sperm-immobilizing activity against human semen are similar to those of nonoxynol-9. However, it also induced enough vaginal cell toxicity to raise concerns about its applicability for long-term microbicidal contraception. Its structure-activity relationship has been established for creating new analogs with less cytotoxicity and higher activity.

Shah, Vishal; Doncel, Gustavo F.; Seyoum, Theodoros; Eaton, Kristin M.; Zalenskaya, Irina; Hagver, Rena; Azim, Abul; Gross, Richard

2005-01-01

10

Analysis of Human APOBEC3H Haplotypes and Anti-Human Immunodeficiency Virus Type 1 Activity? †  

PubMed Central

Human APOBEC3H (A3H) has one cytidine deaminase domain (CDD) and inhibits the replication of retrotransposons and human immunodeficiency virus type 1 (HIV-1) in a Vif-resistant manner. Human A3H has five single amino acid polymorphisms (N15?, R18L, G105R, K121D, and E178D), and four haplotypes (I to IV) have previously been identified in various human populations. Haplotype II was primarily found in African-derived populations, and it was the only one that could be stably expressed. Here, we identified three new haplotypes from six human population samples, which we have named V, VI, and VII. Haplotypes V and VII are stably expressed and inhibit HIV-1 replication. Notably, haplotype V was identified in samples from all African-, Asian-, and Caucasian-derived populations studied. Using haplotype VII, we investigated the A3H anti-HIV-1 mechanism. We found that A3H virion packaging is independent of its CDD but dependent on a 112YYXW115 motif. This motif binds HIV-1 nucleocapsid in an RNA-dependent manner, and a single Y112A mutation completely disrupts A3H virion incorporation. We further studied the mechanism of A3H resistance to Vif. Although the previously identified APOBEC3G Vif-responsive motif 128DPDY131 is not conserved in A3H, placement of this motif into A3H does not make it become less resistant to HIV-1 Vif. We conclude that stably expressed A3H haplotypes may be more broadly distributed in humans than previously realized, and A3H protein is resistant to Vif. These results have important implications for the role of A3H in retrotransposon and HIV-1 inhibition.

Wang, Xiaojun; Abudu, Aierken; Son, SungMo; Dang, Ying; Venta, Patrick J.; Zheng, Yong-Hui

2011-01-01

11

Anti-human immunodeficiency virus activity of oligosaccharides from rooibos tea (Aspalathus linearis) extracts in vitro.  

PubMed

The active substances, acid polysaccharides, were extracted with 1% sodium hydroxide from the leaves of rooibos tea (Aspalathus linearis), Du Zhong Cha (Eucommia ulmoides Oliv.) and Japanese tea leaves (Camellia sinensis var. sinensis). The alkaline extracts of Rooibos tea and Du-Zhong tea leaves, but not Japanese tea leaves suppressed the HIV-induced cytopathicity using HIV (HTLV-III) infected MT-4 cells, having extremely low cytotoxicity: Its 50% effective concentration (EC50) was 12-67 micrograms/mL, white 50% cytotoxic concentration (CC50) was higher than 1.0 mg/mL. The active substances were purified with ethanol precipitation. The substances were composed of 27% of reducing sugar, 46% of neutral sugars and 22% of uronic acid. A LD50 of the alkaline extracts from rooibos tea was higher than 1.2 g/kg body weight. Acid degradated substances composed of disaccharides and trisaccharides, were also suppressed the HIV-induced cytopathicity. From these results, it is probable that acid polysaccharides from rooibos tea were extremely safe, and that HIV infection may be suppressed by daily intake of the alkaline extracts of rooibos tea and Du-Zhong tea. PMID:9209319

Nakano, M; Nakashima, H; Itoh, Y

1997-04-01

12

Expression and functionality of anti-human immunodeficiency virus and anticancer drug uptake transporters in immune cells.  

PubMed

Almost all drugs used in anti-human immunodeficiency virus (HIV)-1 and anticancer therapies require membrane proteins to get into the cell to develop their proper activity. Nevertheless, little is known regarding the expression and activity of specific carriers involved in the uptake of these drugs in immune cells. Here, we assessed the mRNA levels, protein expression profile, and activity of the gene families SLC28 (coding for concentrative nucleoside transporters, hCNT1-3), SLC29 (equilibrative nucleoside transporters, hENT1-2), and SLC22 (organic cation transporters, hOCT1-3 and hOCTN1-2). Both hENTs and hCNT2 were abundant in primary lymphocytes, with a preferential activity of hENT1. A significant up-regulation in hENTs expression (100-fold) and activity (30-fold) was seen under stimulation of primary T lymphocytes. In contrast, monocytes, monocyte-derived macrophages (MDMs), and immature monocyte-derived dendritic cells predominantly expressed hCNT3, a functional transporter in MDMs. Finally, in immune cells, hOCTs showed a more heterogeneous expression profile and a lower activity than human nucleoside transporters (hNTs), although up-regulation of hOCTs also occurred upon lymphocyte activation. Overall, the expression and activity of most of the studied transporters emphasize their relevance in relation to anti-HIV and anticancer therapies. The identification of the transporter involved in each specific drug uptake in immune cells could help to optimize pharmacological therapeutic responses. PMID:18042828

Minuesa, Gerard; Purcet, Sergi; Erkizia, Itziar; Molina-Arcas, Míriam; Bofill, Margarita; Izquierdo-Useros, Nuria; Casado, F Javier; Clotet, Bonaventura; Pastor-Anglada, Marçal; Martinez-Picado, Javier

2008-02-01

13

Trappin-2/Elafin: a novel innate anti-human immunodeficiency virus-1 molecule of the human female reproductive tract  

PubMed Central

Trappin-2/Elafin is a serine protease inhibitor that plays a major role as an anti-inflammatory mediator at mucosal surfaces. In addition, Trappin-2/Elafin has antibacterial activity against Gram-positive and Gram-negative bacterial and fungal pathogens. In this study we examined the production of Trappin-2/Elafin by epithelial cells from the human upper and lower female reproductive tract as well as its activity as an anti-human immunodeficiency virus (HIV)-1 molecule. We found that primary uterine, Fallopian tube, cervical and ectocervical epithelial cells produce Trappin-2/Elafin constitutively and that production of Trappin-2/Elafin is enhanced following stimulation with Poly(I:C), especially by the uterine cells. Given the presence of Trappin-2/Elafin in the reproductive tract, we tested the ability of recombinant Trappin-2/Elafin to inhibit HIV-1, an important sexually transmitted pathogen. We found that recombinant Trappin-2/Elafin was able to inhibit both T-cell-tropic X4/IIIB and macrophage-tropic R5/BaL HIV-1 in a dose-dependent manner. The inhibitory activity was observed when virus was incubated with Trappin-2/Elafin but not when Trappin-2/Elafin was added to cells either before infection or after infection. This suggests that the mechanism of inhibition is likely to be a direct interaction between HIV-1 and Trappin-2/Elafin. Additionally, we measured the levels of secreted Trappin-2/Elafin in cervico-vaginal lavages (CVL) from both HIV-positive and HIV-negative women and found that average levels of secreted Trappin-2/Elafin were higher in the CVL from HIV-negative women, although the values did not reach statistical significance. We also found that women at the secretory phase of the menstrual cycle produced more Trappin-2/Elafin in CVL relative to women at the proliferative phase of the menstrual cycle. Our data suggest that Trappin-2/Elafin might be an important endogenous microbicide of the female reproductive tract that is protective against HIV-1.

Ghosh, Mimi; Shen, Zheng; Fahey, John V; Cu-Uvin, Susan; Mayer, Kenneth; Wira, Charles R

2010-01-01

14

Anti-human immunodeficiency virus synergism by zidovudine (3'-azidothymidine) and didanosine (dideoxyinosine) contrasts with their additive inhibition of normal human marrow progenitor cells.  

PubMed Central

The anti-human immunodeficiency virus (HIV) activity and hemopoietic toxicity of zidovudine (AZT) and didanosine (dideoxyinosine;ddI), alone and in combination, were assessed in a variety of cell types. AZT was more potent than ddI as an inhibitor of HIV in vitro. Synergistic inhibition of HIV by the combination of these agents was observed in MT4 cells, peripheral blood lymphocytes, and macrophages. Toxicity assessment in vitro by using progenitor (erythroid and granulocyte-macrophage) colony-forming assays with normal human bone marrow showed ddI to be less toxic than AZT. Addition of inhibitory concentrations of ddI to AZT resulted in additive inhibition of progenitor CFUs. These in vitro findings suggest that combinations of ddI and AZT at appropriately modified doses may provide an enhanced degree of selectivity in anti-HIV chemotherapy.

Dornsife, R E; St Clair, M H; Huang, A T; Panella, T J; Koszalka, G W; Burns, C L; Averett, D R

1991-01-01

15

Profound CD4+ T lymphocytopenia in human immunodeficiency virus negative individuals, improved with anti-human herpes virus treatment  

PubMed Central

Lymphocytopenia and CD4+ T lymphocytopenia can be associated with many bacterial, fungal, parasite and viral infections. They can also be found in autoimmune and neoplastic diseases, common variable immunodeficiency syndrome, physical, psychological and traumatic stress, malnutrition and immunosuppressive therapy. Besides, they can also be brought into relation, without a known cause, with idiopathic CD4+ T lymphocytopenia. Among viral infections, the Retrovirus, specially the human immunodeficiency virus, is the most frequently cause. However, many acute viral infections, including cytomegalovirus and Epstein Barr virus can be associated with transient lymphocytopenia and CD4+ T lymphocytopenia. As is well known, transient lymphocytopenia and CD4+ T lymphocytopenia are temporary and overcome when the disease improves. Nonetheless, severe CD4+ T Lymphocytopenia associated with chronic infections by human herpes virus has not been reported. We describe 6 cases of human immunodeficiency virus negative patients, with chronic cytomegalovirus and Epstein Barr virus infections and profound lymphocytopenia with clinical symptoms of cellular immunodeficiency. These patients improved rapidly with ganciclovir or valganciclovir treatment. We claim here that it is important to consider the chronic human herpes virus infection in the differential diagnosis of profoundly CD4+ T lymphocytopenia etiology, when human immunodeficiency virus is absent, in order to start effective treatment and to determine, in future studies, the impact of chronic human herpes virus infection in human beings' health.

Klinger Hernandez, Julio Cesar; Nino Castano, Victoria Eugenia

2012-01-01

16

Multivariate analysis of human immunodeficiency virus type 1 neutralization data.  

PubMed Central

We report on the use of spectral map analysis of the inter- and intraclade neutralization data of 14 sera of human immunodeficiency virus type 1 (HIV-1)-infected individuals and 16 primary isolates, representing genetic clades A to H in group M and group O. This multivariate analysis has been used previously to study the interaction between drugs and receptors and between viruses and antiviral compounds. The analysis reveals the existence of neutralization clusters, not correlated with the known genetic clades. The structural factors that have been identified may correlate with the most important neutralization epitopes. Three key primary HIV-1 isolates, which allow discrimination of sera that are likely or unlikely to neutralize primary isolates from most of the genetic clades, were identified. Our method of analysis will facilitate the evaluation as well as the design of suitable HIV-1 vaccines, which induce high-titer interclade cross-neutralizing antibodies.

Nyambi, P N; Nkengasong, J; Lewi, P; Andries, K; Janssens, W; Fransen, K; Heyndrickx, L; Piot, P; van der Groen, G

1996-01-01

17

Cross-neutralization of human immunodeficiency virus type 1 and 2 and simian immunodeficiency virus isolates.  

PubMed Central

In contrast to infrequent and low-titer cross-neutralization of human immunodeficiency virus type 1 (HIV-1) isolates by HIV-2- and simian immunodeficiency virus (SIV)-positive sera, extensive cross-neutralization of HIV-2NIH-Z, SIVMAC251, and SIVAGM208K occurs with high titer, suggesting conservation of epitopes and mechanism(s) of neutralization. The V3 regions of HIV-2 and SIV isolates, minimally related to the HIV-1 homolog, share significant sequence homology and are immunogenic in monkeys as well as in humans. Whereas the crown of the V3 loop is cross-reactive among HIV-1 isolates and elicits neutralizing antibodies of broad specificity, the SIV and especially HIV-2 crown peptides were not well recognized by cross-neutralizing antisera. V3 loop peptides of HIV-2 isolates did not elicit neutralizing antibodies in mice, guinea pigs, or a goat and together with SIV V3 peptides did not inhibit serum neutralization of HIV-2 and SIV. Thus, the V3 loops of HIV-2 and SIV do not appear to constitute simple linear neutralizing epitopes. In view of the immunogenicity of V3 peptides, the failure of conserved crown peptides to react with natural sera implies a significant role of loop conformation in antibody recognition. Our studies suggest that in addition to their grouping by envelope genetic relatedness, HIV-2 and SIV are neutralized similarly to each other but differently from HIV-1. The use of linear peptides of HIV-2 and SIV as immunogens may require greater attention to microconformation, and alternate subunit approaches may be needed in exploiting these viruses as vaccine models. Such approaches may also be applicable to the HIV-1 system in which conformational epitopes, in addition to the V3 loop, participate in virus neutralization.

Robert-Guroff, M; Aldrich, K; Muldoon, R; Stern, T L; Bansal, G P; Matthews, T J; Markham, P D; Gallo, R C; Franchini, G

1992-01-01

18

Characterization of a novel anti-human TNF-? murine monoclonal antibody with high binding affinity and neutralizing activity  

Microsoft Academic Search

In order to develop an anti-human TNF-? mAb, mice were immunized with recombinant human TNF-?. A murine mAb, TSK114, which showed the highest bind- ing activity for human TNF-? was selected and characterized. TSK114 specifically bound to human TNF-? without cross-reactivity with the homologous murine TNF-? and human TNF-?. TSK114 was found to be of IgG1 isotype with ? light

Moo-Young Song; Sang-Koo Park; Chang Seok Kim; Tae Hyoung Yoo; Bongtae Kim; Min-Soo Kim; Yong-Sung Kim; Won Jae Kwag; Byung-Kyu Lee; Kwanghee Baek

2008-01-01

19

Maraviroc (UK427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity  

Microsoft Academic Search

Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary

Patrick Dorr; Mike Westby; Susan Dobbs; Paul Griffin; Becky Irvine; Malcolm Macartney; Julie Mori; Graham Rickett; Caroline Smith-Burchnell; Carolyn Napier; Rob Webster; Duncan Armour; David Price; Blanda Stammen; Anthony Wood; Manos Perros

2005-01-01

20

Aryl phosphate derivatives of bromo-methoxy-azidothymidine are dual-function spermicides with potent anti-human immunodeficiency virus.  

PubMed

Detergent-based vaginal microbicides, in addition to their high contraceptive failure rates, cause mucosal erosion and local inflammation that might increase the risk of heterosexual human immunodeficiency virus (HIV) transmission. In a systematic effort to identify a microbicide contraceptive potentially capable of preventing the sexual transmission of HIV as well as providing fertility control, a series of novel aryl phosphate derivatives of 5-bromo-6-methoxy-3'-azido-3'-deoxythymidine (AZT; zidovudine) were synthesized and examined for dual anti-HIV and sperm-immobilizing activity (SIA). Whereas AZT displayed potent anti-HIV activity (IC50 = 0.006 microM) but lacked SIA (EC50 > 300 microM), two 5-bromo-6-methoxy-aryl phosphate derivatives of AZT, compounds WHI-05 and WHI-07, exhibited potent anti-HIV activity as well as SIA. The IC50 (HIV) and EC50 (SIA) values for WHI-07 were 439-fold and 13.5-fold lower, respectively, than those for the detergent-based virucidal spermicide, nonoxynol-9 (N-9). Sperm motion kinematics using computer-assisted sperm motion analysis combined with confocal laser scanning microscopy, high-resolution low-voltage scanning, and transmission electron microscopy demonstrated that both WHI-05 and WHI-07 cause a complete and irreversible loss of sperm motility in a concentration- and time-dependent fashion without concomitantly affecting the sperm acrosomal membrane integrity. In experiments designed to assess the fertilizing capacity of treated sperm, preincubation of sperm with either compound resulted in a concentration-dependent loss of the ability to adhere to and penetrate zona-free hamster eggs as well as inhibition of binding to human zona. WHI-07 applied intravaginally prior to artificial insemination of epididymal sperm drastically reduced fertility in hormonally primed CD-1 mice. Unlike the intravaginal application of N-9, repetitive intravaginal application of WHI-07 did not damage the vaginal epithelium or cause local inflammation. Structure-function relationship analyses showed that the addition of bromo-methoxy functional groups to AZT was essential for, and the aryl phosphate derivatization contributory to, the SIA of both compounds. Compounds WHI-05 and WHI-07 may be useful as dual-function vaginal contraceptives for women who are at high risk for acquiring HIV/acquired immunodeficiency virus syndrome by heterosexual vaginal transmission. PMID:9716547

D'Cruz, O J; Venkatachalam, T K; Zhu, Z; Shih, M J; Uckun, F M

1998-09-01

21

Some nucleoside analogs with anti-human immunodeficiency virus activity inhibit replication of Epstein-Barr virus.  

PubMed

The effects of (+)-beta-D-dioxolane-cytosine ((+)-D-beta-DOC), (-)-beta-L-dioxolane-cytosine ((-)-L-beta-DOC), (+)-beta-D-oxathiolane-cytosine ((+)-D-beta-OTC), (-)-beta-L-oxathiolane-cytosine ((-)-L-beta-OTC, or 3TC), 3'-azido-2',3'-dideoxy-5-methyl-cytidine (5-Me-AZDC), and 3'-azido-2',3'-dideoxyuridine (AZDU) on Epstein-Barr virus (EBV) DNA replication in vitro were tested in P3HR-1 cells. Two anti-EBV drugs, 3'-azido-3'-deoxythymidine (AZT) and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG, or ganciclovir), were used as positive controls. The inhibitory effects on EBV DNA synthesis were quantified by membrane filter and Southern blot hybridizations with an EBV-specific probe BamHI-W fragment. The 50% effective doses (ED50) for EBV DNA replication were 0.15, 0.83, 1.5, 8.3, 14, and 7.7 microM for DHPG, (-)-L-beta-DOC, (+)-D-beta-DOC, (+)-D-beta-OTC, (-)-L-beta-OTC, and AZT, respectively. In contrast, 5-Me-AZDC and AZDU were not effective at concentrations as high as 30 microM. These results indicated that both (-)-L-beta-DOC and (+)-D-beta-DOC were more potent than AZT, which has previously been shown to have anti-EBV activity. (-)-L-beta-DOC and (+)-D-beta-DOC have also been previously demonstrated to suppress the infectivity of human immunodeficiency virus type 1 (HIV-1). Thus, (-)-L-beta-DOC represents the first nucleoside analog with L-configuration exhibiting significant antiviral activities against both EBV and HIV. PMID:8585756

Mar, E C; Chu, C K; Lin, J C

1995-09-01

22

5-Amino-4-imidazolecarboxamide riboside potentiates the metabolism and anti-human immunodeficiency virus activity of 2',3'-dideoxyinosine.  

PubMed

The antiviral activity of the purine dideoxynucleosides 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) is dependent on their conversion into ddA triphosphate in vivo. 5-Amino-4-imidazolecarboxamide riboside (AICA riboside), a natural metabolite in purine biosynthetic pathways, is converted into IMP, a substrate for the biosynthesis of adenine and guanine nucleotides, and enhances the intracellular purine nucleotide pools. Because IMP also serves as a phosphate donor in the anabolic phosphorylation of ddI (and ddA) into ddI monophosphate by the cytosolic enzyme 5'-nucleotidase, we investigated the effects of AICA riboside on the phosphorylation and antiretroviral activity of these purine nucleoside analogs. At an AICA riboside concentration of 0.5 mM, there was a approximately 2-fold increase in the intracellular ATP and GTP levels, whereas a nearly 8-fold increase was observed for the phosphorylation of ddA (or ddI). A marked reduction in intracellular pools of the pyrimidine nucleotides CTP and UTP was observed in AICA riboside-treated cells and inhibited cell proliferation. However, this growth inhibition was prevented by the addition of uridine to the cultures. Cells pretreated with AICA riboside and ddI were less susceptible to human immunodeficiency virus (HIV) infection and synthesized reduced levels of HIV proviral DNA. A 10-fold potentiation of the effectiveness of ddI against both wild-type HIV (HIVIIIB) and a ddI-resistant variant HIV was observed in the presence of 0.5 mM AICA riboside. These results show that AICA riboside modulates the anabolism and antiviral activity of ddI, and they have implications for possible therapies with dideoxynucleosides. PMID:8341276

Gong, Y F; Srinivas, R V; Fridland, A

1993-07-01

23

In vitro anti-human immunodeficiency virus (HIV) activity of XM323, a novel HIV protease inhibitor.  

PubMed Central

XM323 represents a novel class of potent inhibitors of human immunodeficiency virus (HIV) protease. In vitro studies have shown that inhibition of this enzyme translates into potent inhibition of replication of HIV type 1 (HIV-1) and HIV-2. The inhibition of virus replication was assessed with three assays designed to measure the production of infectious virus, viral RNA, or p24 antigen. The production of mature infectious virions was measured with a yield reduction assay. By this assay, several strains and isolates of HIV-1 and HIV-2 were shown to be susceptible to XM323 in two lymphoid cell lines (MT-2 and H9) and in normal peripheral blood mononuclear cells, with a concentration required for 90% inhibition (IC90) of 0.12 +/- 0.04 microM (mean +/- standard deviation). The production of HIV-1(RF) RNA was measured with an RNA hybridization-capture assay. With this assay, XM323 was shown to be a potent inhibitor of HIV-1(RF) replication, with an IC90 of 0.063 +/- 0.032 microM. A third measure of virus replication, the production of p24 viral antigen, an essential protein component of the virion, was determined with the AIDS Clinical Trial Group-Department of Defense peripheral blood mononuclear cell consensus assay. This assay was used for expanded testing of XM323 against 28 clinical isolates and laboratory strains of HIV-1. XM323 was shown to be equally effective against zidovudine-susceptible and zidovudine-resistant isolates of HIV-1, with an overall IC90 of 0.16 +/- 0.06 microM.

Otto, M J; Reid, C D; Garber, S; Lam, P Y; Scarnati, H; Bacheler, L T; Rayner, M M; Winslow, D L

1993-01-01

24

Multisite Comparison of Anti-Human Immunodeficiency Virus Microbicide Activity in Explant Assays Using a Novel Endpoint Analysis ? †  

PubMed Central

Microbicide candidates with promising in vitro activity are often advanced for evaluations using human primary tissue explants relevant to the in vivo mucosal transmission of human immunodeficiency virus type 1 (HIV-1), such as tonsil, cervical, or rectal tissue. To compare virus growth or the anti-HIV-1 efficacies of candidate microbicides in tissue explants, a novel soft-endpoint method was evaluated to provide a single, objective measurement of virus growth. The applicability of the soft endpoint is shown across several different ex vivo tissue types, with the method performed in different laboratories, and for a candidate microbicide (PRO 2000). The soft-endpoint method was compared to several other endpoint methods, including (i) the growth of virus on specific days after infection, (ii) the area under the virus growth curve, and (iii) the slope of the virus growth curve. Virus growth at the assay soft endpoint was compared between laboratories, methods, and experimental conditions, using nonparametric statistical analyses. Intra-assay variability determinations using the coefficient of variation demonstrated higher variability for virus growth in rectal explants. Significant virus inhibition by PRO 2000 and significant differences in the growth of certain primary HIV-1 isolates were observed by the majority of laboratories. These studies indicate that different laboratories can provide consistent measurements of anti-HIV-1 microbicide efficacy when (i) the soft endpoint or another standardized endpoint is used, (ii) drugs and/or virus reagents are centrally sourced, and (iii) the same explant tissue type and method are used. Application of the soft-endpoint method reduces the inherent variability in comparisons of preclinical assays used for microbicide development.

Richardson-Harman, Nicola; Lackman-Smith, Carol; Fletcher, Patricia S.; Anton, Peter A.; Bremer, James W.; Dezzutti, Charlene S.; Elliott, Julie; Grivel, Jean-Charles; Guenthner, Patricia; Gupta, Phalguni; Jones, Maureen; Lurain, Nell S.; Margolis, Leonid B.; Mohan, Swarna; Ratner, Deena; Reichelderfer, Patricia; Roberts, Paula; Shattock, Robin J.; Cummins, James E.

2009-01-01

25

Multisite comparison of anti-human immunodeficiency virus microbicide activity in explant assays using a novel endpoint analysis.  

PubMed

Microbicide candidates with promising in vitro activity are often advanced for evaluations using human primary tissue explants relevant to the in vivo mucosal transmission of human immunodeficiency virus type 1 (HIV-1), such as tonsil, cervical, or rectal tissue. To compare virus growth or the anti-HIV-1 efficacies of candidate microbicides in tissue explants, a novel soft-endpoint method was evaluated to provide a single, objective measurement of virus growth. The applicability of the soft endpoint is shown across several different ex vivo tissue types, with the method performed in different laboratories, and for a candidate microbicide (PRO 2000). The soft-endpoint method was compared to several other endpoint methods, including (i) the growth of virus on specific days after infection, (ii) the area under the virus growth curve, and (iii) the slope of the virus growth curve. Virus growth at the assay soft endpoint was compared between laboratories, methods, and experimental conditions, using nonparametric statistical analyses. Intra-assay variability determinations using the coefficient of variation demonstrated higher variability for virus growth in rectal explants. Significant virus inhibition by PRO 2000 and significant differences in the growth of certain primary HIV-1 isolates were observed by the majority of laboratories. These studies indicate that different laboratories can provide consistent measurements of anti-HIV-1 microbicide efficacy when (i) the soft endpoint or another standardized endpoint is used, (ii) drugs and/or virus reagents are centrally sourced, and (iii) the same explant tissue type and method are used. Application of the soft-endpoint method reduces the inherent variability in comparisons of preclinical assays used for microbicide development. PMID:19726602

Richardson-Harman, Nicola; Lackman-Smith, Carol; Fletcher, Patricia S; Anton, Peter A; Bremer, James W; Dezzutti, Charlene S; Elliott, Julie; Grivel, Jean-Charles; Guenthner, Patricia; Gupta, Phalguni; Jones, Maureen; Lurain, Nell S; Margolis, Leonid B; Mohan, Swarna; Ratner, Deena; Reichelderfer, Patricia; Roberts, Paula; Shattock, Robin J; Cummins, James E

2009-11-01

26

Anti-Human Immunodeficiency Virus Type 1 Activity, Intracellular Metabolism, and Pharmacokinetic Evaluation of 2?-Deoxy-3?-Oxa-4?-Thiocytidine  

PubMed Central

The racemic nucleoside analogue 2?-deoxy-3?-oxa-4?-thiocytidine (dOTC) is in clinical development for the treatment of human immunodeficiency virus (HIV) type 1 (HIV-1) infection. dOTC is structurally related to lamivudine (3TC), but the oxygen and sulfur in the furanosyl ring are transposed. Intracellular metabolism studies showed that dOTC is phosphorylated within cells via the deoxycytidine kinase pathway and that approximately 2 to 5% of dOTC is converted into the racemic triphosphate derivatives, which had measurable half-lives (2 to 3 hours) within cells. Both 5?-triphosphate (TP) derivatives of dOTC were more potent than 3TC-TP at inhibiting HIV-1 reverse transcriptase (RT) in vitro. The Ki values for dOTC-TP obtained against human DNA polymerases ?, ?, and ? were 5,000-, 78-, and 571-fold greater, respectively, than those for HIV RT (28 nM), indicating a good selectivity for the viral enzyme. In culture experiments, dOTC is a potent inhibitor of primary isolates of HIV-1, which were obtained from antiretroviral drug-naive patients as well as from nucleoside therapy-experienced (3TC- and/or zidovudine [AZT]-treated) patients. The mean 50% inhibitory concentration of dOTC for drug-naive isolates was 1.76 ?M, rising to only 2.53 and 2.5 ?M for viruses resistant to 3TC and viruses resistant to 3TC and AZT, respectively. This minimal change in activity is in contrast to the more dramatic changes observed when 3TC or AZT was evaluated against these same viral isolates. In tissue culture studies, the 50% toxicity levels for dOTC, which were determined by using [3H]thymidine uptake as a measure of logarithmic-phase cell proliferation, was greater than 100 ?M for all cell lines tested. In addition, after 14 days of continuous culture, at concentrations up to 10 ?M, no measurable toxic effect on HepG2 cells or mitochondrial DNA replication within these cells was observed. When administered orally to rats, dOTC was well absorbed, with a bioavailability of approximately 77%, with a high proportion (approximately 16.5% of the levels in serum) found in the cerebrospinal fluid.

de Muys, Jean-Marc; Gourdeau, Henriette; Nguyen-Ba, Nghe; Taylor, Debra L.; Ahmed, Parvin S.; Mansour, Tarek; Locas, Celine; Richard, Nathalie; Wainberg, Mark A.; Rando, Robert F.

1999-01-01

27

Cytochrome P450 3A5 plays a prominent role in the oxidative metabolism of the anti-human immunodeficiency virus drug maraviroc.  

PubMed

Maraviroc is an anti-human immunodeficiency virus drug that acts by blocking viral entry into target cells. With use of ultra-performance liquid chromatography-mass spectrometry several monooxygenated, dioxygenated, and glucuronidated metabolites of maraviroc were identified both in vitro and in vivo. Characterization of the enzymes involved in the production of these metabolites determined that cytochrome P450 3A5 was the principal enzyme responsible for the formation of an abundant metabolite of maraviroc that resulted from oxygenation of the dichlorocyclohexane ring. For the formation of this metabolite, the V(max) values for CYP3A4 and CYP3A5 were 0.04 and 0.93 pmol · min?¹ · pmol P450?¹, and the K(m) values were 11.1 and 48.9 ?M, respectively. Furthermore, human liver microsomes isolated from donors homozygous for the loss-of-function CYP3A5*3 allele exhibited a 79% decrease in formation of this metabolite compared with those homozygous for the wild-type CYP3A5*1 allele. To probe which divergent residues between CYP3A4 and CYP3A5 might play a role in the differential activities of these enzymes toward maraviroc, mutations were introduced into both enzymes and metabolism of maraviroc was measured. A CYP3A5 L57F mutant exhibited a 61% decrease in the formation of this metabolite, whereas formation by a CYP3A4 F57L mutant was increased by 337% compared with that of the wild type. Taken together, these data provide novel insights into the biotransformation of maraviroc as well as the potential role of CYP3A4 and CYP3A5 divergent residues in the enzymatic activities of these two highly homologous enzymes. PMID:22923690

Lu, Yanhui; Hendrix, Craig W; Bumpus, Namandjé N

2012-12-01

28

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile.  

PubMed Central

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83) is a selective anti-human immunodeficiency virus (HIV) agent. When tested in phytohemagglutinin-stimulated normal human peripheral blood lymphocytes against fresh clinical isolates of HIV type 1 (HIV-1) obtained from patients naive to AZT (3'-azido-3'-deoxythymidine [zidovudine]), 935U83 inhibited virus growth with an average 50% inhibitory concentration (IC50) of 1.8 microM; corresponding IC50s were 0.10 microM for FLT (3'-deoxy-3'-fluorothymidine) and 0.23, 0.49, and 0.03 microM for the approved agents AZT, ddI (2',3'-dideoxyinosine), and ddC (2',3'-dideoxycytosine), respectively. Importantly, 935U83 retained activity against HIV strains that were resistant to AZT, ddI, or ddC. Of additional interest, we were unable to generate virus which was resistant to 935U83 by passaging either HXB2 (AZT-sensitive) or RTMC (AZT-resistant) strains in the presence of high concentrations of 935U83. The anabolic profile of 935U83 was similar to that of AZT, and 935U83 triphosphate was a potent inhibitor of HIV-1 reverse transcriptase. Pharmacokinetic evaluation showed good oral bioavailability (86% in mice and 60% in monkeys) and less extensive metabolism to the glucuronide relative to AZT. 935U83 showed low toxicity. In an in vitro assay for toxicity to a human erythrocyte progenitor, erythroid burst-forming unit (BFU-E), the IC50 for 935U83 (> 400 microM) was more than 1,000-fold those of FLT (0.07 microM) and AZT (0.30 microM). Mild reversible reductions in erythrocytes and associated parameters were seen in mice dosed orally with 2,000 mg of 935U83 per kg per day for 1 and 6 months. In monkeys dosed orally with up to 700 mg/kg/day for 1 and 6 months, the only possible treatment-related finding was cataracts in 1 of 12 animals given the intermediate dose of 225 mg/kg/day. At the highest doses in mice and monkeys, maximal concentrations in plasma were more than 100-fold the anti-HIV IC50s against clinical isolates. This safety profile in animals compares very favorably with that of any of the anti-HIV drugs approved to date and has led us to begin evaluation of 935U83 in patients with HIV infection.

Daluge, S M; Purifoy, D J; Savina, P M; St Clair, M H; Parry, N R; Dev, I K; Novak, P; Ayers, K M; Reardon, J E; Roberts, G B

1994-01-01

29

Identification of a New Quaternary Neutralizing Epitope on Human Immunodeficiency Virus Type 1 Virus Particles  

Microsoft Academic Search

The selection of human monoclonal antibodies (MAbs) specific for human immunodeficiency virus (HIV) type 1 by binding assays may fail to identify Abs to quaternary epitopes on the intact virions. The HIV neutralization assay was used for the selection of human MAb 2909, which potently neutralizes SF162 and recognizes an epitope on the virus surface but not on soluble proteins.

Miroslaw K. Gorny; Leonidas Stamatatos; Barbara Volsky; Kathy Revesz; Constance Williams; Xiao-Hong Wang; Sandra Cohen; Robert Staudinger; Susan Zolla-Pazner

2005-01-01

30

Chimpanzees Immunized with Recombinant Soluble CD4 Develop Anti-Self CD4 Antibody Responses with Anti-Human Immunodeficiency Virus Activity  

NASA Astrophysics Data System (ADS)

In view of the efficiency with which human immunodeficiency virus replication can be blocked in vitro with anti-CD4 antibodies, the elicitation of an anti-CD4 antibody response through active immunization might represent a useful therapeutic strategy for AIDS. Here we demonstrate that immunization of chimpanzees with recombinant soluble human CD4 elicited an anti-CD4 antibody response. The elicited antibody bound self CD4 on digitonin-treated but not freshly isolated lymphocytes. Nevertheless, this antibody blocked human immunodeficiency virus replication in chimpanzee and human lymphocytes. These observations suggest that immunization with recombinant soluble CD4 from human immunodeficiency virus-infected humans may be feasible and therapeutically beneficial.

Watanabe, Mamoru; Boyson, Jonathan E.; Lord, Carol I.; Letvin, Norman L.

1992-06-01

31

Preventive and therapeutic applications of neutralizing antibodies to Human Immunodeficiency Virus Type 1 (HIV-1)  

PubMed Central

The development of a preventive vaccine to neutralize the highly variable and antigenically diverse human immunodeficiency virus type 1 (HIV-1) has been an indomitable goal. The recent discovery of a number of cross-neutralizing and potent monoclonal antibodies from elite neutralizers has provided important insights in this field. Neutralizing antibodies (NAbs) are useful in identifying neutralizing epitopes of vaccine utility and for understanding the mechanism of potent and broad cross-neutralization thus providing a modality of preventive and therapeutic value. In this article we review the current understanding on the potential use of broadly neutralizing antibodies (bNAbs) in their full-length IgG structure, engineered domain antibody or bispecific versions towards preventive and therapeutic applications. The potential implications of NAbs are discussed in the light of the recent developments as key components in vaccination against HIV-1. The development of a vaccine immunogen which elicits bNAbs and confers protective immunity remains a real challenge.

Ringe, Rajesh

2013-01-01

32

Human Immunodeficiency Virus Type 1 Superinfection Occurs despite Relatively Robust Neutralizing Antibody Responses  

Microsoft Academic Search

Superinfection by a second human immunodeficiency virus type 1 (HIV-1) strain indicates that gaps in protective immunity occur during natural infection. To define the role of HIV-1-specific neutralizing antibodies (NAbs) in this setting, we examined NAb responses in 6 women who became superinfected between 1t o 5 years following initial infection compared to 18 women with similar risk factors who

Catherine A. Blish; Ozge C. Dogan; Nina R. Derby; Minh-An Nguyen; Bhavna Chohan; Barbra A. Richardson; Julie Overbaugh

2008-01-01

33

Anti-Human Immunodeficiency Virus Interactions of SCH-C (SCH 351125), a CCR5 Antagonist, with Other Antiretroviral Agents In Vitro  

Microsoft Academic Search

SCH-C (SCH 351125) is a small-molecule antagonist of the human immunodeficiency virus type 1(HIV-1) coreceptor CCR5. It has in vitro activity against R5 viruses with 50% inhibitory concentrations ranging from 1.0 to 30.9 nM. We have studied anti-HIV-1 interactions of SCH-C with other antiretroviral agents in vitro. Synergistic interactions were seen with nucleoside reverse transcriptase inhibitors (zidovudine and lamivu- dine),

Cécile L. Tremblay; Françoise Giguel; Christopher Kollmann; Yongbiao Guan; Ting-Chao Chou; Bahige M. Baroudy; Martin S. Hirsch

2002-01-01

34

Strain-specific neutralizing determinant in the transmembrane protein of simian immunodeficiency virus.  

PubMed

Monoclonal antibody SF8/5E11, which recognizes the transmembrane protein (TMP) of simian immunodeficiency virus of macaque monkeys (SIVmac), displayed strict strain specificity. It reacted with cloned and uncloned SIVmac251 but not with cloned SIVmac142 and SIVmac239 on immunoblots. This monoclonal antibody neutralized infection by cloned, cell-free SIVmac251 and inhibited formation of syncytia by cloned SIVmac251-infected cells; these activities were specific to cloned SIVmac251 and did not occur with the other viruses. Site-specific mutagenesis was used to show that TMP amino acids 106 to 110 (Asp-Trp-Asn-Asn-Asp) determined the strain specificity of the monoclonal antibody. This strain-specific neutralizing determinant is located within a variable region of SIVmac and human immunodeficiency virus type 2 (HIV-2) which includes conserved, clustered sites for N-linked glycosylation. The determinant corresponds exactly to a variable, weak neutralizing epitope in HIV-1 TMP which also includes conserved, clustered sites for N-linked glycosylation. Thus, the location of at least one neutralizing epitope appears to be common to both SIVmac and HIV-1. Our results suggest a role for this determinant in the viral entry process. Genetic variation was observed in this neutralizing determinant following infection of a rhesus monkey with molecularly cloned SIVmac239; variant forms of the strain-specific, neutralizing determinant accumulated during persistent infection in vivo. Selective pressure from the host immune response in vivo may result in sequence variation in this neutralizing determinant. PMID:1705994

Kodama, T; Burns, D P; Silva, D P; Veronese, F D; Desrosiers, R C

1991-04-01

35

The Phthalocyanine Prototype Derivative Alcian Blue Is the First Synthetic Agent with Selective Anti-Human Immunodeficiency Virus Activity Due to Its gp120 Glycan-Binding Potential?  

PubMed Central

Alcian Blue (AB), a phthalocyanine derivative, is able to prevent infection by a wide spectrum of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strains in various cell types [T cells, (co)receptor-transfected cells, and peripheral blood mononuclear cells]. With the exception of herpes simplex virus, AB is inactive against a broad variety of other (DNA and RNA) viruses. Time-of-addition studies show that AB prevents HIV-1 infection at the virus entry stage, exactly at the same time as carbohydrate-binding agents do. AB also efficiently prevents fusion between persistently HIV-1-infected HUT-78 cells and uninfected (CD4+) lymphocytes, DC-SIGN-directed HIV-1 capture, and subsequent transmission to uninfected (CD4+) T lymphocytes. Prolonged passaging of HIV-1 at dose-escalating concentrations of AB resulted in the selection of mutant virus strains in which several N-glycans of the HIV-1 gp120 envelope were deleted and in which positively charged amino acid mutations in both gp120 and gp41 appeared. A mutant virus strain in which four N-glycans were deleted showed a 10-fold decrease in sensitivity to the inhibitory effect of AB. These data suggest that AB is likely endowed with carbohydrate-binding properties and can be considered an important lead compound in the development of novel synthetic nonpeptidic antiviral drugs targeting the glycans of the envelope of HIV.

Francois, Katrien O.; Pannecouque, Christophe; Auwerx, Joeri; Lozano, Virginia; Perez-Perez, Maria-Jesus; Schols, Dominique; Balzarini, Jan

2009-01-01

36

Isolation of a novel ubiquitin-like protein from Pleurotus ostreatus mushroom with anti-human immunodeficiency virus, translation-inhibitory, and ribonuclease activities.  

PubMed

A glycoprotein, with a ubiquitin-like N-terminal sequence, has been prepared from an extract of fruiting bodies of the mushroom Pleurotus ostreatus, using a procedure which included ion exchange chromatography on DEAE-cellulose, affinity chromatography on Affi-gel blue gel, ion exchange chromatography on SP-Sepharose and Mono Q and gel filtration on Superdex 75. It exhibited a molecular weight of 12.5 kDa and was unadsorbed on DEAE-cellulose and Mono Q, but adsorbed on Affi-blue gel and SP-Sepharose. It inhibited translation in a rabbit reticulocyte lysate system (IC(50) = 160 nM) and exhibited low ribonucleolytic activity (14 micro/mg) toward yeast tRNA. It also expressed an inhibitory activity toward human immunodeficiency virus-1 reverse transcriptase, which could be enhanced by succinylation. PMID:11027517

Wang, H X; Ng, T B

2000-09-24

37

Anti-Human Immunodeficiency Virus Activity and Cellular Metabolism of a Potential Prodrug of the Acyclic Nucleoside Phosphonate 9-R-(2-Phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA  

PubMed Central

Bis(isopropyloxymethylcarbonyl) 9-R-(2-phosphonomethoxypropyl)adenine [bis(POC)PMPA] has been identified as a novel prodrug of PMPA. The anti-human immunodeficiency virus activity of bis(POC)PMPA was >100-fold greater than that of PMPA in both an established T-cell line and primary peripheral blood lymphocytes. This improved efficacy was shown to be due to a rapid intracellular uptake of the prodrug resulting in an increased intracellular accumulation of PMPA diphosphate (PMPApp), the pharmacologically active metabolite. PMPApp levels in bis(POC)PMPA-treated cells exceeded by >1,000-fold the levels seen in cells treated with unmodified PMPA in both resting and activated peripheral blood lymphocytes. Significant differences in the intracellular catabolism of PMPA metabolites were noted between the resting and activated lymphocytes. The half-life for the disappearance of PMPApp, derived from either bis(POC)PMPA or PMPA, was 12 to 15 h in the activated lymphocytes and 33 to 50 h in the resting lymphocytes. This long persistence of PMPApp, particularly in resting lymphocytes, may be unique to the nucleoside phosphonate analogs and indicates that effective levels of the active metabolite can be achieved and maintained with relatively infrequent administration of the parent drug.

Robbins, Brian L.; Srinivas, Ranga V.; Kim, Choung; Bischofberger, Norbert; Fridland, Arnold

1998-01-01

38

Generation of Neutralizing Activity against Human Immunodeficiency Virus Type 1 in Serum by Antibody Gene Transfer  

Microsoft Academic Search

Although several human immunodeficiency virus (HIV) vaccine approaches have elicited meaningful anti- gen-specific T-cell responses in animal models, no single vaccine candidate has engendered antibodies that broadly neutralize primary isolates of HIV type 1 (HIV-1). Thus, there remains a significant gap in the design of HIV vaccines. To address this issue, we exploited the existence of rare human monoclonal antibodies

Anne D. Lewis; Ruju Chen; David C. Montefiori; Philip R. Johnson; K. Reed Clark

2002-01-01

39

Fine characterization of a V3-region neutralizing epitope in human immunodeficiency virus type 2  

Microsoft Academic Search

We have previously identified two distinct antigenic sites in the third variable region (V3) of human immunodeficiency virus type 2 (HIV-2) corresponding to the principal neutralizing determinant (PND) of HIV-1, the conserved Phe-His-Ser-Gln and Trp-Cys-Arg motifs (positions 315–318 and 329–331), which possibly interact to form a discontinuous antigenic site. The aim of this study was to further identify and characterize

Andreas Mörner; Adnane Achour; Martin Norin; Rigmor Thorstensson; Ewa Björling

1999-01-01

40

Naturally occurring substitutions of conserved residues in human immunodeficiency virus type 1 variants of different clades are involved in PG9 and PG16 resistance to neutralization.  

PubMed

The recently described anti-human immunodeficiency virus type 1 (HIV-1) human mAb PG9 and PG16 are cross-clade broadly neutralizing. Therefore, it can be postulated that the targeted epitope(s) are highly conserved among variants of the entire group M. We analysed the sensitivity to PG9 and PG16 of pseudotyped viruses carrying envelope glycoproteins from the viral quasispecies of three HIV-1 clade CRF01_AE-infected patients. The broad heterogeneity in sensitivity to PG9 and PG16, despite closely genetically related envelope glycoproteins issued from single individuals, allowed us to identify two gp120 cross-clade conserved residues, a lysine at position 168 in the V2 loop and an isoleucine at position 215 in the C2 region, whose substitutions were associated with resistance to PG9 and PG16. By site-directed mutagenesis, we confirmed both in clades B and CRF01_AE that the substitutions K168E and I215M have a major impact on PG9 and PG16 neutralization sensitivity of pseudotyped viruses. PMID:22492917

Thenin, Suzie; Roch, Emmanuelle; Samleerat, Tanawan; Moreau, Thierry; Chaillon, Antoine; Moreau, Alain; Barin, Francis; Braibant, Martine

2012-07-01

41

Novel derivatives of phenethyl-5-bromopyridylthiourea and dihydroalkoxybenzyloxopyrimidine are dual-function spermicides with potent anti-human immunodeficiency virus activity.  

PubMed

Sexually active women represent the fastest growing HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) risk group. In an effort to develop a vaginal microbicidal contraceptive potentially capable of preventing HIV transmission as well as providing fertility control, we have synthesized novel non-nucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT) and examined them for dual-function anti-HIV and spermicidal activity. Structure-based drug design by use of a computer docking procedure for the NNI binding pocket generated from nine RT-NNI crystal structures led to the synthesis of three novel NNIs: N-[2-(2, 5-dimethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (D-PBT); N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (F-PBT); and 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-on e (S-DABO). The anti-HIV activity of these NNIs was compared with that of trovirdine and virucidal/spermicide, nonoxynol-9 (N-9), by measuring viral RT activity and p24 antigen production as markers of viral replication using HTLVIIIB-infected human peripheral blood mononuclear cells (PBMCs). The effects on sperm motion kinematics and sperm membrane integrity were examined by computer-assisted sperm analysis and by confocal laser scanning microscopy (CLSM), respectively. The growth-inhibitory effects of NNI versus N-9 against normal human ectocervical and endocervical epithelial cells were tested using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. All three NNIs were potent inhibitors of purified recombinant HIV RT and abrogated HIV replication in PBMCs at nanomolar concentrations (IC50 < 1 nM) when compared with N-9 or trovirdine (IC50 values of 2.2 microM and 0.007 microM, respectively). Two NNIs, F-PBT and S-DABO, also exhibited concentration- and time-dependent spermicidal activity. The drug concentration required to inhibit sperm motility by 50% (EC50 values) for the lead compound F-PBT versus N-9 was 147 microM and 81 microM, respectively. Sperm-immobilizing activity induced by F-PBT and S-DABO was rapid (t1/2 = 7-13 min) and irreversible. Unlike that of N-9, spermicidal activity of F-PBT and S-DABO was not accompanied by loss of acrosomal membrane as detected by fluorescent-lectin binding assay and CLSM. Whereas N-9 was cytotoxic to normal human ectocervical and endocervical cells at spermicidal doses, both F-PBT and S-DABO were selectively spermicidal. We conclude that as potent anti-HIV agents with spermicidal activity and reduced cytotoxicity, F-PBT and S-DABO show unique clinical potential to become the active ingredients of a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission. PMID:10330101

D'Cruz, O J; Uckun, F M

1999-06-01

42

Anti-Human Immunodeficiency Virus Type 1 Activity of Novel 6-Substituted 1-Benzyl-3-(3,5-Dimethylbenzyl)Uracil Derivatives  

PubMed Central

Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. In screening of chemical libraries, we found 6-azido-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AzBBU) and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AmBBU) to be highly active and selective inhibitors of HIV-1 replication in vitro. To determine the resistance profiles of these compounds, we conducted a long-term culture of HIV-1-infected MT-4 cells with escalating concentrations of each compound. After serial passages of the infected cells, escape viruses were obtained, and they were more than 500-fold resistant to the uracil derivatives compared to the wild type. Sequence analysis was conducted for RT of the escape viruses at passages 12 and 24. The amino acid mutation Y181C in the polymerase domain of RT was detected for all escape viruses. Docking studies using the crystal structure of RT showed that AmBBU requires the amino acid residues Leu100, Val106, Tyr181, and Trp229 for exerting its inhibitory effect on HIV-1. Four additional amino acid changes (K451R, R461K, T468P, and D471N) were identified in the RNase H domain of RT; however, their precise role in the acquisition of resistance is still unclear. In conclusion, the initial mutation Y181C seems sufficient for the acquisition of resistance to the uracil derivatives AzBBU and AmBBU. Further studies are required to determine the precise role of each mutation in the acquisition of HIV-1 resistance.

Ordonez, Paula; Hamasaki, Takayuki; Isono, Yohei; Sakakibara, Norikazu; Ikejiri, Masahiro; Maruyama, Tokumi

2012-01-01

43

In vitro effect of anti-human immunodeficiency virus CCR5 antagonist maraviroc on chemotactic activity of monocytes, macrophages and dendritic cells.  

PubMed

Compounds targeting the chemokine receptor CCR5 have recently been approved for treatment of human immunodeficiency virus (HIV) infection. Given the central role of CCR5 in inflammation and recruitment of antigen-presenting cells (APC), it is important to investigate the immunological consequences of pharmacological inhibition of CCR5. We evaluated the in vitro effect of different concentrations of CCR5 antagonist maraviroc (MVC) on cell migration of monocytes, macrophages (MO) and monocyte-derived dendritic cells (MDC) towards peptide formyl-methionyl-leucyl-phenylalanine (fMLP) and chemokines regulated upon activation normal T cell expressed and secreted (RANTES) and CCL4/macrophage inflammatory protein-1 (MIP-1?) and CCL2/monocyte chemotactic protein-1 (MCP-1). Results of flow cytometric analysis showed that monocytes treated in vitro with MVC exhibited a significant dose-dependent reduction of chemotaxis towards MIP-1? and MCP-1. fMLP-induced chemotactic activity decreased only at higher concentration (1 µM and 10 µM of MVC). In addition, all concentrations of MVC (0·1, 1 and 10 µM) induced in vitro a significant inhibition of chemotaxis of MO and MDC in response to all tested chemoattractants. No change in phenotype (CD1a and CD14) and CCR1, CCR4, CCR5 and formyl peptide receptor (FPR) expression was seen after in vitro treatment with MVC. These findings suggest that CCR5 antagonist MVC may have the in vitro ability of inhibiting the migration of innate immune cells by mechanism which could be independent from the pure anti-HIV effect. The drug might have a potential role in the down-regulation of HIV-associated chronic inflammation by blocking the recirculation and trafficking of MO and MDC. PMID:21985364

Rossi, R; Lichtner, M; De Rosa, A; Sauzullo, I; Mengoni, F; Massetti, A P; Mastroianni, C M; Vullo, V

2011-11-01

44

Anti-Human Immunodeficiency Virus Activity, Cross-Resistance, Cytotoxicity, and Intracellular Pharmacology of the 3?-Azido-2?,3?-Dideoxypurine Nucleosides?  

PubMed Central

Although the approved nucleoside reverse transcriptase (RT) inhibitors (NRTI) are integral components of therapy for human immunodeficiency virus type 1 (HIV-1) infection, they can have significant limitations, including the selection of NRTI-resistant HIV-1 and cellular toxicity. Accordingly, there is a critical need to develop new NRTI that have excellent activity and safety profiles and exhibit little or no cross-resistance with existing drugs. In this study, we report that the 3?-azido-2?,3?-dideoxypurine nucleosides (ADPNs) 3?-azido-2?,3?-dideoxyadenosine (3?-azido-ddA) and 3?-azido-2?,3?-dideoxyguanosine (3?-azido-ddG) exert potent antiviral activity in primary human lymphocytes and HeLa and T-cell lines (50% inhibitory concentrations [IC50s] range from 0.19 to 2.1 ?M for 3?-azido-ddG and from 0.36 to 10 ?M for 3?-azido-ddA) and that their triphosphate forms are incorporated as efficiently as the natural dGTP or dATP substrates by HIV-1 RT. Importantly, both 3?-azido-ddA and 3?-azido-ddG retain activity against viruses containing K65R, L74V, or M184V (IC50 change of <2.0-fold) and against those containing three or more thymidine analog mutations (IC50 change of <3.5-fold). In addition, 3?-azido-ddG does not exhibit cytotoxicity in primary lymphocytes or epithelial or T-cell lines and does not decrease the mitochondrial DNA content of HepG2 cells. Furthermore, 3?-azido-ddG is efficiently phosphorylated to 3?-azido-ddGTP in human lymphocytes, with an intracellular half-life of the nucleoside triphosphate of 9 h. The present data suggest that additional preclinical studies are warranted to assess the potential of ADPNs for treatment of HIV-1 infection.

Sluis-Cremer, Nicolas; Koontz, Dianna; Bassit, Leda; Hernandez-Santiago, Brenda I.; Detorio, Mervi; Rapp, Kim L.; Amblard, Franck; Bondada, Lavanya; Grier, Jason; Coats, Steven J.; Schinazi, Raymond F.; Mellors, John W.

2009-01-01

45

Antibody to adhesion molecule LFA-1 enhances plasma neutralization of human immunodeficiency virus type 1.  

PubMed Central

We have shown that a monoclonal antibody to the cell surface adhesion molecule LFA-1 (CD18/CD11a) enhances plasma neutralization of a laboratory isolate (HIVMN) and a primary isolate (HIV28R) of human immunodeficiency virus type 1. Human phytohemagglutinin blasts were infected with HIVMN or HIV28R in the presence of plasma pooled from HIV-positive individuals (AIDS plasma) or immunoglobulin G from AIDS plasma alone or combined with a monoclonal antibody (MAb) to LFA-1. While AIDS plasma alone at a dilution of 1:1,250 neutralized HIVMN and HIV28R infection by 15 and 0%, respectively, in the presence of a saturating concentration of the MAb to LFA-1 the plasma neutralized both viruses by more than 80% at this dilution. Immunoglobulin G purified from AIDS plasma, when used in combination with the MAb to LFA-1, showed the same synergistic effect in HIV neutralization as seen with the AIDS plasma and anti-LFA-1. The MAb against LFA-1 partially neutralized both viral isolates (45 to 55%) on its own. These results demonstrate significant synergy between the plasma and antibody against LFA-1 in the neutralization of HIV. The observations therefore suggest an important role for adhesion molecules in HIV infectivity and transmission. The results have implications for the recently observed host effect on HIV susceptibility to antibody neutralization.

Gomez, M B; Hildreth, J E

1995-01-01

46

Emergence of gp120 V3 Variants Confers Neutralization Resistance in an R5 Simian-Human Immunodeficiency Virus-Infected Macaque Elite Neutralizer That Targets the N332 Glycan of the Human Immunodeficiency Virus Type 1 Envelope Glycoprotein  

PubMed Central

Neutralization-resistant simian-human immunodeficiency virus AD8 (SHIVAD8) variants that emerged in an infected macaque elite neutralizer targeting the human immunodeficiency virus type 1 (HIV-1) gp120 N332 glycan acquired substitutions of critical amino acids in the V3 region rather than losing the N332 glycosylation site. One of these resistant variants, carrying the full complement of gp120 V3 changes, was also resistant to the potent anti-HIV-1 monoclonal neutralizing antibodies PGT121 and 10-1074, both of which are also dependent on the presence of the gp120 N332 glycan.

Sadjadpour, Reza; Donau, Olivia K.; Shingai, Masashi; Buckler-White, Alicia; Kao, Sandra; Strebel, Klaus; Nishimura, Yoshiaki

2013-01-01

47

Neutralizing antibody and clinical status of human immunodeficiency virus (HIV)-infected individuals.  

PubMed

An assay based on inhibition of cytopathic effect of human immunodeficiency virus (HIV) strains in Molt 4 cells was developed to quantitate neutralizing antibodies (NA) in sera of HIV-infected individuals. The assay was specific and gave results comparable to those obtained by the inhibition of immunofluorescence (IFI) and reverse transcriptase (RT) activity. Attempts were made to correlate the presence and the antibody titres with the clinical status of HIV-infected individuals classified according to Walter Reed staging classification scheme. NA titres correlated inversely with the stage of HIV infection: Compared with acquired immunodeficiency syndrome (AIDS) patients, HIV-infected subjects at stage WR1 had significantly higher NA titres. Moreover, a decrease in NA titre in relation to clinical deterioration was noted in sequential sera of eight of 11 AIDS patients, retrospectively examined, for NA. The symptomless subjects showed either the same level of NA or a trend towards an increasing antibody titre with time. Different isolates of HIV strains showed a variability in the extent of sensitivity to neutralization by sera obtained from different HIV-infected individuals. PMID:2784162

Alesi, D R; Ajello, F; Lupo, G; Vitale, F; Portera, M; Spadaro, F; Romano, N

1989-01-01

48

Role of Human Immunodeficiency Virus Type 1 Envelope Structure in the Induction of Broadly Neutralizing Antibodies  

PubMed Central

Very soon after the discovery of neutralizing antibodies (NAbs) toward human immunodeficiency virus type 1 (HIV-1) infection, it became apparent that characterization of these NAbs would be an important step in finding a cure for or a vaccine to eradicate HIV-1. Since the initial description of broadly cross-clade NAbs naturally produced in HIV-1 patients, numerous studies have described new viral targets for these antibodies. More recently, studies concerning new groups of patients able to control their viremia, such as long-term nonprogressors (LTNPs) or elite controllers, have described the generation of numerous envelope-targeted NAbs. Recent studies have marked a new stage in research on NAbs with the description of antibodies obtained from a worldwide screening of HIV-positive patients. These studies have permitted the discovery of NAb families with great potential for both neutralization and neutralization breadth, such as PG, PGT, CH, and highly active agonistic anti-CD4 binding site antibodies (HAADs), of which VRC01 and its variants are members. These antibodies are able to neutralize more than 80% of circulating strains without any autoreactivity and can be rapidly integrated into clinical trials in order to test their protective potential. In this review, we will focus on new insights into HIV-1 envelope structure and their implications for the generation of potent NAbs.

Benjelloun, F.; Lawrence, P.; Verrier, B.; Genin, C.

2012-01-01

49

Increased Neutralization Sensitivity of CD4-Independent Human Immunodeficiency Virus Variants  

PubMed Central

Naturally occurring human immunodeficiency virus (HIV-1) variants require the presence of CD4 and specific chemokine receptors to enter a cell. In the laboratory, HIV-1 variants that are capable of bypassing CD4 and utilizing only the CCR5 chemokine receptor for virus entry have been generated. Here we report that these CD4-independent viruses are significantly more sensitive to neutralization by soluble CD4 and a variety of antibodies. The same amino acid changes in the HIV-1 gp120 envelope glycoprotein determined CD4 independence and neutralization sensitivity. The CD4-independent envelope glycoproteins exhibited higher affinity for antibodies against CD4-induced gp120 epitopes but not other neutralizing ligands. The CD4-independent envelope glycoproteins did not exhibit increased lability relative to the wild-type envelope glycoproteins. The utilization of two receptors apparently allows HIV-1 to maintain a more neutralization-resistant state prior to engaging CD4 on the target cell, explaining the rarity of CD4 independence in wild-type HIV-1.

Kolchinsky, Peter; Kiprilov, Enko; Sodroski, Joseph

2001-01-01

50

Continuous Viral Escape and Selection by Autologous Neutralizing Antibodies in Drug-Naive Human Immunodeficiency Virus Controllers  

Microsoft Academic Search

We assessed differences in the character and specificity of autologous neutralizing antibodies (ANAbs) against individual viral variants of the quasispecies in a cohort of drug-naïve subjects with long-term con- trolled human immunodeficiency virus type 1 (HIV-1) infection and moderate levels of broad heterologous neutralizing antibodies (HNAb). Functional plasma virus showed continuous env evolution despite a short time frame and low

Madhumita Mahalanabis; Pushpa Jayaraman; Toshiyuki Miura; Florencia Pereyra; E. Michael Chester; Barbra Richardson; Bruce Walker; Nancy L. Haigwood

2009-01-01

51

Fine characterization of a V3-region neutralizing epitope in human immunodeficiency virus type 2.  

PubMed

We have previously identified two distinct antigenic sites in the third variable region (V3) of human immunodeficiency virus type 2 (HIV-2) corresponding to the principal neutralizing determinant (PND) of HIV-1, the conserved Phe-His-Ser-Gln and Trp-Cys-Arg motifs (positions 315-318 and 329-331), which possibly interact to form a discontinuous antigenic site. The aim of this study was to further identify and characterize the immunogenic sites in the V3-loop of HIV-2 that are important in the binding of neutralizing antibodies and to study in detail the importance of different configurations of peptides corresponding to this region. Peptides representing modifications of the V3-region of HIV-2(SBL6669-ISY) were used for immunization of guinea pigs. With one exception, both the Phe-His-Ser-Gln and the Trp-Cys-Arg motifs were required in the peptide sequences to obtain neutralizing hyperimmune guinea pig sera, and the highest titers were obtained after immunization with 20-27 amino acids (aa) long peptides. Neither substitutions nor deletions of residues between the two motifs, nor the addition of peptide sequences representing a T-helper epitope improved the induction of neutralizing antibodies. Computer simulation modeling revealed that the Phe-315, His-316, Trp-329 and Cys-330 are likely to participate in the formation of a discontinuous epitope. Taken together, these data support the hypothesis that the well conserved motifs FHSQ (positions 315-318) and WCR (positions 329-331) of the HIV-2(SBL6669) V3 region are important targets for neutralizing antibodies, and this may have implications for the design of a future HIV-2 vaccine. PMID:10854165

Mörner, A; Achour, A; Norin, M; Thorstensson, R; Björling, E

1999-01-01

52

Neutralizing antibody-independent containment of immunodeficiency virus challenges by DNA priming and recombinant pox virus booster immunizations  

Microsoft Academic Search

Eight different protocols were compared for their ability to raise protection against immunodeficiency virus challenges in rhesus macaques. The most promising containment of challenge infections was achieved by intradermal DNA priming followed by recombinant fowl pox virus booster immunizations. This containment did not require neutralizing antibody and was active for a series of challenges ending with a highly virulent virus

David C. Montefiori; R. Paul Johnson; Kelledy H. Manson; Marcia L. Kalish; Jeffrey D. Lifson; Tahir A. Rizvi; Shan Lu; Shiu-Lok Hu; Gail P. Mazzara; Dennis L. Panicali; James G. Herndon; Rhona Glickman; Maria A. Candido; Shari L. Lydy; Michael S. Wyand; Harold M. McClure; Harriet L. Robinson

1999-01-01

53

Enfuvirtide Resistance Mutations: Impact on Human Immunodeficiency Virus Envelope Function, Entry Inhibitor Sensitivity, and Virus Neutralization  

PubMed Central

Enfuvirtide (ENF/T-20/Fuzeon), the first human immunodeficiency virus (HIV) entry inhibitor to be licensed, targets a structural intermediate of the entry process. ENF binds the HR1 domain in gp41 after Env has bound CD4, preventing conformational changes needed for membrane fusion. Mutations in HR1 that confer ENF resistance can arise following ENF therapy. ENF resistance mutations were introduced into an R5- and X4-tropic Env to examine their impact on fusion, infection, and sensitivity to different classes of entry inhibitors and neutralizing antibodies. HR1 mutations could reduce infection and fusion efficiency and also delay fusion kinetics, likely accounting for their negative impact on viral fitness. HR1 mutations had minimal effect on virus sensitivity to other classes of entry inhibitors, including those targeting CD4 binding (BMS-806 and a CD4-specific monoclonal antibody [MAb]), coreceptor binding (CXCR4 inhibitor AMD3100 and CCR5 inhibitor TAK-779), or fusion (T-1249), indicating that ENF-resistant viruses can remain sensitive to other entry inhibitors in vivo. Some HR1 mutations conferred increased sensitivity to a subset of neutralizing MAbs that likely target fusion intermediates or with epitopes preferentially exposed following receptor interactions (17b, 48D, 2F5, 4E10, and IgGb12), as well as sera from some HIV-positive individuals. Mechanistically, enhanced neutralization correlated with reduced fusion kinetics, indicating that, in addition to steric constraints, kinetics may also limit virus neutralization by some antibodies. Therefore, escape from ENF comes at a cost to viral fitness and may confer enhanced sensitivity to humoral immunity due to prolonged exposure of epitopes that are not readily accessible in the native Env trimer. Resistance to other entry inhibitors was not observed.

Reeves, Jacqueline D.; Lee, Fang-Hua; Miamidian, John L.; Jabara, Cassandra B.; Juntilla, Marisa M.; Doms, Robert W.

2005-01-01

54

Enfuvirtide resistance mutations: impact on human immunodeficiency virus envelope function, entry inhibitor sensitivity, and virus neutralization.  

PubMed

Enfuvirtide (ENF/T-20/Fuzeon), the first human immunodeficiency virus (HIV) entry inhibitor to be licensed, targets a structural intermediate of the entry process. ENF binds the HR1 domain in gp41 after Env has bound CD4, preventing conformational changes needed for membrane fusion. Mutations in HR1 that confer ENF resistance can arise following ENF therapy. ENF resistance mutations were introduced into an R5- and X4-tropic Env to examine their impact on fusion, infection, and sensitivity to different classes of entry inhibitors and neutralizing antibodies. HR1 mutations could reduce infection and fusion efficiency and also delay fusion kinetics, likely accounting for their negative impact on viral fitness. HR1 mutations had minimal effect on virus sensitivity to other classes of entry inhibitors, including those targeting CD4 binding (BMS-806 and a CD4-specific monoclonal antibody [MAb]), coreceptor binding (CXCR4 inhibitor AMD3100 and CCR5 inhibitor TAK-779), or fusion (T-1249), indicating that ENF-resistant viruses can remain sensitive to other entry inhibitors in vivo. Some HR1 mutations conferred increased sensitivity to a subset of neutralizing MAbs that likely target fusion intermediates or with epitopes preferentially exposed following receptor interactions (17b, 48D, 2F5, 4E10, and IgGb12), as well as sera from some HIV-positive individuals. Mechanistically, enhanced neutralization correlated with reduced fusion kinetics, indicating that, in addition to steric constraints, kinetics may also limit virus neutralization by some antibodies. Therefore, escape from ENF comes at a cost to viral fitness and may confer enhanced sensitivity to humoral immunity due to prolonged exposure of epitopes that are not readily accessible in the native Env trimer. Resistance to other entry inhibitors was not observed. PMID:15795284

Reeves, Jacqueline D; Lee, Fang-Hua; Miamidian, John L; Jabara, Cassandra B; Juntilla, Marisa M; Doms, Robert W

2005-04-01

55

Monoclonal Antibodies to Phosphatidylinositol Phosphate Neutralize Human Immunodeficiency Virus Type 1: Role of Phosphate-Binding Subsites?  

PubMed Central

Both a murine monoclonal antibody to phosphatidylinositol phosphate (PIP) and a human monoclonal antibody (4E10) that is known to have broadly neutralizing capabilities against primary isolates of human immunodeficiency virus type 1 (HIV-1) bound to PIP, as determined by enzyme-linked immunosorbent assay. Each of the antibodies had antigen subsite binding specificities in aqueous medium for small phosphate-containing molecules and for inositol. The anti-PIP monoclonal antibody inhibited infection by two HIV-1 primary isolates in neutralization assays employing primary human peripheral blood mononuclear cells. The data suggest that PIP or related lipids having free phosphates could serve as targets for the neutralization of HIV-1.

Brown, Bruce K.; Karasavvas, Nicos; Beck, Zoltan; Matyas, Gary R.; Birx, Deborah L.; Polonis, Victoria R.; Alving, Carl R.

2007-01-01

56

Primary Virus Envelope Cross-Reactivity of the Broadening Neutralizing Antibody Response during Early Chronic Human Immunodeficiency Virus Type 1 Infection  

Microsoft Academic Search

To test the hypothesis that changing neutralizing antibody responses against human immunodeficiency virus type 1 (HIV-1) during chronic infection were a response to emergence of neutralization escape mutants, we cloned expressed and characterized envelope clones from patients in the Multicenter AIDS Cohort Study (MACS). Pseudotyped HIV-1 envelope clones obtained from differing time points were assessed for sensitivity to neutralization by

PENG FEI ZHANG; XI CHEN; WEI FU; JOSEPH B. MARGOLICK; GERALD V. QUINNAN

1999-01-01

57

CD4 Independence of Simian Immunodeficiency Virus Envs Is Associated with Macrophage Tropism, Neutralization Sensitivity, and Attenuated Pathogenicity  

Microsoft Academic Search

To investigate the basis for envelope (Env) determinants influencing simian immunodeficiency virus (SIV) tropism, we studied a number of Envs that are closely related to that of SIVmac239, a pathogenic, T-tropic virus that is neutralization resistant. The Envs from macrophage-tropic (M-tropic) virus strains SIVmac316, 1A11, 17E-Fr, and 1100 facilitated infection of CCR5-positive, CD4-negative cells. In contrast, the SIVmac239 Env was

Bridget A. Puffer; Stefan Pöhlmann; Aimee L. Edinger; Dan Carlin; Melissa D. Sanchez; Julie Reitter; Debbie D. Watry; Howard S. Fox; Ronald C. Desrosiers; Robert W. Doms

2002-01-01

58

Chimeric Gag-V3 Virus-Like Particles of Human Immunodeficiency Virus Induce Virus-Neutralizing Antibodies  

Microsoft Academic Search

A 41-kDa unprocessed human immunodeficiency virus 2 (HIV-2) gag precursor protein that has a deletion of a portion of the viral protease assembles as virus-like particles by budding through the cytoplasmic membrane of recombinant baculovirus-infected insect cells. We have constructed six different combinations of chimeric genes by coupling the truncated HIV-2 gag gene to the neutralizing domain (V3) or the

Lizhong Luo; Yan Li; Paula M. Cannon; Sunyoung Kim; C. Yong Kang

1992-01-01

59

Access of Antibody Molecules to the Conserved Coreceptor Binding Site on Glycoprotein gp120 Is Sterically Restricted on Primary Human Immunodeficiency Virus Type 1  

Microsoft Academic Search

Anti-human immunodeficiency virus type 1 (HIV-1) antibodies whose binding to gp120 is enhanced by CD4 binding (CD4i antibodies) are generally considered nonneutralizing for primary HIV-1 isolates. However, a novel CD4i-specific Fab fragment, X5, has recently been found to neutralize a wide range of primary isolates. To investigate the precise nature of the extraordinary neutralizing ability of Fab X5, we evaluated

Aran F. Labrijn; Pascal Poignard; Aarti Raja; Michael B. Zwick; Karla Delgado; Michael Franti; James Binley; Veronique Vivona; Christoph Grundner; Chih-Chin Huang; Miro Venturi; Christos J. Petropoulos; Terri Wrin; Dimiter S. Dimitrov; James Robinson; Peter D. Kwong; Richard T. Wyatt; Joseph Sodroski; Dennis R. Burton

2003-01-01

60

Identification of a linear neutralization site within the third variable region of the feline immunodeficiency virus envelope.  

PubMed Central

Synthetic peptides have been used to map linear B-cell epitopes of the third variable (V3) region of the feline immunodeficiency virus (FIV) external membrane glycoprotein gp120. The analysis of sera from naturally and experimentally FIV-infected cats by Pepscan and enzyme immunoassay with four partially overlapping peptides evidenced three antibody-binding domains, two of which mapped in the carboxyl-terminal half of V3. In particular, the V3.3 sequence (Gly-392-Phe-413) turned out to be important for in vitro neutralization of the virus in that the peptide inhibited the FIV-neutralizing activity of pooled immune cat sera, and on the other hand, cat sera raised against this peptide effectively neutralized FIV infectivity for Crandell feline kidney cells.

Lombardi, S; Garzelli, C; La Rosa, C; Zaccaro, L; Specter, S; Malvaldi, G; Tozzini, F; Esposito, F; Bendinelli, M

1993-01-01

61

Monoclonal antibodies to phosphatidylinositol phosphate neutralize human immunodeficiency virus type 1: role of phosphate-binding subsites.  

PubMed

Both a murine monoclonal antibody to phosphatidylinositol phosphate (PIP) and a human monoclonal antibody (4E10) that is known to have broadly neutralizing capabilities against primary isolates of human immunodeficiency virus type 1 (HIV-1) bound to PIP, as determined by enzyme-linked immunosorbent assay. Each of the antibodies had antigen subsite binding specificities in aqueous medium for small phosphate-containing molecules and for inositol. The anti-PIP monoclonal antibody inhibited infection by two HIV-1 primary isolates in neutralization assays employing primary human peripheral blood mononuclear cells. The data suggest that PIP or related lipids having free phosphates could serve as targets for the neutralization of HIV-1. PMID:17151131

Brown, Bruce K; Karasavvas, Nicos; Beck, Zoltan; Matyas, Gary R; Birx, Deborah L; Polonis, Victoria R; Alving, Carl R

2007-02-01

62

Broad neutralization of human immunodeficiency virus type 1 mediated by plasma antibodies against the gp41 membrane proximal external region.  

PubMed

We identified three cross-neutralizing plasma samples with high-titer anti-membrane proximal external region (MPER) peptide binding antibodies from among 156 chronically human immunodeficiency virus type 1-infected individuals. In order to establish if these antibodies were directly responsible for the observed neutralization breadth, we used MPER-coated magnetic beads to deplete plasmas of these specific antibodies. Depletion of anti-MPER antibodies from BB34, CAP206, and SAC21 resulted in 77%, 68%, and 46% decreases, respectively, in the number of viruses neutralized. Antibodies eluted from the beads showed neutralization profiles similar to those of the original plasmas, with potencies comparable to those of the known anti-MPER monoclonal antibodies (MAbs), 4E10, 2F5, and Z13e1. The anti-MPER neutralizing antibodies in BB34 were present in the immunoglobulin G3 subclass-enriched fraction. Alanine scanning of the MPER showed that the antibodies from these three plasmas had specificities distinct from those of the known MAbs, requiring one to three crucial residues at positions 670, 673, and 674. These data demonstrate the existence of MPER-specific cross-neutralizing antibodies in plasma, although the ability to elicit such potent antiviral antibodies during natural infection appears to be rare. Nevertheless, the identification of three novel antibody specificities within the MPER supports its further study as a promising target for vaccine design. PMID:19692477

Gray, Elin S; Madiga, Maphuti C; Moore, Penny L; Mlisana, Koleka; Abdool Karim, Salim S; Binley, James M; Shaw, George M; Mascola, John R; Morris, Lynn

2009-11-01

63

Neutralizing Monoclonal Antibodies Block Human Immunodeficiency Virus Type 1 Infection of Dendritic Cells and Transmission to T Cells  

PubMed Central

Prevention of the initial infection of mucosal dendritic cells (DC) and interruption of the subsequent transmission of HIV-1 from DC to T cells are likely to be important attributes of an effective human immunodeficiency virus type 1 (HIV-1) vaccine. While anti-HIV-1 neutralizing antibodies have been difficult to elicit by immunization, there are several human monoclonal antibodies (MAbs) that effectively neutralize virus infection of activated T cells. We investigated the ability of three well-characterized neutralizing MAbs (IgG1b12, 2F5, and 2G12) to block HIV-1 infection of human DC. DC were generated from CD14+ blood cells or obtained from cadaveric human skin. The MAbs prevented viral entry into purified DC and the ensuing productive infection in DC/T-cell cultures. When DC were first pulsed with HIV-1, MAbs blocked the subsequent transmission to unstimulated CD3+ T cells. Thus, neutralizing antibodies can block HIV-1 infection of DC and the cell-to-cell transmission of virus from infected DC to T cells. These data suggest that neutralizing antibodies could interrupt the initial events associated with mucosal transmission and regional spread of HIV-1.

Frankel, Sarah S.; Steinman, Ralph M.; Michael, Nelson L.; Kim, Silvia Ratto; Bhardwaj, Nina; Pope, Melissa; Louder, Mark K.; Ehrenberg, Philip K.; Parren, Paul W. H. I.; Burton, Dennis R.; Katinger, Hermann; VanCott, Thomas C.; Robb, Merlin L.; Birx, Deborah L.; Mascola, John R.

1998-01-01

64

Heterogeneity in Neutralization Sensitivities of Viruses Comprising the Simian Immunodeficiency Virus SIVsmE660 Isolate and Vaccine Challenge Stock  

PubMed Central

The sooty mangabey-derived simian immunodeficiency virus (SIV) strain E660 (SIVsmE660) is a genetically heterogeneous, pathogenic isolate that is commonly used as a vaccine challenge strain in the nonhuman primate (NHP) model of human immunodeficiency virus type 1 (HIV-1) infection. Though it is often employed to assess antibody-based vaccine strategies, its sensitivity to antibody-mediated neutralization has not been well characterized. Here, we utilize single-genome sequencing and infectivity assays to analyze the neutralization sensitivity of the uncloned SIVsmE660 isolate, individual viruses comprising the isolate, and transmitted/founder (T/F) viruses arising from low-dose mucosal inoculation of macaques with the isolate. We found that the SIVsmE660 isolate overall was highly sensitive to neutralization by SIV-infected macaque plasma samples (50% inhibitory concentration [IC50] < 10?5) and monoclonal antibodies targeting V3 (IC50 < 0.01 ?g/ml), CD4-induced (IC50 < 0.1 ?g/ml), CD4 binding site (IC50 ? 1 ?g/ml), and V4 (IC50, ?5 ?g/ml) epitopes. In comparison, SIVmac251 and SIVmac239 were highly resistant to neutralization by these same antibodies. Differences in neutralization sensitivity between SIVsmE660 and SIVmac251/239 were not dependent on the cell type in which virus was produced or tested. These findings indicate that in comparison to SIVmac251/239 and primary HIV-1 viruses, SIVsmE660 generally exhibits substantially less masking of antigenically conserved Env epitopes. Interestingly, we identified a minor population of viruses (?10%) in both the SIVsmE660 isolate and T/F viruses arising from it that were substantially more resistant (>1,000-fold) to antibody neutralization and another fraction (?20%) that was intermediate in neutralization resistance. These findings may explain the variable natural history and variable protection afforded by heterologous Env-based vaccines in rhesus macaques challenged by high-dose versus low-dose SIVsmE660 inoculation regimens.

Lopker, Michael; Easlick, Juliet; Sterrett, Sarah; Decker, Julie M.; Barbian, Hannah; Learn, Gerald; Keele, Brandon F.; Robinson, James E.; Li, Hui; Hahn, Beatrice H.; Shaw, George M.

2013-01-01

65

Human Immunodeficiency Virus Type 1 Elite Neutralizers: Individuals with Broad and Potent Neutralizing Activity Identified by Using a High-Throughput Neutralization Assay together with an Analytical Selection Algorithm? †  

PubMed Central

The development of a rapid and efficient system to identify human immunodeficiency virus type 1 (HIV-1)-infected individuals with broad and potent HIV-1-specific neutralizing antibody responses is an important step toward the discovery of critical neutralization targets for rational AIDS vaccine design. In this study, samples from HIV-1-infected volunteers from diverse epidemiological regions were screened for neutralization responses using pseudovirus panels composed of clades A, B, C, and D and circulating recombinant forms (CRFs). Initially, 463 serum and plasma samples from Australia, Rwanda, Uganda, the United Kingdom, and Zambia were screened to explore neutralization patterns and selection ranking algorithms. Samples were identified that neutralized representative isolates from at least four clade/CRF groups with titers above prespecified thresholds and ranked based on a weighted average of their log-transformed neutralization titers. Linear regression methods selected a five-pseudovirus subset, representing clades A, B, and C and one CRF01_AE, that could identify top-ranking samples with 50% inhibitory concentration (IC50) neutralization titers of ?100 to multiple isolates within at least four clade groups. This reduced panel was then used to screen 1,234 new samples from the Ivory Coast, Kenya, South Africa, Thailand, and the United States, and 1% were identified as elite neutralizers. Elite activity is defined as the ability to neutralize, on average, more than one pseudovirus at an IC50 titer of 300 within a clade group and across at least four clade groups. These elite neutralizers provide promising starting material for the isolation of broadly neutralizing monoclonal antibodies to assist in HIV-1 vaccine design.

Simek, Melissa D.; Rida, Wasima; Priddy, Frances H.; Pung, Pham; Carrow, Emily; Laufer, Dagna S.; Lehrman, Jennifer K.; Boaz, Mark; Tarragona-Fiol, Tony; Miiro, George; Birungi, Josephine; Pozniak, Anton; McPhee, Dale A.; Manigart, Olivier; Karita, Etienne; Inwoley, Andre; Jaoko, Walter; DeHovitz, Jack; Bekker, Linda-Gail; Pitisuttithum, Punnee; Paris, Robert; Walker, Laura M.; Poignard, Pascal; Wrin, Terri; Fast, Patricia E.; Burton, Dennis R.; Koff, Wayne C.

2009-01-01

66

Protection of Macaques against Pathogenic Simian/Human Immunodeficiency Virus 89.6PD by Passive Transfer of Neutralizing Antibodies  

PubMed Central

The role of antibody in protection against human immunodeficiency virus (HIV-1) has been difficult to study in animal models because most primary HIV-1 strains do not infect nonhuman primates. Using a chimeric simian/human immunodeficiency virus (SHIV) based on the envelope of a primary isolate (HIV-89.6), we performed passive-transfer experiments in rhesus macaques to study the role of anti-envelope antibodies in protection. Based on prior in vitro data showing neutralization synergy by antibody combinations, we evaluated HIV immune globulin (HIVIG), and human monoclonal antibodies (MAbs) 2F5 and 2G12 given alone, compared with the double combination 2F5/2G12 and the triple combination HIVIG/2F5/2G12. Antibodies were administered 24 h prior to intravenous challenge with the pathogenic SHIV-89.6PD. Six control monkeys displayed high plasma viremia, rapid CD4+-cell decline, and clinical AIDS within 14 weeks. Of six animals given HIVIG/2F5/2G12, three were completely protected; the remaining three animals became SHIV infected but displayed reduced plasma viremia and near normal CD4+-cell counts. One of three monkeys given 2F5/2G12 exhibited only transient evidence of infection; the other two had marked reductions in viral load. All monkeys that received HIVIG, 2F5, or 2G12 alone became infected and developed high-level plasma viremia. However, compared to controls, monkeys that received HIVIG or MAb 2G12 displayed a less profound drop in CD4+ T cells and a more benign clinical course. These data indicate a general correlation between in vitro neutralization and protection and suggest that a vaccine that elicits neutralizing antibody should have a protective effect against HIV-1 infection or disease.

Mascola, John R.; Lewis, Mark G.; Stiegler, Gabriela; Harris, Dawn; VanCott, Thomas C.; Hayes, Deborah; Louder, Mark K.; Brown, Charles R.; Sapan, Christine V.; Frankel, Sarah S.; Lu, Yichen; Robb, Merlin L.; Katinger, Hermann; Birx, Deborah L.

1999-01-01

67

Increased neutralization sensitivity and reduced replicative capacity of human immunodeficiency virus type 1 after short-term in vivo or in vitro passage through chimpanzees  

Microsoft Academic Search

Development of disease is extremely rare in chimpanzees when inoculated with either T-cell-line-adapted neutralization-sensitive or primary human immunodeficiency virus type 1 (HIV-1), at first excluding a role for HIV-1 neutralization sensitivity in the clinical course of infection. Interestingly, we observed that short-term in vivo and in vitro passage of primary HIV-1 isolates through chimpanzee peripheral blood mononuclear cells (PBMC) resulted

TIM BEAUMONT; SILVIA BROERSEN; AD VAN NUENEN; HAN G. HUISMAN; Roda Husman de A. M; JONATHAN L. HEENEY; HANNEKE SCHUITEMAKER

2000-01-01

68

Human Immunodeficiency Virus Type 1 env Clones from Acute and Early Subtype B Infections for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies  

Microsoft Academic Search

Induction of broadly cross-reactive neutralizing antibodies is a high priority for AIDS vaccine development but one that has proven difficult to be achieved. While most immunogens generate antibodies that neutralize a subset of T-cell-line-adapted strains of human immunodeficiency virus type 1 (HIV-1), none so far have generated a potent, broadly cross-reactive response against primary isolates of the virus. Even small

Ming Li; Feng Gao; John R. Mascola; Leonidas Stamatatos; Victoria R. Polonis; Marguerite Koutsoukos; Gerald Voss; Paul Goepfert; Peter Gilbert; Kelli M. Greene; Miroslawa Bilska; Denise L. Kothe; Jesus F. Salazar-Gonzalez; Xiping Wei; Julie M. Decker; Beatrice H. Hahn; David C. Montefiori

2005-01-01

69

Neutralizing Antibodies from the Sera of Human Immunodeficiency Virus Type 1Infected Individuals Bind to Monomeric gp120 and Oligomeric gp140  

Microsoft Academic Search

Antibodies that neutralize primary isolates of human immunodeficiency virus type 1 (HIV-1) appear during HIV-1 infection but are difficult to elicit by immunization with current vaccine products comprised of mono- meric forms of HIV-1 envelope glycoprotein gp120. The limited neutralizing antibody response generated by gp120 vaccine products could be due to the absence or inaccessibility of the relevant epitopes. To

NICHOLAS M. STAMATOS; JOHN R. MASCOLA; VANIAMBADI S. KALYANARAMAN; MARK K. LOUDER; LYNN M. FRAMPTON; DEBORAH L. BIRX; THOMAS C. VANCOTT

1998-01-01

70

Structure-Function Analysis of the Epitope for 4E10, a Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody†  

PubMed Central

The human immunodeficiency virus type 1 (HIV-1) neutralizing antibody 4E10 binds to a linear, highly conserved epitope within the membrane-proximal external region of the HIV-1 envelope glycoprotein gp41. We have delineated the peptide epitope of the broadly neutralizing 4E10 antibody to gp41 residues 671 to 683, using peptides with different lengths encompassing the previously suggested core epitope (NWFDIT). Peptide binding to the 4E10 antibody was assessed by competition enzyme-linked immunosorbent assay, and the Kd values of selected peptides were determined using surface plasmon resonance. An Ala scan of the epitope indicated that several residues, W672, F673, and T676, are essential (>1,000-fold decrease in binding upon replacement with alanine) for 4E10 recognition. In addition, five other residues, N671, D674, I675, W680, and L679, make significant contributions to 4E10 binding. In general, the Ala scan results agree well with the recently reported crystal structure of 4E10 in complex with a 13-mer peptide and with our circular dichroism analyses. Neutralization competition assays confirmed that the peptide NWFDITNWLWYIKKKK-NH2 could effectively inhibit 4E10 neutralization. Finally, to limit the conformational flexibility of the peptides, helix-promoting 2-aminoisobutyric acid residues and helix-inducing tethers were incorporated. Several peptides have significantly improved affinity (>1,000-fold) over the starting peptide and, when used as immunogens, may be more likely to elicit 4E10-like neutralizing antibodies. Hence, this study represents the first stage toward iterative development of a vaccine based on the 4E10 epitope.

Brunel, Florence M.; Zwick, Michael B.; Cardoso, Rosa M. F.; Nelson, Josh D.; Wilson, Ian A.; Burton, Dennis R.; Dawson, Philip E.

2006-01-01

71

Phase I Dose Escalation Trial Evaluating the Pharmacokinetics, Anti-Human Cytomegalovirus (HCMV) Activity, and Safety of 1263W94 in Human Immunodeficiency Virus-Infected Men with Asymptomatic HCMV Shedding  

PubMed Central

1263W94 [maribavir; 5,6-dichloro-2-(isopropylamino)-1,?-l-ribofuranosyl-1-H-benzimidazole] is a novel benzimidazole compound for treatment of human cytomegalovirus (HCMV) infection and disease, with potent in vitro activity against HCMV and good oral bioavailability. A phase I study was conducted to determine the pharmacokinetics (PK), anti-HCMV activity, and safety of 1263W94 administered as multiple oral doses to human immunodeficiency virus type 1-infected adult male subjects with asymptomatic HCMV shedding. Subjects received one of six dosage regimens (100, 200, or 400 mg three times a day, or 600, 900, or 1,200 mg twice a day) or a placebo for 28 days. 1263W94 demonstrated linear PK, with steady-state plasma 1263W94 profiles predictable based on single-dose data. 1263W94 was rapidly absorbed following oral dosing, and values for the maximum concentration of the drug in plasma and the area under the concentration-time curve increased in proportion to the dose. 1263W94 demonstrated in vivo anti-HCMV activity in semen at all of the dosage regimens tested, with mean reductions in semen HCMV titers of 2.9 to 3.7 log10 PFU/ml among the four regimens evaluated for anti-HCMV activity. 1263W94 was generally well tolerated; taste disturbance was the most frequently reported adverse event over the 28-day dosing period.

Lalezari, Jacob P.; Aberg, Judith A.; Wang, Laurene H.; Wire, Mary Beth; Miner, Richard; Snowden, Wendy; Talarico, Christine L.; Shaw, Shuching; Jacobson, Mark A.; Drew, W. Lawrence

2002-01-01

72

Cell-to-cell transmission of human immunodeficiency virus type 1 in the presence of azidothymidine and neutralizing antibody.  

PubMed Central

Very few peripheral blood lymphocytes of seropositive individuals are presumably actively infected with human immunodeficiency virus type 1 (HIV-1). During coculture of lymphocytes of a seropositive individual with mitogen-stimulated normal peripheral blood lymphocytes, the number of infected cells becomes amplified such that detectable HIV-1 is produced. We report here that in addition to transmission by extracellular virus, cell-to-cell transmission is responsible for spreading HIV-1 infection from infected to uninfected cells. Azidothymidine and virus-neutralizing antibody had no effect on cell-to-cell transmission of HIV-1. Monoclonal antibodies to the CD4 receptor, but not to the CD3 receptor, prevented cell-to-cell transmission, which suggests that CD4 receptor-mediated cell fusion is involved in cell-to-cell transmission. Spread of infection in a cell-to-cell manner may be important in development of drug therapies for HIV-1 infection.

Gupta, P; Balachandran, R; Ho, M; Enrico, A; Rinaldo, C

1989-01-01

73

Location, exposure, and conservation of neutralizing and nonneutralizing epitopes on human immunodeficiency virus type 2 SU glycoprotein.  

PubMed Central

Eleven rat monoclonal antibodies (MAbs) that recognize the SU glycoprotein of human immunodeficiency virus type 2 (HIV-2) ROD were produced and characterized. Binding sites for eight of these MAbs were mapped to epitopes within the Cl, V1/V2, C2, and V3 envelope regions. The three other MAbs defined at least two conformation-dependent, strain-specific epitopes outside Vl/V2, V3, and the CD4-binding site. The MAbs were used to probe the tertiary structure of oligomeric envelope glycoprotein expressed on the surfaces of infected cells. Epitopes at the apices of V2 and V3 were exposed on the native molecule, whereas other epitopes on V1/V2, Cl, and C2 were hidden. The MAbs defined three neutralization targets on exposed domains: two linear epitopes in the V2 and the V3 loops and one conformational epitope outside V1, V2, and V3.

McKnight, A; Shotton, C; Cordell, J; Jones, I; Simmons, G; Clapham, P R

1996-01-01

74

Neutralizing IgG at the Portal of Infection Mediates Protection against Vaginal Simian/Human Immunodeficiency Virus Challenge  

PubMed Central

Neutralizing antibodies may have critical importance in immunity against human immunodeficiency virus type 1 (HIV-1) infection. However, the amount of protective antibody needed at mucosal surfaces has not been fully established. Here, we evaluated systemic and mucosal pharmacokinetics (PK) and pharmacodynamics (PD) of 2F5 IgG and 2F5 Fab fragments with respect to protection against vaginal challenge with simian-human immunodeficiency virus-BaL in macaques. Antibody assessment demonstrated that 2F5 IgG was more potent than polymeric forms (IgM and IgA) across a range of cellular and tissue models. Vaginal challenge studies demonstrated a dose-dependent protection for 2F5 IgG and no protection with 2F5 Fab despite higher vaginal Fab levels at the time of challenge. Animals receiving 50 or 25 mg/kg of body weight 2F5 IgG were completely protected, while 3/5 animals receiving 5 mg/kg were protected. In the control animals, infection was established by a minimum of 1 to 4 transmitted/founder (T/F) variants, similar to natural human infection by this mucosal route; in the two infected animals that had received 5 mg 2F5 IgG, infection was established by a single T/F variant. Serum levels of 2F5 IgG were more predictive of sterilizing protection than measured vaginal levels. Fc-mediated antiviral activity did not appear to influence infection of primary target cells in cervical explants. However, PK studies highlighted the importance of the Fc portion in tissue biodistribution. Data presented in this study may be important in modeling serum levels of neutralizing antibodies that need to be achieved by either vaccination or passive infusion to prevent mucosal acquisition of HIV-1 infection in humans.

Klein, Katja; Veazey, Ronald S.; Warrier, Ranjit; Hraber, Peter; Doyle-Meyers, Lara A.; Buffa, Viviana; Liao, Hua-Xin; Haynes, Barton F.; Shaw, George M.

2013-01-01

75

Neutralizing IgG at the portal of infection mediates protection against vaginal simian/human immunodeficiency virus challenge.  

PubMed

Neutralizing antibodies may have critical importance in immunity against human immunodeficiency virus type 1 (HIV-1) infection. However, the amount of protective antibody needed at mucosal surfaces has not been fully established. Here, we evaluated systemic and mucosal pharmacokinetics (PK) and pharmacodynamics (PD) of 2F5 IgG and 2F5 Fab fragments with respect to protection against vaginal challenge with simian-human immunodeficiency virus-BaL in macaques. Antibody assessment demonstrated that 2F5 IgG was more potent than polymeric forms (IgM and IgA) across a range of cellular and tissue models. Vaginal challenge studies demonstrated a dose-dependent protection for 2F5 IgG and no protection with 2F5 Fab despite higher vaginal Fab levels at the time of challenge. Animals receiving 50 or 25 mg/kg of body weight 2F5 IgG were completely protected, while 3/5 animals receiving 5 mg/kg were protected. In the control animals, infection was established by a minimum of 1 to 4 transmitted/founder (T/F) variants, similar to natural human infection by this mucosal route; in the two infected animals that had received 5 mg 2F5 IgG, infection was established by a single T/F variant. Serum levels of 2F5 IgG were more predictive of sterilizing protection than measured vaginal levels. Fc-mediated antiviral activity did not appear to influence infection of primary target cells in cervical explants. However, PK studies highlighted the importance of the Fc portion in tissue biodistribution. Data presented in this study may be important in modeling serum levels of neutralizing antibodies that need to be achieved by either vaccination or passive infusion to prevent mucosal acquisition of HIV-1 infection in humans. PMID:23966410

Klein, Katja; Veazey, Ronald S; Warrier, Ranjit; Hraber, Peter; Doyle-Meyers, Lara A; Buffa, Viviana; Liao, Hua-Xin; Haynes, Barton F; Shaw, George M; Shattock, Robin J

2013-11-01

76

Human erythrocytes bearing electroinserted CD4 neutralize infection in vitro by primary isolates of human immunodeficiency virus type 1.  

PubMed

Human erythrocytes bearing electroinserted full-length CD4 (RBC-CD4) can bind and fuse with a laboratory strain of human immunodeficiency virus type 1 (HIV-1) or with T cells infected by HIV-1. Here we show that RBC-CD4 neutralize primary HIV-1 strains in an assay of cocultivation of peripheral blood mononuclear cells (PBMC) from HIV-1-infected persons with uninfected PBMC. RBC-CD4 inhibited viral p24 core antigen accumulation in these cocultures up to 10,000-fold compared with RBC alone. Viral p24 accumulation was inhibited equally well when measured in culture supernatants or in call extracts. The inhibition was dose-dependent and long-lived. Two types of recombinant CD4 tested in parallel were largely ineffective. The neutralization of primary HIV-1 by RBC-CD4 in vitro was demonstrated in PBMC cultures from 21 of a total of 23 patients tested at two independent sites. RBC-CD4 may offer a route to blocking HIV-1 infection in vivo. PMID:8639857

Tosi, P F; Schwartz, D; Sharma, U; Mouneimne, Y; Hannig, J; Li, G; McKinley, G; Grieco, M; Flexner, C W; Lazarte, J; Norse, D; Nicolau, C; Volsky, D J

1996-06-01

77

Impact of amino acid substitutions in the V2 and C2 regions of human immunodeficiency virus type 1 CRF01_AE envelope glycoprotein gp120 on viral neutralization susceptibility to broadly neutralizing antibodies specific for the CD4 binding site  

PubMed Central

Background The CD4 binding site (CD4bs) of envelope glycoprotein (Env) gp120 is a functionally conserved, important target of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies. Two neutralizing human monoclonal antibodies, IgG1 b12 (b12) and VRC01, are broadly reactive neutralizing antibodies which recognize conformational epitopes that overlap the CD4bs of Env gp120; however, many CRF01_AE viruses are resistant to neutralization mediated by these antibodies. We examined the mechanism underlying the b12 resistance of the viruses using CRF01_AE Env (AE-Env)-recombinant viruses in this study. Results Our results showed that an amino acid substitution at position 185 in the V2 region of gp120 played a crucial role in regulating the b12 susceptibility of AE-Env-recombinant viruses by cooperating with 2 previously reported potential N-linked glycosylation (PNLG) sites at positions 186 (N186) and 197 (N197) in the V2 and C2 regions of Env gp120. The amino acid residue at position 185 and 2 PNLG sites were responsible for the b12 resistance of 21 of 23 (>91%) AE-Env clones tested. Namely, the introduction of aspartic acid at position 185 (D185) conferred b12 susceptibility of 12 resistant AE-Env clones in the absence of N186 and/or N197, while the introduction of glycine at position 185 (G185) reduced the b12 susceptibility of 9 susceptible AE-Env clones in the absence of N186 and/or N197. In addition, these amino acid mutations altered the VRC01 susceptibility of many AE-Env clones. Conclusions We propose that the V2 and C2 regions of AE-Env gp120 contain the major determinants of viral resistance to CD4bs antibodies. CRF01_AE is a major circulating recombinant form of HIV-1 prevalent in Southeast Asia. Our data may provide important information to understand the molecular mechanism regulating the neutralization susceptibility of CRF01_AE viruses to CD4bs antibodies.

2014-01-01

78

Human Monoclonal Antibodies Specific for Conformation-Sensitive Epitopes of V3 Neutralize Human Immunodeficiency Virus Type 1 Primary Isolates from Various Clades  

Microsoft Academic Search

The epitopes of the V3 domain of the human immunodeficiency virus type 1 (HIV-1) gp120 glycoprotein have complex structures consisting of linear and conformational antigenic determinants. Anti-V3 antibodies (Abs) recognize both types of elements, but Abs which preferentially react to the conformational aspect of the epitopes may have more potent neutralizing activity against HIV-1, as recently suggested. To test this

Miroslaw K. Gorny; Constance Williams; Barbara Volsky; Kathy Revesz; Sandra Cohen; Victoria R. Polonis; William J. Honnen; Samuel C. Kayman; Chavdar Krachmarov; Abraham Pinter; Susan Zolla-Pazner

2002-01-01

79

Antibodies with Specificity to Native gp120 and Neutralization Activity against Primary Human Immunodeficiency Virus Type 1 Isolates Elicited by Immunization with Oligomeric gp160  

Microsoft Academic Search

Current human immunodeficiency virus type 1 (HIV-1) envelope vaccine candidates elicit high antibody binding titers with neutralizing activity against T-cell line-adapted but not primary HIV-1 isolates. Serum antibodies from these human vaccine recipients were also found to be preferentially directed to linear epitopes within gp120 that are poorly exposed on native gp120. Systemic immunization of rabbits with an affinity- purified

THOMAS C. VANCOTT; J. R. MASCOLA; R. W. KAMINSKI; V. KALYANARAMAN; P. L. HALLBERG; P. R. BURNETT; J. T. ULRICH; D. J. RECHTMAN; D. L. BIRX; Henry M. Jackson; Ribi ImmunoChem

1997-01-01

80

Neutralizing Antibodies Do Not Mediate Suppression of Human Immunodeficiency Virus Type 1 in Elite Suppressors or Selection of Plasma Virus Variants in Patients on Highly Active Antiretroviral Therapy  

Microsoft Academic Search

Neutralizing antibodies (NAb) against autologous virus can reach high titers in human immunodeficiency virus type 1 (HIV-1)-infected patients with progressive disease. Less is known about the role of NAb in HIV-1-infected patients with viral loads of <50 copies\\/ml of plasma, including patients on effective highly active antiretroviral therapy (HAART) and elite suppressors, who control HIV-1 replication without antiretroviral therapy. In

Justin R. Bailey; Kara G. Lassen; Hung-Chih Yang; Thomas C. Quinn; Stuart C. Ray; Joel N. Blankson; Robert F. Siliciano

2006-01-01

81

The impact of envelope glycoprotein cleavage on the antigenicity, infectivity, and neutralization sensitivity of Env-pseudotyped human immunodeficiency virus type 1 particles  

Microsoft Academic Search

Endoproteolytic processing of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoproteins is an obligate part of the biosynthetic pathway that generates functional, fusion-competent Env complexes, which are then incorporated into infectious virions. We have examined the influence of cleavage on Env-specific antibody reactivity, Env incorporation into pseudovirions, and the infectivity and neutralization sensitivity of Env-pseudotyped viruses. To do

Carolina Herrera; Per Johan Klasse; Elizabeth Michael; Shivani Kake; Kelly Barnes; Christopher W. Kibler; Lila Campbell-Gardener; Zhihai Si; Joseph Sodroski; John P. Moore; Simon Beddows

2005-01-01

82

The prolonged culture of human immunodeficiency virus type 1 in primary lymphocytes increases its sensitivity to neutralization by soluble CD4  

Microsoft Academic Search

Primary strains of human immunodeficiency virus type 1 (HIV-1) are known to adapt to replication in cell lines in vitro by becoming sensitive to soluble CD4 (sCD4) and neutralizing antibodies (NAb). T-cell lines favor isolation of variants that use CXCR4 as a co-receptor, while primary isolates predominantly use CCR5. We have now studied how a primary R5 isolate, CC1\\/85, adapts

Pavel Pugach; Shawn E Kuhmann; Joann Taylor; Andre J Marozsan; Amy Snyder; Thomas Ketas; Steven M Wolinsky; Bette T Korber; John P Moore

2004-01-01

83

A simple procedure to generate chimeric Pr55gag virus-like particles expressing the principal neutralization domain of human immunodeficiency virus type  

Microsoft Academic Search

The Pr55gag human immunodeficiency virus type 1 (HIV-1) precursor protein that is capable of auto-assembling was used as a carrier for a consensus sequence of the principal neutralization domain (PND) of the HIV-1 envelope. For this purpose, a modified HTV-1 gag gene with deletion of the sequence encoding a previously described p24 epitope (amino acids 196–228 of Pr55gag) was first

Denys Brand; François Mallet; Catherine Truong; Philippe Roingeard; Alain Goudeau; Francis Barin

1995-01-01

84

Recombinant Modified Vaccinia Virus Ankara Expressing the Surface gp120 of Simian Immunodeficiency Virus (SIV) Primes for a Rapid Neutralizing Antibody Response to SIV Infection in Macaques  

Microsoft Academic Search

Neutralizing antibodies were assessed before and after intravenous challenge with pathogenic SIVsmE660 in rhesus macaques that had been immunized with recombinant modified vaccinia virus Ankara expressing one or more simian immunodeficiency virus gene products (MVA-SIV). Animals received either MVA-gag-pol, MVA-env, MVA-gag-pol-env, or nonrecombinant MVA. Although no animals were completely protected from infection with SIV, animals immunized with recombinant MVA-SIV vaccines

ILNOUR OURMANOV; MIROSLAWA BILSKA; VANESSA M. HIRSCH; DAVID C. MONTEFIORI

2000-01-01

85

Primary Isolates of Human Immunodeficiency Virus Type 1 Are Relatively Resistant to Neutralization by Monoclonal Antibodies to gp120, and Their Neutralization Is Not Predicted by Studies with Monomeric gp120  

Microsoft Academic Search

A panel of anti-gp120 human monoclonal antibodies (HuMAbs), CD4-IgG, and sera from people infected with human immunodeficiency virus type 1 (HIV-1) was tested for neutralization of nine primary HIV-1 isolates, one molecularly cloned primary strain (JR-CSF), and two strains (IIIB and MN) adapted for growth in transformed T-cell lines. All the viruses were grown in mitogen-stimulated peripheral blood mononuclear cellsandweretestedfortheirabilitytoinfectthesecellsinthepresenceandabsenceofthereagentsmentioned

JOHN P. MOORE; YUNZHEN CAO; LIMO QING; QUENTIN J. SATTENTAU; JAYASHREE PYATI; RAJU KODURI; JAMES ROBINSON; CARLOS F. BARBAS; DENNIS R. BURTON; ANDDAVID D. HO; R. W. Johnson

1995-01-01

86

Induction of Mucosal and Systemic Neutralizing Antibodies against Human Immunodeficiency Virus Type 1 (HIV1) by Oral Immunization with Bovine Papillomavirus-HIV1 gp41 Chimeric Virus-Like Particles  

Microsoft Academic Search

Human immunodeficiency virus type 1 (HIV-1) envelope-specific neutralizing antibodies are generated late after initial infection, and the neutralizing antibody response is weak in the infected individuals. Administra- tion of neutralizing antibodies such as 2F5 to HIV-1-infected individuals resulted in reductions in viral loads. Because HIV-1 is transmitted mainly via mucosa and because HIV-specific neutralizing antibodies reduce HIV-1 in infected individuals,

Hongtao Zhang; Yujun Huang; Raja Fayad; Gregory T. Spear; Liang Qiao

2004-01-01

87

Role of Complex Carbohydrates in Human Immunodeficiency Virus Type 1 Infection and Resistance to Antibody Neutralization?  

PubMed Central

Complex N-glycans flank the receptor binding sites of the outer domain of HIV-1 gp120, ostensibly forming a protective “fence” against antibodies. Here, we investigated the effects of rebuilding this fence with smaller glycoforms by expressing HIV-1 pseudovirions from a primary isolate in a human cell line lacking N-acetylglucosamine transferase I (GnTI), the enzyme that initiates the conversion of oligomannose N-glycans into complex N-glycans. Thus, complex glycans, including those that surround the receptor binding sites, are replaced by fully trimmed oligomannose stumps. Conversely, the untrimmed oligomannoses of the silent domain of gp120 are likely to remain unchanged. For comparison, we produced a mutant virus lacking a complex N-glycan of the V3 loop (N301Q). Both variants exhibited increased sensitivities to V3 loop-specific monoclonal antibodies (MAbs) and soluble CD4. The N301Q virus was also sensitive to “nonneutralizing” MAbs targeting the primary and secondary receptor binding sites. Endoglycosidase H treatment resulted in the removal of outer domain glycans from the GnTI- but not the parent Env trimers, and this was associated with a rapid and complete loss in infectivity. Nevertheless, the glycan-depleted trimers could still bind to soluble receptor and coreceptor analogs, suggesting a block in post-receptor binding conformational changes necessary for fusion. Collectively, our data show that the antennae of complex N-glycans serve to protect the V3 loop and CD4 binding site, while N-glycan stems regulate native trimer conformation, such that their removal can lead to global changes in neutralization sensitivity and, in extreme cases, an inability to complete the conformational rearrangements necessary for infection.

Binley, James M.; Ban, Yih-En Andrew; Crooks, Emma T.; Eggink, Dirk; Osawa, Keiko; Schief, William R.; Sanders, Rogier W.

2010-01-01

88

Additive Effects Characterize the Interaction of Antibodies Involved in Neutralization of the Primary Dualtropic Human Immunodeficiency Virus Type 1 Isolate 89.6  

PubMed Central

Human immunodeficiency virus-type I (HIV-1) infection elicits antibodies (Abs) directed against several regions of the gp120 and gp41 envelope glycoproteins. Many of these Abs are able to neutralize T-cell-line-adapted strains (TCLA) of HIV-1, but only a few effectively neutralize primary HIV-1 isolates. The nature of HIV-1 neutralization has been carefully studied using human monoclonal Abs (MAbs), and the ability of such MAbs to act in synergy to neutralize HIV-1 has also been extensively studied. However, most synergy studies have been conducted using TCLA strains. To determine the nature of Ab interaction in HIV-1 primary isolate neutralization, a panel of 12 anti-HIV-1 human immunoglobulin G (IgG) MAbs, specific for epitopes in gp120 and gp41, were used. Initial tests showed that six of these MAbs, as well as sCD4, used individually, were able to neutralize the dualtropic primary isolate HIV-189.6; MAbs giving significant neutralization at 2 to 10 ?g/ml included 2F5 (anti-gp41), 50-69 (anti-gp41), IgG1b12 (anti-gp120CD4bd), 447-52D (anti-gp120V3), 2G12 (anti-gp120), and 670-D (anti-gp120C5). For studies of reagent interaction, 16 binary combinations of reagents were tested for their ability to neutralize HIV-189.6. Reagent combinations tested included one neutralizing MAb with sCD4, six pairs consisting of two neutralizing MAbs, and nine pairs consisting of one neutralizing MAb with another non-neutralizing MAb. To assess the interaction of the latter type of combination, a new mathematical treatment of reagent interaction was developed since previously used methods could be used only when both reagents neutralize. Synergy was noted between sCD4 and a neutralizing anti-gp120V3 MAb. Antagonism was noted between two pairs of anti-gp41 MAbs (one neutralizing and one non-neutralizing). All of the other 13 pairs of MAbs tested displayed only additive effects. These studies suggest that Abs rarely act in synergy to neutralize primary isolate HIV-189.6; many anti-HIV-1 Abs act additively to mediate this biological function.

Verrier, Florence; Nadas, Arthur; Gorny, Miroslaw K.; Zolla-Pazner, Susan

2001-01-01

89

Increased neutralization sensitivity and reduced replicative capacity of human immunodeficiency virus type 1 after short-term in vivo or in vitro passage through chimpanzees.  

PubMed

Development of disease is extremely rare in chimpanzees when inoculated with either T-cell-line-adapted neutralization-sensitive or primary human immunodeficiency virus type 1 (HIV-1), at first excluding a role for HIV-1 neutralization sensitivity in the clinical course of infection. Interestingly, we observed that short-term in vivo and in vitro passage of primary HIV-1 isolates through chimpanzee peripheral blood mononuclear cells (PBMC) resulted in a neutralization-sensitive phenotype. Furthermore, an HIV-1 variant reisolated from a chimpanzee 10 years after experimental infection was still sensitive to neutralization by soluble CD4, the CD4 binding site recognizing antibody IgG1b12 and autologous chimpanzee serum samples, but had become relatively resistant to neutralization by polyclonal human sera and neutralizing monoclonal antibodies. The initial adaptation of HIV-1 to replicate in chimpanzee PBMC seemed to coincide with a selection for viruses with low replicative kinetics. Neither coreceptor usage nor the expression level of CD4, CCR5, or CXCR4 on chimpanzee PBMC compared to human cells could explain the phenotypic changes observed in these chimpanzee-passaged viruses. Our data suggest that the increased neutralization sensitivity of HIV-1 after replication in chimpanzee cells may in part contribute to the long-term asymptomatic HIV-1 infection in experimentally infected chimpanzees. PMID:10933675

Beaumont, T; Broersen, S; van Nuenen, A; Huisman, H G; de Roda Husman, A M; Heeney, J L; Schuitemaker, H

2000-09-01

90

Enhanced Binding of Antibodies to Neutralization Epitopes following Thermal and Chemical Inactivation of Human Immunodeficiency Virus Type 1  

Microsoft Academic Search

Inactivation of viral particles is the basis for several vaccines currently in use. Initial attempts to use simian immunodeficiency virus to model a killed human immunodeficiency virus type 1 (HIV-1) vaccine were unsuc- cessful, and limited subsequent effort has been directed toward a systematic study of the requirements for a protective killed HIV-1 vaccine. Recent insights into HIV-1 virion and

K. Grovit-Ferbas; J. F. Hsu; J. Ferbas; V. Gudeman; I. S. Y. Chen

2000-01-01

91

Human Immunodeficiency Virus Type 1 Neutralization Epitope with Conserved Architecture Elicits Early Type-Specific Antibodies in Experimentally Infected Chimpanzees  

Microsoft Academic Search

Chimpanzees are susceptible to infection by divergent strains of human immunodeficiency virus type 1 (HIV-1), none of which cause clinical or immunological abnormalities. Chimpanzees were inoculated with one of four strains of HIV-1: human T-lymphotropic virus (HTLV) type IIIB, lymphadenopathy virus (LAV) type 1, HTLV type IIIRF, or an isolate from the brain of a patient with acquired immunodeficiency syndrome.

Jaap Goudsmit; Christine Debouck; Rob H. Meloen; Lia Smit; Margreet Bakker; David M. Asher; Axel V. Wolff; Clarence J. Gibbs; D. Carleton Gajdusek

1988-01-01

92

Envelope Glycoprotein Determinants of Neutralization Resistance in a Simian-Human Immunodeficiency Virus (SHIV-HXBc2P 3.2) Derived by Passage in Monkeys  

PubMed Central

The simian-human immunodeficiency virus SHIV-HXBc2 contains the envelope glycoproteins of a laboratory-adapted, neutralization-sensitive human immunodeficiency virus type 1 variant, HXBc2. Serial in vivo passage of the nonpathogenic SHIV-HXBc2 generated SHIV KU-1, which causes rapid CD4+ T-cell depletion and an AIDS-like illness in monkeys. A molecularly cloned pathogenic SHIV, SHIV-HXBc2P 3.2, was derived from the SHIV KU-1 isolate and differs from the parental SHIV-HXBc2 by only 12 envelope glycoprotein amino acid residues. Relative to SHIV-HXBc2, SHIV-HXBc2P 3.2 was resistant to neutralization by all of the antibodies tested with the exception of the 2G12 antibody. The sequence changes responsible for neutralization resistance were located in variable regions of the gp120 exterior envelope glycoprotein and in the gp41 transmembrane envelope glycoprotein. The 2G12 antibody, which neutralized SHIV-HXBc2 and SHIV-HXBc2P 3.2 equally, bound the HXBc2 and HXBc2P 3.2 envelope glycoproteins on the cell surface comparably. The ability of the other tested antibodies to achieve saturation was less for the HXBc2P 3.2 envelope glycoproteins than for the HXBc2 envelope glycoproteins, even though the affinity of the antibodies for the two envelope glycoproteins was similar. Thus, a highly neutralization-sensitive SHIV, by modifying both gp120 and gp41 glycoproteins, apparently achieves a neutralization-resistant state by decreasing the saturability of its envelope glycoproteins by antibodies.

Si, Zhihai; Cayabyab, Mark; Sodroski, Joseph

2001-01-01

93

Neutralizing Antibodies from the Sera of Human Immunodeficiency Virus Type 1-Infected Individuals Bind to Monomeric gp120 and Oligomeric gp140  

PubMed Central

Antibodies that neutralize primary isolates of human immunodeficiency virus type 1 (HIV-1) appear during HIV-1 infection but are difficult to elicit by immunization with current vaccine products comprised of monomeric forms of HIV-1 envelope glycoprotein gp120. The limited neutralizing antibody response generated by gp120 vaccine products could be due to the absence or inaccessibility of the relevant epitopes. To determine whether neutralizing antibodies from HIV-1-infected patients bind to epitopes accessible on monomeric gp120 and/or oligomeric gp140 (ogp140), purified total immunoglobulin from the sera of two HIV-1-infected patients as well as pooled HIV immune globulin were selectively depleted of antibodies which bound to immobilized gp120 or ogp140. After passage of each immunoglobulin preparation through the respective columns, antibody titers against gp120 and ogp140 were specifically reduced at least 128-fold. The gp120- and gp140-depleted antibody fraction from each serum displayed reduced neutralization activity against three primary and two T-cell line-adapted (TCLA) HIV-1 isolates. Significant residual neutralizing activity, however, persisted in the depleted sera, indicating additional neutralizing antibody specificities. gp120- and ogp140-specific antibodies eluted from each column neutralized both primary and TCLA viruses. These data demonstrate the presence and accessibility of epitopes on both monomeric gp120 and ogp140 that are specific for antibodies that are capable of neutralizing primary isolates of HIV-1. Thus, the difficulties associated with eliciting neutralizing antibodies by using current monomeric gp120 subunit vaccines may be related less to improper protein structure and more to ineffective immunogen formulation and/or presentation.

Stamatos, Nicholas M.; Mascola, John R.; Kalyanaraman, Vaniambadi S.; Louder, Mark K.; Frampton, Lynn M.; Birx, Deborah L.; VanCott, Thomas C.

1998-01-01

94

Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian–human immunodeficiency virus infection  

Microsoft Academic Search

Although maternal human immunodeficiency virus type 1 (HIV-1) transmission occurs during gestation, intrapartum and postpartum (by breast-feeding), 50–70% of all infected children seem to acquire HIV-1 shortly before or during delivery. Epidemiological evidence indicates that mucosal exposure is an important aspect of intrapartum HIV transmission. A simian immunodeficiency virus (SIV) macaque model has been developed that mimics the mucosal exposure

Timothy W. Baba; Vladimir Liska; Regina Hofmann-Lehmann; Josef Vlasak; Weidong Xu; Seyoum Ayehunie; Lisa A. Cavacini; Marshall R. Posner; Hermann Katinger; Gabriela Stiegler; Bruce J. Bernacky; Tahir A. Rizvi; Russell Schmidt; Lori R. Hill; Michale E. Keeling; Yichen Lu; Joel E. Wright; Ting-Chao Chou; Ruth M. Ruprecht

2000-01-01

95

Polyclonal Immunoglobulin G from Patients Neutralizes Human Immunodeficiency Virus Type 1 Primary Isolates by Binding Free Virions, but without Interfering with an Initial CD4Independent Attachment of the Virus to Primary Blood Mononuclear Cells  

Microsoft Academic Search

We investigated the relationship between human immunodeficiency virus type 1 (HIV-1) primary isolate (PI) antibody-mediated neutralization and attachment to primary blood mononuclear cells (PBMC). Incubation of PIs with immunoglobulin G (IgG) purified from infected patients did not inhibit attachment of the viruses with PBMC, but partial to complete neutralization was achieved. Neutralization of PIs already fixed on the cells was

Renaud Burrer; Sandrine Haessig-Einius; Anne-Marie Aubertin; Christiane Moog

2003-01-01

96

Human antibodies that neutralize primary human immunodeficiency virus type 1 in vitro do not provide protection in an in vivo model.  

PubMed

Recently, conflicting data have been published about the ability of antibodies which efficiently neutralize T cell-adapted human immunodeficiency virus type 1 (HIV-1) strains to neutralize primary HIV-1 strains in vitro and in vivo. Here we present data indicating that such antibodies fail to neutralize primary HIV-1 strains in vivo. To this end, a newly developed chimeric human-to-mouse model was used, in which several aspects of primary HIV-1 infection are mimicked. Poly- and monoclonal antibodies protected the grafted human cells, in a dose-dependent way, from infection with T cell-adapted HIV-1 in this system. A human monoclonal antibody specific for the CD4 binding domain that efficiently neutralizes HIV-1 IIIB in vitro did not protect the human graft from HIV-1 IIIB infection. None of the antibodies provided protection in the in vivo model against infection with primary HIV-1 strains, although they were able to neutralize these same strains in vitro. PMID:8760413

Schutten, M; Tenner-Racz, K; Racz, P; van Bekkum, D W; Osterhaus, A D

1996-08-01

97

The Membrane-Proximal External Region of the Human Immunodeficiency Virus Type 1 Envelope: Dominant Site of Antibody Neutralization and Target for Vaccine Design  

PubMed Central

Summary: Enormous efforts have been made to produce a protective vaccine against human immunodeficiency virus type 1; there has been little success. However, the identification of broadly neutralizing antibodies against epitopes on the highly conserved membrane-proximal external region (MPER) of the gp41 envelope protein has delineated this region as an attractive vaccine target. Furthermore, emerging structural information on the MPER has provided vaccine designers with new insights for building relevant immunogens. This review describes the current state of the field regarding (i) the structure and function of the gp41 MPER; (ii) the structure and binding mechanisms of the broadly neutralizing antibodies 2F5, 4E10, and Z13; and (iii) the development of an MPER-targeting vaccine. In addition, emerging approaches to vaccine design are presented.

Montero, Marinieve; van Houten, Nienke E.; Wang, Xin; Scott, Jamie K.

2008-01-01

98

Replication and neutralization of human immunodeficiency virus type 1 lacking the V1 and V2 variable loops of the gp120 envelope glycoprotein.  

PubMed Central

A human immunodeficiency virus type 1 (HIV-1) mutant lacking the V1 and V2 variable loops in the gp120 exterior envelope glycoprotein replicated in Jurkat lymphocytes with only modest delays compared with the wild-type virus. Revertants that replicated with wild-type efficiency rapidly emerged and contained only a few amino acid changes in the envelope glycoproteins compared with the parent virus. Both the parent and revertant viruses exhibited increased sensitivity to neutralization by antibodies directed against the V3 loop or a CD4-induced epitope on gp120 but not by soluble CD4 or an antibody against the CD4 binding site. This result demonstrates the role of the gp120 V1 and V2 loops in protecting HIV-1 from some subsets of neutralizing antibodies.

Cao, J; Sullivan, N; Desjardin, E; Parolin, C; Robinson, J; Wyatt, R; Sodroski, J

1997-01-01

99

21 CFR 660.50 - Anti-Human Globulin.  

Code of Federal Regulations, 2011 CFR

...DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR LABORATORY TESTS Anti-Human Globulin § 660.50 Anti-Human Globulin. (a) Proper name and definition. The proper name...

2011-04-01

100

Human immunodeficiency virus type 1 neutralizing antibodies accelerate clearance of cell–free virions from blood plasma  

Microsoft Academic Search

The concentration of human immunodeficiency virus type 1 (HIV–1) particles in blood plasma is very predictive of the subsequent disease course in an infected individual; its measurement has become one of the most important parameters for monitoring clinical status. Steady–state virus levels in plasma reflect a balance between the rates of virions entering and leaving the peripheral blood. We analyzed

Tatsuhiko Igarashi; Charles Brown; Ali Azadegan; Nancy Haigwood; Dimiter Dimitrov; Malcolm A. Martin; Riri Shibata

1999-01-01

101

Virion-bound ICAM-1 and activated LFA-1: a combination of factors conferring resistance to neutralization by sera from human immunodeficiency virus type 1-infected individuals independently of the disease status and phase  

Microsoft Academic Search

The role of the supplementary interaction between virion-bound host ICAM-1 and LFA-1 on target cells in sensitivity to neutralization of human immunodeficiency virus type 1 (HIV-1) is poorly studied. Serum samples from four long-term nonprogressors (LTNPs) and sequential sera from one progressor were used to assess neutralization sensitivity of isogenic ICAM-1-negative and ICAM-1-bearing HIV-1NL4-3, a prototype of T-cell-line-adapted viruses. We

Martine Losier; Jean-Francois Fortin; Rejean Cantin; Michel G. Bergeron; Michel J. Tremblaya

102

The Ability of an Oligomeric Human Immunodeficiency Virus Type 1 (HIV1) Envelope Antigen To Elicit Neutralizing Antibodies against Primary HIV1 Isolates Is Improved following Partial Deletion of the Second Hypervariable Region  

Microsoft Academic Search

Partial deletion of the second hypervariable region from the envelope of the primary-like SF162 virus increases the exposure of certain neutralization epitopes and renders the virus, SF162DV2, highly susceptible to neutralization by clade B and non-clade B human immunodeficiency virus (HIV-positive) sera (L. Stama- tatos and C. Cheng-Mayer, J. Virol. 78:7840-7845, 1998). This observation led us to propose that the

S. W. Barnett; S. Lu; I. Srivastava; S. Cherpelis; A. Gettie; J. Blanchard; S. Wang; I. Mboudjeka; L. Leung; Y. Lian; A. Fong; C. Buckner; A. Ly; S. Hilt; J. Ulmer; C. T. Wild; J. R. Mascola; L. Stamatatos

2001-01-01

103

Enhanced Exposure of the CD4-Binding Site to Neutralizing Antibodies by Structural Design of a Membrane-Anchored Human Immunodeficiency Virus Type 1 gp120 Domain?  

PubMed Central

The broadly neutralizing antibody immunoglobulin G1 (IgG1) b12 binds to a conformationally conserved surface on the outer domain of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope (Env) glycoprotein. To develop outer domain proteins (ODs) that could be recognized selectively by CD4-binding-site (CD4-BS) antibodies, membrane-anchored ODs were generated from an HIV-1 clade B virus, TA1 R3A, which was highly sensitive to neutralization by the IgG1 b12 antibody. A 231-residue fragment of gp120 (residues 252 to 482) linked to transmembrane regions from CD4 showed b12 binding comparable to that of the native Env spike as measured by flow cytometry. Truncation of the ?20-?21 hairpin (residues 422 to 436 to Gly-Gly) improved overall protein expression. Replacement of the immunodominant central 20 amino acids of the V3 loop (residues 302 to 323) with a basic hexapeptide (NTRGRR) increased b12 reactivity further. Surface calculations indicated that the ratio of b12 epitope to exposed immunogenic surface in the optimized OD increased to over 30%. This OD variant [OD(GSL)(??20-21)(hCD4-TM)] was recognized by b12 and another CD4-BS-reactive antibody, b13, but not by eight other CD4-BS antibodies with limited neutralization potency. Furthermore, optimized membrane-anchored OD selectively absorbed neutralizing activity from complex antisera and b12. Structurally designed membrane-anchored ODs represent candidate immunogens to elicit or to allow the detection of broadly neutralizing antibodies to the conserved site of CD4 binding on HIV-1 gp120.

Wu, Lan; Zhou, Tongqing; Yang, Zhi-yong; Svehla, Krisha; O'Dell, Sijy; Louder, Mark K.; Xu, Ling; Mascola, John R.; Burton, Dennis R.; Hoxie, James A.; Doms, Robert W.; Kwong, Peter D.; Nabel, Gary J.

2009-01-01

104

Cross-Subtype Neutralizing Antibodies Induced in Baboons by a Subtype E gp120 Immunogen Based on an R5 Primary Human Immunodeficiency Virus Type 1 Envelope  

PubMed Central

Global human immunodeficiency virus type 1 (HIV-1) diversity may require engineering vaccines to express antigens representing strains prevalent in the target population of vaccine testing. The majority (90%) of incident infections in Thailand are genetic subtype E, with a small percentage of subtype B infections in the intravenous drug user populations. We have evaluated and compared the binding and HIV-1 neutralizing properties of serum antibodies induced in baboons by CHO cell-expressed monomeric gp120 derived from a CCR5-using (R5) subtype E primary HIV-1CM235 or a CXCR4-using (X4) subtype B T-cell line-adapted (TCLA) HIV-1SF2 isolate. In contrast to the subtype-specific HIV-1 neutralizing antibodies induced with recombinant HIV-1SF2 gp120 (rgp120SF2), rgp120CM235 immunization induced antibodies capable of neutralizing both subtype E and subtype B TCLA HIV-1 isolates. However, neither immunogen induced antibodies capable of neutralizing primary HIV-1 isolates. Antibody induced by rgp120CM235 preferentially bound natively folded gp120 and retained strong cross-reactivity against multiple gp120 strains within subtype E as well as subtype B. In contrast, antibody responses to rgp120SF2 were directed predominantly to linear epitopes poorly exposed on native gp120 and had more limited cross-recognition of divergent gp120. Fine epitope mapping revealed differences in antibody specificities. While both rgp120CM235 and rgp120SF2 induced antibodies to regions within C1, V1/V2, V3, and C5, unique responses were induced by rgp120CM235 to multiple epitopes within C2 and by rgp120SF2 to multiple epitopes within C3, V4, and C4. These data demonstrate that strain and/or phenotypic differences of HIV-1 subunit gp120 immunogens can substantially alter antibody binding specificities and subsequent HIV-1 neutralizing capacity.

VanCott, Thomas C.; Mascola, John R.; Loomis-Price, Lawrence D.; Sinangil, Faruk; Zitomersky, Naamah; McNeil, John; Robb, Merlin L.; Birx, Deborah L.; Barnett, Susan

1999-01-01

105

Envelope variable region 4 is the first target of neutralizing antibodies in early simian immunodeficiency virus mac251 infection of rhesus monkeys.  

PubMed

A major goal of AIDS vaccine development is to design vaccination strategies that can elicit broad and potent protective antibodies. The initial viral targets of neutralizing antibodies (NAbs) early after human or simian immunodeficiency virus (HIV/SIV) infection are not known. The identification of early NAb epitopes that induce protective immunity or retard the progression of disease is important for AIDS vaccine development. The aim of this study was to determine the Env residues targeted by early SIV NAbs and to assess the influence of prior vaccination on neutralizing antibody kinetics and specificity during early infection. We previously described stereotypic env sequence variations in SIVmac251-infected rhesus monkeys that resulted in viral escape from NAbs. Here, we defined the early viral targets of neutralization and determined whether the ability of serum antibody from infected monkeys to neutralize SIV was altered in the setting of prior vaccination. To localize the viral determinants recognized by early NAbs, a panel of mutant pseudoviruses was assessed in a TZM-bl reporter gene neutralization assay to define the precise changes that eliminate recognition by SIV Env-specific NAbs in 16 rhesus monkeys. Changing R420 to G or R424 to Q in V4 of Env resulted in the loss of recognition by NAbs in vaccinated monkeys. In contrast, mutations in the V1 region of Env did not alter the NAb profile. These findings indicate that early NAbs are directed toward SIVmac251 Env V4 but not the V1 region, and that this env vaccination regimen did not alter the kinetics or the breadth of NAbs during early infection. PMID:22532675

Yeh, Wendy W; Brassard, Laura M; Miller, Caroline A; Basavapathruni, Aravind; Zhang, Jinrong; Rao, Srinivas S; Nabel, Gary J; Mascola, John R; Letvin, Norman L; Seaman, Michael S

2012-07-01

106

Glycosylation inhibitors and neuraminidase enhance human immunodeficiency virus type 1 binding and neutralization by mannose-binding lectin  

Microsoft Academic Search

Mannose-binding lectin (MBL), a C-type lectin component of the human innate immune system, binds to the gp120 envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1). The objective of this studywas to assessthe effects of inhibitors of endoplasmic reticulum glucosidases and Golgi mannosidase as well as neuraminidase (NA) on the interaction between HIV and MBL. Production of HIV in the

Melanie L. Hart; Mohammed Saifuddin; Gregory T. Spear

2003-01-01

107

Modeling how many envelope glycoprotein trimers per virion participate in human immunodeficiency virus infectivity and its neutralization by antibody  

Microsoft Academic Search

Trimers of the HIV-1 envelope glycoprotein (Env) effectuate viral entry into susceptible cells. Therefore Env trimers are the targets for neutralizing antibodies. This study models the number of trimers required for virion infectivity. It also delineates the minimum number of antibody molecules that would neutralize a virion. First, Env function was assumed to be incremental (all envelope glycoprotein units contribute

Per Johan Klasse

2007-01-01

108

Highly efficient neutralization by plasma antibodies from human immunodeficiency virus type-1 infected individuals on antiretroviral drug therapy.  

PubMed

Little is known about the neutralizing antibodies induced in HIV-1 patients on antiretroviral treatment, which constitute an interesting group of individuals with improved B cell profile. Plasma samples from 34 HIV-1 seropositive antiretroviral drug treated (ART) patients were tested for neutralization against a panel of 14 subtype-A, B and C tier 1 and tier 2 viruses in TZM-bl assay. Of the 34 plasma samples, remarkably all the plasma samples were able to neutralize at least one virus while 32 (94 %) were found to neutralize ?50 % viruses tested. In terms of overall neutralization frequency, approximately 86 %, 68 % and 17 % of the virus/plasma combinations showed 50 % neutralizing activity at 1?>?60, 1???200 and 1???2000 dilutions respectively. The improvement in neutralizing activity was shown to be associated with ART in two follow up patients. The neutralization of viruses by two representative plasma samples, AIIMS221 and AIIMS265, was exclusively mediated by immunoglobulin G fractions independent of ART drugs and IgG retained cross-reactive binding to recombinant gp120 proteins. We observed a positive trend of neutralization with duration of ART (p?=?0.06), however no such correlation was found with clinical and immunological variables like CD4 count (p?=?0.35), viral load (p?=?0.09) and plasma total IgG (p?=?0.46). Our study suggests that the plasma antibodies from ART patients display high neutralizing activity most likely due to an improved B cell function induced by ART despite low antigenic stimulation. PMID:24682667

Andrabi, Raiees; Makhdoomi, M A; Kumar, Rajesh; Bala, Manju; Parray, Hilal; Gupta, Arjun; Kotnala, Ankita; Thirumurthy, Velpandian; Luthra, Kalpana

2014-05-01

109

Development of a tier 1 R5 clade C simian-human immunodeficiency virus as a tool to test neutralizing antibody-based immunoprophylaxis  

PubMed Central

Background While some recently transmitted HIV clade C (HIV-C) strains exhibited tier 1 neutralization phenotypes, most were tier 2 strains (J Virol 2010; 84:1439). Because induction of neutralizing antibodies (nAbs) through vaccination against tier 2 viruses has proven difficult, we have generated a tier 1, clade C simian–human immunodeficiency virus (SHIV-C) to permit efficacy testing of candidate AIDS vaccines against tier 1 viruses. Methods SHIV-1157ipEL was created by swapping env of a late-stage virus with that of a tier 1, early form. Results After adaptation to rhesus macaques (RM), passaged SHIV-1157ipEL-p replicated vigorously in vitro and in vivo while maintaining R5 tropism. The virus was reproducibly transmissible intrarectally. Phylogenetically, SHIV-1157ipEL-p Env clustered with HIV-C sequences. All RM chronically infected with SHIV-1157ipEL-p developed high nAb titers against autologous as well as heterologous tier 1 strains. Conclusions SHIV-1157ipEL-p was reproducibly transmitted in RM, induced cross-clade nAbs, and represents a tool to evaluate anti-HIV-C nAb responses in primates.

Siddappa, Nagadenahalli B.; Hemashettar, Girish; Wong, Yin Ling; Lakhashe, Samir; Rasmussen, Robert A.; Watkins, Jennifer D.; Novembre, Francis J.; Villinger, Francois; Else, James G.; Montefiori, David C.; Ruprecht, Ruth M.

2012-01-01

110

Neutralization of the human immunodeficiency virus type 1 primary isolate JR-FL by human monoclonal antibodies correlates with antibody binding to the oligomeric form of the envelope glycoprotein complex.  

PubMed Central

To test whether antibodies that are neutralizing or nonneutralizing for human immunodeficiency virus type 1 (HIV-1) primary isolates can be distinguished by their affinities for the oligomeric envelope glycoproteins, we selected HIV-1(JR-FL) as a model primary virus and a panel of 13 human monoclonal antibodies (MAbs) and evaluated three parameters: (i) half-maximal binding to recombinant monomeric envelope, gp120(JR-FL); (ii) half-maximal binding to oligomeric envelope of HIV-1(JR-FL) expressed on the surface of transfected 293 cells; and (iii) neutralization of HIV-1(JR-FL) in a peripheral blood mononuclear cell-based neutralization assay. Two conclusions can be drawn from these experiments. First, we confirm that antibody interactions with monomeric gp120 do not predict primary virus neutralization. Second, we show that neutralization correlates qualitatively with the relative affinity of an antibody for the oligomeric envelope glycoproteins, at least for HIV-1(JR-FL).

Fouts, T R; Binley, J M; Trkola, A; Robinson, J E; Moore, J P

1997-01-01

111

Human immunodeficiency virus 1. Predominance of a group-specific neutralizing epitope that persists despite genetic variation  

PubMed Central

HIV-1 is known to show a high degree of genetic diversity, which may have major implications for disease pathogenesis and prevention. If every divergent isolate represented a distinct serotype, then effective vaccination might be impossible. However, using a sensitive new plaque- forming assay for HIV-1, we have found that most infected patients make neutralizing antibodies, predominantly to a group-specific epitope shared among three highly divergent isolates. This epitope persists among divergent isolates and rarely mutates, despite the rapid overall mutation rate of HIV-1, suggesting that it may participate in an essential viral function. These findings, plus the rarity of reinfections among these patients, suggest that HIV-1 may be more susceptible to a vaccine strategy based on a group-specific neutralizing epitope than was previously suspected.

1989-01-01

112

Evolution of the human immunodeficiency virus type 2 envelope in the first years of infection is associated with the dynamics of the neutralizing antibody response  

PubMed Central

Background Differently from HIV-1, HIV-2 disease progression usually takes decades without antiretroviral therapy and the majority of HIV-2 infected individuals survive as elite controllers with normal CD4+ T cell counts and low or undetectable plasma viral load. Neutralizing antibodies (Nabs) are thought to play a central role in HIV-2 evolution and pathogenesis. However, the dynamic of the Nab response and resulting HIV-2 escape during acute infection and their impact in HIV-2 evolution and disease progression remain largely unknown. Our objective was to characterize the Nab response and the molecular and phenotypic evolution of HIV-2 in association with Nab escape in the first years of infection in two children infected at birth. Results CD4+ T cells decreased from about 50% to below 30% in both children in the first five years of infection and the infecting R5 viruses were replaced by X4 viruses within the same period. With antiretroviral therapy, viral load in child 1 decreased to undetectable levels and CD4+ T cells recovered to normal levels, which have been sustained at least until the age of 12. In contrast, viral load increased in child 2 and she progressed to AIDS and death at age 9. Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous. Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed. Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2. Rates of R5-to-X4 tropism switch, of V1 and V3 sequence diversification, and of convergence of V3 to a ?-hairpin structure were related with rate of escape from the neutralizing antibodies. Conclusion Our data suggests that the molecular and phenotypic evolution of the human immunodeficiency virus type 2 envelope are related with the dynamics of the neutralizing antibody response providing further support for a model in which Nabs play an important role in HIV-2 pathogenesis.

2013-01-01

113

Neutralization of the Human Immunodeficiency Virus Type 1 Primary Isolate JR-FL by Human Monoclonal Antibodies Correlates with Antibody Binding to the Oligomeric Form of the Envelope Glycoprotein Complex  

Microsoft Academic Search

To test whether antibodies that are neutralizing or nonneutralizing for human immunodeficiency virus type 1(HIV-1)primaryisolatescanbedistinguishedbytheiraffinitiesfortheoligomericenvelopeglycoproteins,we selected HIV-1JR-FL as a model primary virus and a panel of 13 human monoclonal antibodies (MAbs) and evaluated three parameters: (i) half-maximal binding to recombinant monomeric envelope, gp120JR-FL; (ii) half-maximal binding to oligomeric envelope of HIV-1JR-FLexpressed on the surface of transfected 293 cells; and (iii)

TIMOTHY R. FOUTS; JAMES M. BINLEY; ALEXANDRA TRKOLA; JAMES E. ROBINSON

114

Modeling how many envelope glycoprotein trimers per virion participate in human immunodeficiency virus infectivity and its neutralization by antibody.  

PubMed

Trimers of the HIV-1 envelope glycoprotein (Env) effectuate viral entry into susceptible cells. Therefore Env trimers are the targets for neutralizing antibodies. This study models the number of trimers required for virion infectivity. It also delineates the minimum number of antibody molecules that would neutralize a virion. First, Env function was assumed to be incremental (all envelope glycoprotein units contribute equally) or liminal (characterized by thresholds). Then, such models were combined and shown to fit published data on phenotypically mixed pseudotype viruses. Virions with 9 trimers would require around a median of 5 of them for strong infectivity; the proportion varies among strains and mutants. In addition, the models account for both liminal and incremental protomeric effects at the trimer level: different inert Env mutants may affect trimer function in different degrees. Because of compensatory effects at the virion and trimer levels, however, current data cannot differentiate between all plausible models. But the biophysically and mathematically rationalized blurring of thresholds yields candidate models that fit different data excellently. PMID:17825343

Klasse, Per Johan

2007-12-20

115

Three-dimensional structure and antigenicity of transmembrane-protein peptides of the human immunodeficiency virus type 1. Effects of a neutralization-escape substitution.  

PubMed

A point mutation (Ala-589 to Thr) in the transmembrane protein of the human immunodeficiency virus type 1 (HIV-1) has been shown to decrease the sensitivity of the virus to the neutralizing effect of human HIV-1 specific antibodies [(1990) J. Virol. 64, 3240-3248]. Here 17-residue peptides with the parental and mutant sequences were compared: the parental peptide bound antibodies of sera from HIV-1 infected persons more frequently and with higher affinity than the mutant peptide. However, according to circular dichroism (CD), NMR spectroscopy and molecular modelling the peptides have indistinguishable backbone conformations under a variety of experimental conditions. These techniques showed for both peptides that no ordered helix was present in water solution. However, for both peptides in alcohol-water solutions approximately 60% alpha-helix could be induced. The three-dimensional structures of these peptides provide a basis for understanding how this mutation in the transmembrane protein may affect the interaction with both the outer envelope glycoprotein and with antibodies. PMID:8495750

Klasse, J; Pipkorn, R; Blomberg, J; Han, K H; Hilton, B; Ferretti, J A

1993-05-24

116

Interclade neutralization and enhancement of human immunodeficiency virus type 1 identified by an assay using HeLa cells expressing both CD4 receptor and CXCR4/CCR5 coreceptors.  

PubMed

We report on the development and evaluation of a human immunodeficiency virus (HIV) neutralization assay that uses P4P cells, which are CD4+CXCR4+CCR5+ HeLa cells that carry the lacZ gene under the control of the HIV-1 long terminal repeat. The results of the present study suggest that the P4P assay can be used for the extensive study of both neutralizing and enhancing activity in serum samples from HIV-1-infected patients and from vaccinated individuals. PMID:14722898

Barin, Francis; Brunet, Sylvie; Brand, Denys; Moog, Christiane; Peyre, Robert; Damond, Florence; Charneau, Pierre; Barre-Sinoussi, Françoise

2004-01-15

117

CD4-Induced Conformational Changes in the Human Immunodeficiency Virus Type 1 gp120 Glycoprotein: Consequences for Virus Entry and Neutralization  

PubMed Central

Human immunodeficiency virus type 1 (HIV-1) entry into target cells involves sequential binding of the gp120 exterior envelope glycoprotein to CD4 and to specific chemokine receptors. Soluble CD4 (sCD4) is thought to mimic membrane-anchored CD4, and its binding alters the conformation of the HIV-1 envelope glycoproteins. Two cross-competing monoclonal antibodies, 17b and CG10, that recognize CD4-inducible gp120 epitopes and that block gp120-chemokine receptor binding were used to investigate the nature and functional significance of gp120 conformational changes initiated by CD4 binding. Envelope glycoproteins derived from both T-cell line-adapted and primary HIV-1 isolates exhibited increased binding of the 17b antibody in the presence of sCD4. CD4-induced exposure of the 17b epitope on the oligomeric envelope glycoprotein complex occurred over a wide range of temperatures and involved movement of the gp120 V1/V2 variable loops. Amino acid changes that reduced the efficiency of 17b epitope exposure following CD4 binding invariably compromised the ability of the HIV-1 envelope glycoproteins to form syncytia or to support virus entry. Comparison of the CD4 dependence and neutralization efficiencies of the 17b and CG10 antibodies suggested that the epitopes for these antibodies are minimally accessible following attachment of gp120 to cell surface CD4. These results underscore the functional importance of these CD4-induced changes in gp120 conformation and illustrate viral strategies for sequestering chemokine receptor-binding regions from the humoral immune response.

Sullivan, Nancy; Sun, Ying; Sattentau, Quentin; Thali, Markus; Wu, Dona; Denisova, Galina; Gershoni, Jonathan; Robinson, James; Moore, John; Sodroski, Joseph

1998-01-01

118

Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12.  

PubMed Central

Three antibody reagents that neutralize primary human immunodeficiency virus type 1 (HIV-1) isolates were tested for magnitude and breadth of neutralization when used alone or in double or triple combinations. Hyperimmune anti-HIV immunoglobulin (HIVIG) is derived from the plasma of HIV-1-infected donors, and monoclonal antibodies (MAbs) 2F5 and 2G12 bind to distinct regions of the HIV-1 envelope glycoprotein. The antibodies were initially tested against a panel of 15 clade B HIV-1 isolates, using a single concentration that is achievable in vivo (HIVIG, 2,500 microg/ml; MAbs, 25 microg/ml). Individual antibody reagents neutralized many of the viruses tested, but antibody potency varied substantially among the viruses. The virus neutralization produced by double combinations of HIVIG plus 2F5 or 2G12, the two MAbs together, or the triple combination of HIVIG, 2F5, and 2G12 was generally equal to or greater than that predicted by the effect of individual antibodies. Overall, the triple combination displayed the greatest magnitude and breadth of neutralization. Synergistic neutralization was evaluated by analyzing data from dose-response curves of each individual antibody reagent compared to the triple combination and was demonstrated against each of four viruses tested. Therefore, combinations of polyclonal and monoclonal anti-HIV antibodies can produce additive or synergistic neutralization of primary HIV-1 isolates. Passive immunotherapy for treatment or prophylaxis of HIV-1 should consider mixtures of potent neutralizing antibody reagents to expand the magnitude and breadth of virus neutralization.

Mascola, J R; Louder, M K; VanCott, T C; Sapan, C V; Lambert, J S; Muenz, L R; Bunow, B; Birx, D L; Robb, M L

1997-01-01

119

21 CFR 660.50 - Anti-Human Globulin.  

Code of Federal Regulations, 2010 CFR

...proper name of this product shall be Anti-Human Globulin which shall consist of one or more... The source of this product shall be either serum from animals immunized with one or more human serum globulins or protein-rich fluids...

2010-04-01

120

21 CFR 660.50 - Anti-Human Globulin.  

Code of Federal Regulations, 2010 CFR

...proper name of this product shall be Anti-Human Globulin which shall consist of one or more... The source of this product shall be either serum from animals immunized with one or more human serum globulins or protein-rich fluids...

2009-04-01

121

Cross-Subtype Neutralizing Antibodies Induced in Baboons by a Subtype E gp120 Immunogen Based on an R5 Primary Human Immunodeficiency Virus Type 1 Envelope  

Microsoft Academic Search

Global human immunodeficiency virus type 1 (HIV-1) diversity may require engineering vaccines to express antigens representing strains prevalent in the target population of vaccine testing. The majority (90%) of inci- dent infections in Thailand are genetic subtype E, with a small percentage of subtype B infections in the intra- venous drug user populations. We have evaluated and compared the binding

THOMAS C. VANCOTT; JOHN R. MASCOLA; LAWRENCE D. LOOMIS-PRICE; FARUK SINANGIL; NAAMAH ZITOMERSKY; JOHN MCNEIL; MERLIN L. ROBB; DEBORAH L. BIRX; SUSAN BARNETT

1999-01-01

122

Human Rhinovirus Type 14:Human Immunodeficiency Virus Type 1 (HIV1) V3 Loop Chimeras from a Combinatorial Library Induce Potent Neutralizing Antibody Responses against HIV1  

Microsoft Academic Search

In an effort to develop a useful AIDS vaccine or vaccine component, we have generated a combinatorial library of chimeric viruses in which the sequence IGPGRAFYTTKN from the V3 loop of the MN strain of human immunodeficiency virus type 1 (HIV-1) is displayed in many conformations on the surface of human rhinovirus 14 (HRV14). The V3 loop sequence was inserted

ALLEN D. SMITH; SHEILA C. GEISLER; ANNE A. CHEN; DAWN A. RESNICK; BIRGIT M. ROY; PAUL J. LEWI; EDWARD ARNOLD; GAIL FERSTANDIG ARNOLD

1998-01-01

123

Formaldehyde-Treated, Heat-Inactivated Virions with Increased Human Immunodeficiency Virus Type 1 Env Can Be Used To Induce High-Titer Neutralizing Antibody Responses  

Microsoft Academic Search

Received 3 January 2005\\/Accepted 4 May 2005 The lack of success of subunit human immunodeficiency virus (HIV) type 1 vaccines to date suggests that multiple components or a complex virion structure may be required. We hypothesized that the failure of current vaccine strategies to induce protective antibodies is linked to the inability of native envelope structures to readily elicit these

B. Poon; J. F. Hsu; V. Gudeman; I. S. Y. Chen; K. Grovit-Ferbas

2005-01-01

124

Envelope Variants from Women Recently Infected with Clade A Human Immunodeficiency Virus Type 1 Confer Distinct Phenotypes That Are Discerned by Competition and Neutralization Experiments  

Microsoft Academic Search

Women infected with clade A human immunodeficiency virus type 1 harbor a virus population that is genetically diverse in the envelope gene, a fact that contrasts with the homogeneous virus population identified in newly infected men. It is not known whether viral genetic diversity at this early stage of infection is manifested as phenotypic diversity. This is a significant question

Sally L. Painter; Roman Biek; David C. Holley; Mary Poss

2003-01-01

125

Induction of Neutralizing Antibodies to T-Cell Line-Adapted and Primary Human Immunodeficiency Virus Type 1 Isolates with a Prime-Boost Vaccine Regimen in Chimpanzees  

Microsoft Academic Search

Five chimpanzees were immunized by administration of one or more intranasal priming doses of one to three recombinant adenoviruses containing a gp160 insert from human immunodeficiency virus type 1 (HIV-1) MN (HIV-1MN) followed by one or more boosts of recombinant HIV-1SF2 gp120 delivered intramuscularly with MF59 adjuvant. This regimen resulted in humoral immune responses in three of five animals. Humoral

SUSAN ZOLLA-PAZNER; MICHAEL LUBECK; SERENA XU; SHERRI BURDA; ROBERT J. NATUK; FARUK SINANGIL; KATHELYN STEIMER; ROBERT C. GALLO; JORG W. EICHBERG; THOMAS MATTHEWS; MARJORIE ROBERT-GUROFF

126

Vaccine-induced virus-neutralizing antibodies and cytotoxic T cells do not protect macaques from experimental infection with simian immunodeficiency virus SIVmac32H (J5)  

Microsoft Academic Search

To gain further insight into the ability of subunit vaccines to protect monkeys from experimental infection with simian immunodeficiency virus (SIV), two groups of cynomolgus macaques were immunized with either recombinant SIVmac32H-derived envelope glycoproteins (Env) incorporated into immune-stimulating complexes (iscoms) (group A) or with these SIV Env iscoms in combination with p27gag iscoms and three Nef lipopeptides (group B). Four

ELLEN G. J. HULSKOTTE; ANNA-MARIA GERETTI; C. H. J. Siebelink; Amerongen van G; MARTIN P. CRANAGE; ERLING W. RUD; STEPHEN G. NORLEY; Vries de P; ALBERT D. M. E. OSTERHAUS

1995-01-01

127

Engineered CD4- and CXCR4-Using Simian Immunodeficiency Virus from African Green Monkeys Is Neutralization Sensitive and Replicates in Nonstimulated Lymphocytes  

Microsoft Academic Search

During human immunodeficiency virus type 1 (HIV-1) infection, disease progression correlates with the occurrence of variants using the coreceptor CXCR4 for cell entry. In contrast, apathogenic simian immuno- deficiency virus (SIV) from African green monkeys (SIVagm), specifically the molecular virus clone SIVagm3mc, uses CCR5, Bob, and Bonzo as coreceptors throughout the course of infection. The influence of an altered coreceptor

Renate R. Konig; Egbert Flory; Stefanie Steidl; Jeanette Neumann; Cheick Coulibaly; Edgar Holznagel; Silke Holzammer; Stephen Norley; Klaus Cichutek

2002-01-01

128

Infection of Specific Dendritic Cells by CCR5Tropic Human Immunodeficiency Virus Type 1 Promotes Cell-Mediated Transmission of Virus Resistant to Broadly Neutralizing Antibodies  

Microsoft Academic Search

The tropism of human immunodeficiency virus type 1 for chemokine receptors plays an important role in the transmission of AIDS. Although CXCR4-tropic virus is more cytopathic for T cells, CCR5-tropic strains are transmitted more frequently in humans for reasons that are not understood. Phenotypically immature myeloid dendritic cells (mDCs) are preferentially infected by CCR5-tropic virus, in contrast to mature mDCs,

Lakshmanan Ganesh; Kwanyee Leung; Karin Lore; Reuven Levin; Amos Panet; Owen Schwartz; Richard A. Koup; Gary J. Nabel

2004-01-01

129

Human Immunodeficiency Virus Type 1 Primary Isolate Neutralization Resistance Is Associated with the Syncytium-Inducing Phenotype and Lower CD4 Cell Counts in Subtype CRF01_AE-Infected Patients  

PubMed Central

A number of human immunodeficiency virus type 1 (HIV-1) non-B-subtype products have been developed for present or future vaccine trials; in Thailand, several studies using subtype B and/or CRF01_AE vaccines have been conducted. To better characterize the biologic properties of these subtypes, 70 HIV-1 subtype B and E isolates were phenotyped as syncytium-inducing (SI) or non-syncytium-inducing (NSI) isolates and assessed for sensitivity to neutralizing antibody (NAb). A significantly higher number of NSI subtype E viruses were neutralization sensitive than SI subtype E viruses (P = 0.009), while no association between viral phenotype and sensitivity to NAb was observed for subtype B (P = 0.856), suggesting a difference in the neutralization patterns of subtypes B and E. Strikingly, concurrent CD4 T-cell numbers were significantly lower for subtype E-infected patients whose isolates were more resistant to NAb, both for the overall study group (P < 0.001) as well as for the 22 patients with NSI isolates (P = 0.013). Characterization of the evolution of biologic properties of both B and non-B HIV-1 subtypes will provide a clearer understanding of the repertoire of antibodies that must be elicited for a vaccine to be effective against all phenotypes and subtypes.

Polonis, Victoria R.; Souza, Mark S. de; Darden, Janice M.; Chantakulkij, Somsak; Chuenchitra, Thippawan; Nitayaphan, Sorachai; Brown, Arthur E.; Robb, Merlin L.; Birx, Deborah L.

2003-01-01

130

Human immunodeficiency virus type 1 primary isolate neutralization resistance is associated with the syncytium-inducing phenotype and lower CD4 cell counts in subtype CRF01_AE-infected patients.  

PubMed

A number of human immunodeficiency virus type 1 (HIV-1) non-B-subtype products have been developed for present or future vaccine trials; in Thailand, several studies using subtype B and/or CRF01_AE vaccines have been conducted. To better characterize the biologic properties of these subtypes, 70 HIV-1 subtype B and E isolates were phenotyped as syncytium-inducing (SI) or non-syncytium-inducing (NSI) isolates and assessed for sensitivity to neutralizing antibody (NAb). A significantly higher number of NSI subtype E viruses were neutralization sensitive than SI subtype E viruses (P = 0.009), while no association between viral phenotype and sensitivity to NAb was observed for subtype B (P = 0.856), suggesting a difference in the neutralization patterns of subtypes B and E. Strikingly, concurrent CD4 T-cell numbers were significantly lower for subtype E-infected patients whose isolates were more resistant to NAb, both for the overall study group (P < 0.001) as well as for the 22 patients with NSI isolates (P = 0.013). Characterization of the evolution of biologic properties of both B and non-B HIV-1 subtypes will provide a clearer understanding of the repertoire of antibodies that must be elicited for a vaccine to be effective against all phenotypes and subtypes. PMID:12857927

Polonis, Victoria R; de Souza, Mark S; Darden, Janice M; Chantakulkij, Somsak; Chuenchitra, Thippawan; Nitayaphan, Sorachai; Brown, Arthur E; Robb, Merlin L; Birx, Deborah L

2003-08-01

131

Association of Structural Changes in the V2 and V3 Loops of the gp120 Envelope Glycoprotein with Acquisition of Neutralization Resistance in a Simian-Human Immunodeficiency Virus Passaged In Vivo  

PubMed Central

The in vivo passage of a neutralization-sensitive, laboratory-adapted simian-human immunodeficiency virus (SHIV-HXBc2) generated a pathogenic, neutralization-resistant virus, SHIV-HXBc2P 3.2. SHIV-HXBc2P 3.2 differs from SHIV-HXBc2 only in 13 amino acid residues of the viral envelope glycoproteins. Here we used antibody competition analysis to examine the structural changes that occurred in the SHIV-HXBc2P 3.2 gp120 exterior envelope glycoprotein. The relationships among the antibody epitopes on the conserved gp120 core of SHIV-HXBc2 and SHIV-HXBc2P 3.2 were similar. The third variable (V3) loop was more closely associated with the fourth conserved (C4) region and CD4-induced epitopes on the gp120 core in the HXBc2P 3.2 gp120 glycoprotein compared with the HXBc2 gp120 glycoprotein. Rearrangements of the second variable (V2) loop with respect to the CD4 binding site and associated epitopes were evident in comparisons of the two gp120 glycoproteins. Thus, the in vivo evolution of a neutralization-resistant virus involves conformational adjustments of the V2 and V3 variable loops with respect to the conserved receptor-binding regions of the gp120 core.

Ye, Yongjun; Si, Zhi Hai; Moore, John P.; Sodroski, Joseph

2000-01-01

132

Role of V1V2 and Other Human Immunodeficiency Virus Type 1 Envelope Domains in Resistance to Autologous Neutralization during Clade C Infection  

Microsoft Academic Search

Biologically functional clade C envelope (Env) glycoproteins from the chronically (donor) and newly (re- cipient) infected partners of four heterosexual transmission pairs in Zambia were cloned and characterized previously. In each case, the donor viral quasispecies contained Envs that were resistant to autologous neutralization by contemporaneous plasma, while the recipient Envs were sensitive to neutralizing antibodies in this donor plasma

Rong Rong; Frederic Bibollet-Ruche; Joseph Mulenga; Susan Allen; Jerry L. Blackwell; Cynthia A. Derdeyn

2007-01-01

133

Identification of 81LGxGxxIxW89 and 171EDRW174 Domains from Human Immunodeficiency Virus Type 1 Vif That Regulate APOBEC3G and APOBEC3F Neutralizing Activity?  

PubMed Central

The human cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) potently restrict human immunodeficiency virus type 1 (HIV-1) replication, but they are neutralized by the viral protein Vif. Vif bridges A3G and A3F with a Cullin 5 (Cul5)-based E3 ubiquitin ligase and mediates their proteasomal degradation. This mechanism has been extensively studied, and several Vif domains have been identified that are critical for A3G and A3F neutralization. Here, we identified two additional domains. Via sequence analysis of more than 2,000 different HIV-1 Vif proteins, we identified two highly conserved amino acid sequences, 81LGxGxSIEW89 and 171EDRWN175. Within the 81LGxGxSIEW89 sequence, residues L81, G82, G84, and, to a lesser extent, I87 and W89 play very critical roles in A3G/A3F neutralization. In particular, residues L81 and G82 determine Vif binding to A3F, residue G84 determines Vif binding to both A3G and A3F, and residues 86SIEW89 affect Vif binding to A3F, A3G, and Cul5. Accordingly, this 81LGxGxSIEW89 sequence was designated the 81LGxGxxIxW89 domain. Within the 171EDRWN175 sequence, all residues except N175 are almost equally important for regulation of A3F neutralization, and consistently, they determine Vif binding only to A3F. Accordingly, this domain was designated 171EDRW174. The LGxGxxIxW domain is also partially conserved in simian immunodeficiency virus Vif from rhesus macaques (SIVmac239) and has a similar activity. Thus, 81LGxGxxIxW89 and 171EDRW174 are two novel functional domains that are very critical for Vif function. They could become new targets for inhibition of Vif activity during HIV replication.

Dang, Ying; Davis, Roderick W.; York, Ian A.; Zheng, Yong-Hui

2010-01-01

134

Identification of 81LGxGxxIxW89 and 171EDRW174 domains from human immunodeficiency virus type 1 Vif that regulate APOBEC3G and APOBEC3F neutralizing activity.  

PubMed

The human cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) potently restrict human immunodeficiency virus type 1 (HIV-1) replication, but they are neutralized by the viral protein Vif. Vif bridges A3G and A3F with a Cullin 5 (Cul5)-based E3 ubiquitin ligase and mediates their proteasomal degradation. This mechanism has been extensively studied, and several Vif domains have been identified that are critical for A3G and A3F neutralization. Here, we identified two additional domains. Via sequence analysis of more than 2,000 different HIV-1 Vif proteins, we identified two highly conserved amino acid sequences, (81)LGxGxSIEW(89) and (171)EDRWN(175). Within the (81)LGxGxSIEW(89) sequence, residues L81, G82, G84, and, to a lesser extent, I87 and W89 play very critical roles in A3G/A3F neutralization. In particular, residues L81 and G82 determine Vif binding to A3F, residue G84 determines Vif binding to both A3G and A3F, and residues (86)SIEW(89) affect Vif binding to A3F, A3G, and Cul5. Accordingly, this (81)LGxGxSIEW(89) sequence was designated the (81)LGxGxxIxW(89) domain. Within the (171)EDRWN(175) sequence, all residues except N175 are almost equally important for regulation of A3F neutralization, and consistently, they determine Vif binding only to A3F. Accordingly, this domain was designated (171)EDRW(174). The LGxGxxIxW domain is also partially conserved in simian immunodeficiency virus Vif from rhesus macaques (SIVmac239) and has a similar activity. Thus, (81)LGxGxxIxW(89) and (171)EDRW(174) are two novel functional domains that are very critical for Vif function. They could become new targets for inhibition of Vif activity during HIV replication. PMID:20335268

Dang, Ying; Davis, Roderick W; York, Ian A; Zheng, Yong-Hui

2010-06-01

135

Human Immunodeficiency Virus Type-1 (HIV-1) Continues to Evolve in Presence of Broadly Neutralizing Antibodies More than Ten Years after Infection  

PubMed Central

Background The evolution of HIV-1 and its immune escape to autologous neutralizing antibodies (Nabs) during the acute/early phases of infection have been analyzed in depth in many studies. In contrast, little is known about neither the long-term evolution of the virus in patients who developed broadly Nabs (bNabs) or the mechanism of escape in presence of these bNabs. Results We have studied the viral population infecting a long term non progressor HIV-1 infected patient who had developed broadly neutralizing antibodies toward all tier 2/3 viruses (6 clades) tested, 9 years after infection, and was then followed up over 7 years. The autologous neutralization titers of the sequential sera toward env variants representative of the viral population significantly increased during the follow-up period. The most resistant pseudotyped virus was identified at the last visit suggesting that it represented a late emerging escape variant. We identified 5 amino acids substitutions that appeared associated with escape to broadly neutralizing antibodies. They were V319I/S, R/K355T, R/W429G, Q460E and G/T463E, in V3, C3 and V5 regions. Conclusion This study showed that HIV-1 may continue to evolve in presence of both broadly neutralizing antibodies and increasing autologous neutralizing activity more than 10 years post-infection.

Chaillon, Antoine; Braibant, Martine; Hue, Stephane; Bencharif, Samia; Enard, David; Moreau, Alain; Samri, Assia; Agut, Henri; Barin, Francis

2012-01-01

136

Studies on GM-CSF DNA as an adjuvant for neutralizing Ab elicited by a DNA/MVA immunodeficiency virus vaccine.  

PubMed

Here, we use a vaccine consisting of DNA priming followed by MVA boosting in rhesus macaques to investigate the ability of GM-CSF DNA to serve as an adjuvant for the elicitation of neutralizing Ab against an HIV-1 Env. The trial used Gag, Pol, and Env sequences from SHIV-89.6 in the immunogens and a neutralization escape variant of SHIV-89.6, SHIV-89.6P, for challenge. Co-delivery of GM-CSF and vaccine DNAs enhanced the temporal appearance of neutralizing Ab and broadened the specificity of the neutralizing activity to include SHIV-89.6P. Two long-term SHIV-89.6 infections elicited neutralizing activity for SHIV-89.6 but not SHIV-89.6P. Studies on the avidity of the anti-Env antisera revealed that the GM-CSF-adjuvanted vaccine had elicited higher avidity Ab than the non-adjuvanted vaccine or the infection. The GM-CSF-adjuvanted group showed a trend towards better control of the challenge infection and had better control of re-emergent virus (P < 0.01) than the non-adjuvanted group. PMID:16740288

Robinson, Harriet L; Montefiori, David C; Villinger, Francois; Robinson, James E; Sharma, Sunita; Wyatt, Linda S; Earl, Patricia L; McClure, Harold M; Moss, Bernard; Amara, Rama Rao

2006-09-01

137

TXU (Anti-CD7)Pokeweed Antiviral Protein as a Potent Inhibitor of Human Immunodeficiency Virus  

Microsoft Academic Search

We have evaluated the clinical potential of TXU (anti-CD7)-pokeweed antiviral protein (PAP) immunocon- jugate (TXU-PAP) as a new biotherapeutic anti-human immunodeficiency virus (anti-HIV) agent by evaluating its anti-HIV type 1 (anti-HIV-1) activity in vitro, as well as in a surrogate human peripheral blood lymphocyte- severe combined immunodeficient (Hu-PBL-SCID) mouse model of human AIDS. The present report docu- ments in a

FATIH M. UCKUN; LISA M. CHELSTROM; LISA TUEL-AHLGREN; ILKER DIBIRDIK; JAMES D. IRVIN; MRIDULA-CHANDAN LANGLIE; DOROTHEA E. MYERS

138

The First Hypervariable Region of the gp120 Env Glycoprotein Defines the Neutralizing Susceptibility of Heterologous Human Immunodeficiency Virus Type 1 Isolates to Neutralizing Antibodies Elicited by the SF162gp140 Immunogen  

Microsoft Academic Search

Current vaccine efforts to elicit cross-reactive neutralizing antibodies (NAbs) against human immunodefi- ciency virus (HIV) focus on the engineering of soluble mimetics of the trimeric HIV Env glycoprotein (com- monly termed gp140 immunogens). Such immunogens are thought to be more effective than previously tested monomeric gp120 immunogens at eliciting cross-reactive NAbs. Still, the breadth of neutralizing antibody responses elicited by

Lance K. Ching; Giorgos Vlachogiannis; Katherine A. Bosch; Leonidas Stamatatos

2008-01-01

139

Neutralization activity in a geographically diverse East London cohort of human immunodeficiency virus type 1-infected patients: clade C infection results in a stronger and broader humoral immune response than clade B infection.  

PubMed

The array of human immunodeficiency virus (HIV) subtypes encountered in East London, an area long associated with migration, is unusually heterogeneous, reflecting the diverse geographical origins of the population. In this study it was shown that viral subtypes or clades infecting a sample of HIV type 1 (HIV-1)-positive individuals in East London reflect the global pandemic. The authors studied the humoral response in 210 treatment-naïve chronically HIV-1-infected (>1 year) adult subjects against a panel of 12 viruses from six different clades. Plasmas from individuals infected with clade C, but also plasmas from clade A, and to a lesser degree clade CRF02_AG and CRF01_AE, were significantly more potent at neutralizing the tested viruses compared with plasmas from individuals infected with clade B. The difference in humoral robustness between clade C- and B-infected patients was confirmed in titration studies with an extended panel of clade B and C viruses. These results support the approach to develop an HIV-1 vaccine that includes clade C or A envelope protein (Env) immunogens for the induction of a potent neutralizing humoral response. PMID:20685933

Dreja, Hanna; O'Sullivan, Eithne; Pade, Corinna; Greene, Kelli M; Gao, Hongmei; Aubin, Keith; Hand, James; Isaksen, Are; D'Souza, Carl; Leber, Werner; Montefiori, David; Seaman, Michael S; Anderson, Jane; Orkin, Chloe; McKnight, Aine

2010-11-01

140

Evidence that Ecotropic Murine Leukemia Virus Contamination in TZM-bl Cells Does Not Affect the Outcome of Neutralizing Antibody Assays with Human Immunodeficiency Virus Type 1  

Microsoft Academic Search

The TZM-bl cell line that is commonly used to assess neutralizing antibodies against human immuno- deficiency virus type 1 (HIV-1) was recently reported to be contaminated with an ecotropic murine leukemia virus (MLV) (Y. Takeuchi, M. O. McClure, and M. Pizzato, J. Virol. 82:12585-12588, 2008), raising questions about the validity of results obtained with this cell line. Here we confirm

Emily J. Platt; Miroslawa Bilska; Susan L. Kozak; David Kabat; David C. Montefiori

2009-01-01

141

Immunization of rabbits with highly purified, soluble, trimeric human immunodeficiency virus type 1 envelope glycoprotein induces a vigorous B cell response and broadly cross-reactive neutralization.  

PubMed

Previously we described induction of cross-reactive HIV-1 neutralizing antibody responses in rabbits using a soluble HIV-1 gp140 envelope glycoprotein (Env) in an adjuvant containing monophosphoryl lipid A (MPL) and QS21 (AS02A). Here, we compared different forms of the same HIV-1 strain R2 Env for antigenic and biophysical characteristics, and in rabbits characterized the extent of B cell induction for specific antibody expression and secretion and neutralizing responses. The forms of this Env that were produced in and purified from stably transformed 293T cells included a primarily dimeric gp140, a trimeric gp140 appended to a GCN4 trimerization domain (gp140-GCN4), gp140-GCN4 with a 15 amino acid flexible linker between the gp120 and gp41 ectodomain (gp140-GCN4-L), also trimeric, and a gp140 with the flexible linker purified from cell culture supernatants as either dimer (gp140-L(D)) or monomer (gp140-L(M)). Multimeric states of the Env proteins were assessed by native gel electrophoresis and analytical ultracentrifugation. The different forms of gp140 bound broadly cross-reactive neutralizing (BCN) human monoclonal antibodies (mAbs) similarly in ELISA and immunoprecipitation assays. All Envs bound CD4i mAbs in the presence and absence of sCD4, as reported for the R2 Env. Weak neutralization of some strains of HIV-1 was seen after two additional doses in AS02A. Rabbits that were given a seventh dose of gp140-GCN4-L developed BCN responses that were weak to moderate, similar to our previous report. The specificity of these responses did not appear similar to that of any of the known BCN human mAbs. Induction of spleen B cell and plasma cells producing immunoglobulins that bound trimeric gp140-GCN4-L was vigorous, based on ELISpot and flow cytometry analyses. The results demonstrate that highly purified gp140-GCN4-L trimer in adjuvant elicits BCN responses in rabbits accompanied by vigorous B cell induction. PMID:24846288

Quinnan, Gerald V; Onabajo, Olusegun; Zhang, Pengfei; Yan, Lianying; Mattapallil, Joseph J; Zhang, Zhiqiang; Dong, Ming; Lu, Min; Montefiori, David; LaBranche, Celia; Broder, Christopher C

2014-01-01

142

Immunization of Rabbits with Highly Purified, Soluble, Trimeric Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Induces a Vigorous B Cell Response and Broadly Cross-Reactive Neutralization  

PubMed Central

Previously we described induction of cross-reactive HIV-1 neutralizing antibody responses in rabbits using a soluble HIV-1 gp140 envelope glycoprotein (Env) in an adjuvant containing monophosphoryl lipid A (MPL) and QS21 (AS02A). Here, we compared different forms of the same HIV-1 strain R2 Env for antigenic and biophysical characteristics, and in rabbits characterized the extent of B cell induction for specific antibody expression and secretion and neutralizing responses. The forms of this Env that were produced in and purified from stably transformed 293T cells included a primarily dimeric gp140, a trimeric gp140 appended to a GCN4 trimerization domain (gp140-GCN4), gp140-GCN4 with a 15 amino acid flexible linker between the gp120 and gp41 ectodomain (gp140-GCN4-L), also trimeric, and a gp140 with the flexible linker purified from cell culture supernatants as either dimer (gp140-L(D)) or monomer (gp140-L(M)). Multimeric states of the Env proteins were assessed by native gel electrophoresis and analytical ultracentrifugation. The different forms of gp140 bound broadly cross-reactive neutralizing (BCN) human monoclonal antibodies (mAbs) similarly in ELISA and immunoprecipitation assays. All Envs bound CD4i mAbs in the presence and absence of sCD4, as reported for the R2 Env. Weak neutralization of some strains of HIV-1 was seen after two additional doses in AS02A. Rabbits that were given a seventh dose of gp140-GCN4-L developed BCN responses that were weak to moderate, similar to our previous report. The specificity of these responses did not appear similar to that of any of the known BCN human mAbs. Induction of spleen B cell and plasma cells producing immunoglobulins that bound trimeric gp140-GCN4-L was vigorous, based on ELISpot and flow cytometry analyses. The results demonstrate that highly purified gp140-GCN4-L trimer in adjuvant elicits BCN responses in rabbits accompanied by vigorous B cell induction.

Quinnan, Gerald V.; Onabajo, Olusegun; Zhang, Pengfei; Yan, Lianying; Mattapallil, Joseph J.; Zhang, Zhiqiang; Dong, Ming; Lu, Min; Montefiori, David; LaBranche, Celia; Broder, Christopher C.

2014-01-01

143

Stable Docking of Neutralizing Human Immunodeficiency Virus Type 1 gp41 Membrane-Proximal External Region Monoclonal Antibodies 2F5 and 4E10 Is Dependent on the Membrane Immersion Depth of Their Epitope Regions ?  

PubMed Central

The binding of neutralizing antibodies 2F5 and 4E10 to human immunodeficiency virus type 1 (HIV-1) gp41 involves both the viral membrane and gp41 membrane proximal external region (MPER) epitopes. In this study, we have used several biophysical tools to examine the secondary structure, orientation, and depth of immersion of gp41 MPER peptides in liposomes and to determine how the orientation of the MPER with lipids affects the binding kinetics of monoclonal antibodies (MAbs) 2F5 and 4E10. The binding of 2F5 and 4E10 both to their respective nominal epitopes and to a biepitope (includes 2F5 and 4E10 epitopes) MPER peptide-liposome conjugate was best described by a two-step encounter-docking model. Analysis of the binding kinetics and the effect of temperature on the binding stability of 2F5 and 4E10 to MPER peptide-liposome conjugates revealed that the docking of 4E10 was relatively slower and thermodynamically less favorable. The results of fluorescence-quenching and fluorescence resonance energy transfer experiments showed that the 2F5 epitope was more solvent exposed, whereas the 4E10 epitope was immersed in the polar-apolar interfacial region of the lipid bilayer. A circular dichroism spectroscopic study demonstrated that the nominal epitope and biepitope MPER peptides adopted ordered structures with differing helical contents when anchored to liposomes. Furthermore, anchoring of MPER peptides to the membrane via a hydrophobic anchor sequence was required for efficient MAb docking. These results support the model that the ability of 2F5 and 4E10 to bind to membrane lipid is required for stable docking to membrane-embedded MPER residues. These data have important implications for the design and use of peptide-liposome conjugates as immunogens for the induction of MPER-neutralizing antibodies.

Dennison, S. Moses; Stewart, Shelley M.; Stempel, Kathryn C.; Liao, Hua-Xin; Haynes, Barton F.; Alam, S. Munir

2009-01-01

144

[Autoimmune hypoglycemia syndrome with specific anti-human insulin antibodies].  

PubMed

A 33 year old woman with episodes of severe hypoglycemia is presented. The studies showed anti-insulin antibodies and variable C-peptide levels. Circulating insulin measured after acid-ethanol extraction, was of 1,600 uU/ml and shown to be human insulin after characterization by HLPC. Specific anti-human insulin antibodies were of high affinity (Ka1: 6.20 x 10(10) M-1; Ka2: 2.42 x 10(9) M-1). A small cross-reactive porcine and bovine antibody subpopulation was also detected (IgG, light k type chain). Plasmapheresis was undertaken when symptoms were spontaneously declining and turned antibody title negative. Prolonged follow-up showed no relapse of this syndrome. PMID:9035485

Cresto, J C; Abdenur, J E; Chamoles, N; Bresciani, P; Ruiz, M; Massa, B; Camberos, M C; Basabe, J C

1996-01-01

145

Anti-human cytomegalovirus activity and toxicity of sulfonated anthraquinones and anthraquinone derivatives.  

PubMed

Sulfonated anthraquinones and other anthraquinone derivatives were evaluated for anti-human cytomegalovirus (HCMV) activity, cytotoxicity and genotoxicity. Acid blues 40 and 129, acid black 48, alizarin violet R and reactive blue 2 were the most active compounds having selective indices of greater than 30 and EC50 values of 4-30 microM. When tested against a clinical isolate, the 4 compounds were 2- to 5-fold less active. The antiviral activity was distinctly separate from the virucidal activity (> 1000 microM). The compounds were weakly toxic to either log phase or stationary cells in most of the following cytotoxicity assays: neutral red uptake assay, lactic acid dehydrogenase assay, trypan blue exclusion assay and radiolabeled macromolecular precursor uptake assays. Using a genotoxicity assay, the comet assay, only reactive blue 2 and acid black 48 were found to cause DNA strand breakage. This occurred at concentrations of 30 and 170 microM, respectively. These results suggest that these compounds could be a prototype for synthesizing even more effective HCMV-inhibitory anthraquinone derivatives. PMID:8669891

Barnard, D L; Fairbairn, D W; O'Neill, K L; Gage, T L; Sidwell, R W

1995-12-01

146

Broad neutralization coverage of HIV by multiple highly potent antibodies  

Microsoft Academic Search

Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost

Laura M. Walker; Michael Huber; Katie J. Doores; Emilia Falkowska; Robert Pejchal; Jean-Philippe Julien; Sheng-Kai Wang; Alejandra Ramos; Po-Ying Chan-Hui; Matthew Moyle; Jennifer L. Mitcham; Phillip W. Hammond; Ole A. Olsen; Pham Phung; Steven Fling; Chi-Huey Wong; Sanjay Phogat; Terri Wrin; Melissa D. Simek; Wayne C. Koff; Ian A. Wilson; Dennis R. Burton; Pascal Poignard

2011-01-01

147

Antiretroviral Spermicide WHI-07 Prevents Vaginal and Rectal Transmission of Feline Immunodeficiency Virus in Domestic Cats  

Microsoft Academic Search

WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3-azidothymidine-5-(p-bromophenyl)-methoxy alaninyl phos- phate) is a novel dual-function aryl phosphate derivative of zidovudine with potent anti-human immunodefi- ciency virus (HIV) and spermicidal activities. WHI-07 was active against the feline immunodeficiency virus (FIV). This study evaluated whether topical application of WHI-07 as a single agent and in combination with an organometallic vanadium complex, vanadocene dithiocarbamate (VDDTC), via a nontoxic gel

Osmond J. D'Cruz; Barbara Waurzyniak; Fatih M. Uckun

2004-01-01

148

In Vitro Comparison of Topical Microbicides for Prevention of Human Immunodeficiency Virus Type 1 Transmission  

Microsoft Academic Search

A standardized protocol was used to compare cellular toxicities and anti-human immunodeficiency virus type 1 (HIV-1) activities of candidate microbicides formulated for human use. The microbicides evaluated were cellulose acetate phthalate (CAP), Carraguard, K-Y plus nonoxynol-9 (KY-N9), PRO 2000 (0.5 and 4%), SPL7013 (5%), UC781 (0.1 and 1%), and Vena Gel, along with their accompanying placebos. Products were evaluated for

Charlene S. Dezzutti; V. Nicole James; Artur Ramos; Sharon T. Sullivan; Aladin Siddig; Timothy J. Bush; Lisa A. Grohskopf; Lynn Paxton; Shambavi Subbarao; Clyde E. Hart

2004-01-01

149

Type-specific epitopes targeted by monoclonal antibodies with exceptionally potent neutralizing activities for selected strains of human immunodeficiency virus type 1 map to a common region of the V2 domain of gp120 and differ only at single positions from the clade B consensus sequence.  

PubMed

Only a few monoclonal antibodies (MAbs) have been isolated that recognize conserved sites in human immunodeficiency virus type 1 (HIV-1) Env proteins and possess broad neutralizing activities. Other MAbs directed against targets in various domains of Env have been described that are strongly neutralizing, but they possess limited breadth. One such MAb, 2909, possesses a uniquely potent neutralizing activity specific for a quaternary epitope on SF162 Env that requires the presence of both the V2 and the V3 domains. We now show that replacement of the SF162 V3 sequence with consensus V3 sequences of multiple subtypes led to attenuated but still potent neutralization by 2909 and that the main determinants for the type specificity of 2909 reside in the V2 domain. A substitution at position 160 completely eliminated 2909 reactivity, and mutations at position 167 either attenuated or potentiated neutralization by this antibody. Different substitutions at the same positions in V2 were previously shown to introduce epitopes recognized by MAbs 10/76b and C108g and to allow potent neutralization by these MAbs. Two substitutions at key positions in the V2 domain of JR-FL Env also allowed potent expression of the 2909 epitope, and single substitutions in YU2 V2 were sufficient for expression of the 2909, C108g, and 10/76b epitopes. These results demonstrate that the minimal epitopes for 2909, C108g, and 10/76b differed from that of the clade B consensus sequence only at single positions and suggest that all three MAbs recognize distinct variants of a relatively conserved sequence in V2 that is a particularly sensitive mediator of HIV-1 neutralization. PMID:17121806

Honnen, W J; Krachmarov, C; Kayman, S C; Gorny, M K; Zolla-Pazner, S; Pinter, A

2007-02-01

150

Involvement of IL6 in the anti-human immunodeficiency virus activity of IFN  in human macrophages  

Microsoft Academic Search

IFN-s is a non-cytotoxic type I IFN responsible for maternal recognition of the foetus in ruminants. IFN-s has been found to inhibit HIV replication more strongly than human IFN-a, particularly in human monocyte-derived macrophages, without associated toxicity. Ovine IFN-s uses the same anti-viral cellular pathways as human IFN-a in human macrophages, principally inhibiting the early steps of the biological cycle

Christine Rogez-Kreuz; Benjamin Maneglier; Marc Martin; Nathalie Dereuddre-Bosquet; Jacques Martal; Dominique Dormont; Pascal Clayette

2005-01-01

151

Design of a novel cyclotide-based CXCR4 antagonist with anti-human immunodeficiency virus (HIV)-1 activity.  

PubMed

Herein, we report for the first time the design and synthesis of a novel cyclotide able to efficiently inhibit HIV-1 viral replication by selectively targeting cytokine receptor CXCR4. This was accomplished by grafting a series of topologically modified CVX15 based peptides onto the loop 6 of cyclotide MCoTI-I. The most active compound produced in this study was a potent CXCR4 antagonist (EC50?20 nM) and an efficient HIV-1 cell-entry blocker (EC50?2 nM). This cyclotide also showed high stability in human serum, thereby providing a promising lead compound for the design of a novel type of peptide-based anticancer and anti-HIV-1 therapeutics. PMID:23151033

Aboye, Teshome L; Ha, Helen; Majumder, Subhabrata; Christ, Frauke; Debyser, Zeger; Shekhtman, Alexander; Neamati, Nouri; Camarero, Julio A

2012-12-13

152

Design of a novel cyclotide-based CXCR4 antagonist with anti-human immunodeficiency virus (HIV)-1 activity  

PubMed Central

Herein, we report for the first time the design and synthesis of a novel cyclotide able to efficiently inhibit HIV-1 viral replication by selectively targeting cytokine receptor CXCR4. This was accomplished by grafting a series of topologically modified CVX15 based peptides onto the loop 6 of cyclotide MCoTI-I. The most active compound produced in this study was a potent CXCR4 antagonist (EC50 ? 20 nM) and an efficient HIV-1 cell-entry blocker (EC50 ? 2 nM). This cyclotide also showed high stability in human serum thereby providing a promising lead compound for the design of a novel type of peptide-based anti-cancer and anti-HIV-1 therapeutics.

Aboye, Teshome L.; Ha, Helen; Majumber, Subhabrata; Christ, Frauke; Debyser, Zeger; Shekhtman, Alexander; Neamati, Nouri; Camarero, Julio A.

2012-01-01

153

Polyvalent HIV1 Env vaccine formulations delivered by the DNA priming plus protein boosting approach are effective in generating neutralizing antibodies against primary human immunodeficiency virus type 1 isolates from subtypes A, B, C, D and E  

Microsoft Academic Search

A major challenge in developing an HIV-1 vaccine is to identify immunogens and their delivery methods that can elicit broad neutralizing antibodies against primary isolates of different genetic subtypes. Recently, we demonstrated that priming with DNA vaccines expressing primary HIV-1 envelope glycoprotein (Env) followed by recombinant Env protein boosting was successful in generating positive neutralizing antibody responses against a clade

Shixia Wang; Ranajit Pal; John R. Mascola; Te-Hui W. Chou; Innocent Mboudjeka; Siyuan Shen; Qin Liu; Stephen Whitney; Timothy Keen; B. C. Nair; V. S. Kalyanaraman; Philip Markham; Shan Lu

2006-01-01

154

Comparison of human immunodeficiency virus type 1 tropism profiles in clinical samples by the Trofile and MT2 assays  

Microsoft Academic Search

The recent availability of CCR5 antagonists as anti-human immunodeficiency virus (anti-HIV) therapeutics has highlighted the need to accurately identify CXCR4-using variants in patient samples when use of this new drug class is considered. The Trofile assay (Monogram Biosciences) has become the method that is the most widely used to define tropism in the clinic prior to the use of a

E. Coakley; J. D. Reeves; W. Huang; M. Mangas-Ruiz; I. Maurer; A. M. Harskamp; S. Gupta; Y. Lie; C. J. Petropoulos; H. Schuitemaker; Wout van't A. B

2009-01-01

155

Development of new versions of anti-human CD34 monoclonal antibodies with potentially reduced immunogenicity  

SciTech Connect

Despite the widespread clinical use of CD34 antibodies for the purification of human hematopoietic stem/progenitor cells, all the current anti-human CD34 monoclonal antibodies (mAbs) are murine, which have the potential to elicit human antimouse antibody (HAMA) immune response. In the present study, we developed three new mouse anti-human CD34 mAbs which, respectively, belonged to class I, class II and class III CD34 epitope antibodies. In an attempt to reduce the immunogenicity of these three murine mAbs, their chimeric antibodies, which consisted of mouse antibody variable regions fused genetically to human antibody constant regions, were constructed and characterized. The anti-CD34 chimeric antibodies were shown to possess affinity and specificity similar to that of their respective parental murine antibodies. Due to the potentially better safety profiles, these chimeric antibodies might become alternatives to mouse anti-CD34 antibodies routinely used for clinical application.

Qian Weizhu [International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433 (China); Shanghai Center for Cell Engineering and Antibody, Shanghai 201203 (China); Wang Ling [International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433 (China); Li Bohua; Wang Hao; Hou Sheng [International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433 (China); Shanghai Center for Cell Engineering and Antibody, Shanghai 201203 (China); Hong Xueyu; Zhang Dapeng [International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433 (China); Guo Yajun [International Joint Cancer Institute, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433 (China); Shanghai Center for Cell Engineering and Antibody, Shanghai 201203 (China)], E-mail: yjguo@smmu.edu.cn

2008-03-07

156

Commercially available rabbit anti-human polyclonal antisera as a useful tool for immune system studies in veterinary species  

Microsoft Academic Search

We have used selected rabbit anti-human polyclonal antibodies as an example of useful and easily available tools for studies on immune system structure and development in important veterinary species, many of which also represent animal models in biomedicine. The cocktail of anti-human Ig?-FITC\\/anti-Ig?-RPE F(ab?)2 fragments was used for two-colour and, in combination with the cross-reactive anti-CD79? monoclonal antibody HM-57, for

J. Sinkora; P. Samankova; V. Kummer; L. Leva; J. Maskova; Z. Rehakova; M. Faldyna

2007-01-01

157

Neutralizer optimization  

NASA Technical Reports Server (NTRS)

The preliminary results of a test program to optimize a neutralizer design for 30 cm xenon ion thrusters are discussed. The impact of neutralizer geometry, neutralizer axial location, and local magnetic fields on neutralizer performance is discussed. The effect of neutralizer performance on overall thruster performance is quantified, for thruster operation in the 0.5-3.2 kW power range. Additionally, these data are compared to data published for other north-south stationkeeping (NSSK) and primary propulsion xenon ion thruster neutralizers.

Patterson, Michael J.; Mohajeri, Kayhan

1991-01-01

158

Disparate Actions of Hydroxyurea in Potentiation of Purine and Pyrimidine 2',3'-Dideoxynucleoside Activities Against Replication of Human Immunodeficiency Virus  

Microsoft Academic Search

We and other groups have recently reported the potentiation by ribonucleotide reductase inhibitors such as hydroxyurea of the anti-human immunodeficiency virus type 1 (HIV-1) activity of purine and pyrimidine 2',3'-dideoxynucleosides in both resting and phytohemagglutininstimulated peripheral blood mononuclear cells. Little agreement prevails, however, as to the mechanism of the synergistic effects described. We report here that in phytohemagglutininstimulated peripheral blood

Wen-Yi Gao; David G. Johns; Sudhichai Chokekijchai; Hiroaki Mitsuya

1995-01-01

159

Pokeweed Antiviral Protein Isoforms PAP-I, PAP-II, and PAP-III Depurinate RNA of Human Immunodeficiency Virus (HIV)-1  

Microsoft Academic Search

Pokeweed antiviral protein (PAP) is a naturally occurring broad-spectrum antiviral agent with potent anti-human immunodeficiency virus (HIV)-1 activity by an as yet undeciphered molecular mechanism. In the present study, we sought to determine if PAP is capable of recognizing and depurinating viral RNA. Depurination of viral RNA was monitored by directly measuring the amount of the adenine base released from

Francis Rajamohan; Taracad K. Venkatachalam; James D. Irvin; Fatih M. Uckun

1999-01-01

160

Synthetic multimeric peptides derived from the principal neutralization domain (V3 loop) of human immunodeficiency virus type 1 (HIV-1) gp120 bind to galactosylceramide and block HIV-1 infection in a human CD4-negative mucosal epithelial cell line.  

PubMed Central

The glycosphingolipid galactosylceramide (GalCer), which binds gp120 with high affinity and specificity, is a potential alternative receptor for human immunodeficiency virus type 1 (HIV-1) in some CD4-negative neural and epithelial human cells, including the human colonic epithelial cell line HT-29. In the present study, we demonstrate that synthetic multibranched peptides derived from the consensus sequence of the HIV-1 V3 loop block HIV-1 infection in HT-29 cells. The most active peptide was an eight-branched multimer of the motif Gly-Pro-Gly-Arg-Ala-Phe which at a concentration of 1.8 microM induced a 50% inhibition of HIV-1 infection in competition experiments. This peptide was not toxic to HT-29 cells, and preincubation with HIV-1 did not affect viral infectivity, indicating that the antiviral activity was not due to a nonspecific virucidal effect. Using a high-performance thin-layer chromatography binding assay, we found that multibranched V3 peptides recognized GalCer and inhibited binding of recombinant gp120 to the glycosphingolipid. In addition, these peptides abolished the binding of an anti-GalCer monoclonal antibody to GalCer on the surface of live HT-29 cells. These data provide additional evidence that the V3 loop is involved in the binding of gp120 to the GalCer receptor and show that multibranched V3 peptides are potent inhibitors of the GalCer-dependent pathway of HIV-1 infection in CD4-negative mucosal epithelial cells.

Yahi, N; Sabatier, J M; Baghdiguian, S; Gonzalez-Scarano, F; Fantini, J

1995-01-01

161

Characterization of anti-human interleukin-18 (IL18)\\/interferon- ?-inducing factor (IGIF) monoclonal antibodies and their application in the measurement of human IL18 by ELISA  

Microsoft Academic Search

Interleukin-18 (IL-18)\\/interferon-?-inducing factor (IGIF) is a novel cytokine, which is a potent inducer of IFN-? production and plays an important role in Th1 responses. In order to develop a specific ELISA for the measurement of human IL-18, we established 13 anti-human IL-18 monoclonal antibodies and characterized them. 7 murine anti-human IL-18 mAbs and 6 rat anti-human IL-18 mAbs were obtained

Mutsuko Taniguchi; Katsue Nagaoka; Toshio Kunikata; Tohru Kayano; Hiroshi Yamauchi; Shuji Nakamura; Masao Ikeda; Kunzo Orita; Masashi Kurimoto

1997-01-01

162

Common variable immunodeficiency  

PubMed Central

Common variable immunodeficiency (CVID) is a common primary immunodeficiency characterized by a failure in B-cell differentiation with defective immunoglobulin production. Affected patients are uniquely susceptible to recurrent infection with encapsulated organisms and have an increased propensity for the development of inflammatory and autoimmune manifestations. The diagnosis of CVID is commonly delayed and the underlying cause of the disorder is not understood. Replacement antibody therapy reduces the risk of serious infections. However, optimal treatment regimens for the uncommon manifestations associated with this disease, such as granulomatous lymphocytic interstitial lung disease, require further research.

Tam, Jonathan S.

2013-01-01

163

Characterization of a DNA vaccine expressing a human immunodeficiency virus-like particle  

Microsoft Academic Search

An ideal human immunodeficiency virus type-1 (HIV-1) vaccine will most likely need to elicit cross-reactive neutralizing antibodies and a strong cell-mediated immune response against multiple HIV-1 antigens to confer protection against challenge. In this study, DNA vaccines were constructed to express virally regulated human immunodeficiency virus-like particles (VLP) to elicit broad-spectrum immune responses to multiple HIV-1 antigens. VLPs were efficiently

Kelly R. Young; James M. Smith; Ted M. Ross

2004-01-01

164

Inhibitory effects of Korean medicinal plants and camelliatannin H from Camellia japonica on human immunodeficiency virus type 1 protease.  

PubMed

To identify substances with anti-human immunodeficiency virus (HIV) activity in traditional medicines, 101 extracts of Korean medicinal plants were screened for their inhibitory effects on HIV type 1 protease (PR). The enzyme activity was determined by HPLC. Of the extracts tested, strong inhibitory effects were observed in the acetone extracts of the pericarp and leaves of Camellia japonica, the water extract of the leaves of Sageretia theezans and the methanol extract of the aerial part of Sophora flavescens. Camelliatannin H from the pericarp of C. japonica, showed a potent inhibitory activity on HIV-1 PR with IC(50) of 0.9 microM. PMID:12203260

Park, Jong Cheol; Hur, Jong Moon; Park, Ju Gwon; Hatano, Tsutomu; Yoshida, Takashi; Miyashiro, Hirotsugu; Min, Byung Sun; Hattori, Masao

2002-08-01

165

Intracellular expression of single-chain variable fragments to inhibit early stages of the viral life cycle by targeting human immunodeficiency virus type 1 integrase.  

PubMed Central

Integration of viral DNA into a chromosome of the infected host cell is required for efficient replication of a retroviral genome, and this reaction is mediated by the virus-encoded enzyme integrase (IN). As IN plays a pivotal role in establishing infection during the early stages of the retroviral life cycle, it is an attractive target for therapeutic intervention. However, the lack of effective antiviral drug therapy against this enzyme has led to the testing of other novel approaches towards its inhibition. In these studies, a panel of anti-human immunodeficiency virus type 1 (anti-HIV-1) IN hybridomas has been used in the construction of single-chain variable antibody fragments (SFvs). The monoclonal antibodies produced by these hybridomas, and derived SFvs, bind to different domains within IN. We now demonstrate that intracellular expression of SFvs which bind to IN catalytic and carboxy-terminal domains results in resistance to productive HIV-1 infection. This inhibition of HIV-1 replication is observed with SFvs localized in either the cytoplasmic or nuclear compartment of the cell. The expression of anti-IN SFvs in human T-lymphocytic cells and peripheral blood mononuclear cells appears to specifically neutralize IN activity prior to integration and, thus, has an effect on the integration process itself. These data support our previous studies with an anti-HIV-1 reverse transcriptase SFv and demonstrate further that intracellularly expressed SFvs can gain access to viral proteins of the HIV-1 preintegration complex. This panel of anti-HIV-1 IN SFvs also provides the tools with which to dissect the molecular mechanism(s) directly involved in integration within HIV-1-infected cells.

Levy-Mintz, P; Duan, L; Zhang, H; Hu, B; Dornadula, G; Zhu, M; Kulkosky, J; Bizub-Bender, D; Skalka, A M; Pomerantz, R J

1996-01-01

166

Human Immunodeficiency Virus  

Microsoft Academic Search

Oral health is an integral component of overall health and well-being in all patients. However, for an immunocompromised patient,\\u000a many common oral conditions may have a significant impact on quality of life. Intraoral pain, which is a common complaint\\u000a among patients with human immunodeficiency virus (HIV), will compromise patients’ ability to maintain adequate and appropriate\\u000a oral intake. Furthermore, the polypharmacopeia

Anita Patel; Michael Glick

167

X-linked immunodeficiencies  

Microsoft Academic Search

Recent advances in molecular genetics have allowed identification of at least seven genes involved in X-linked immunodeficiencies.\\u000a This has resulted not only in improved diagnostic possibilities but also in a better understanding of the pathophysiology\\u000a of these disorders. In some cases, mutations in the same gene have been shown to cause distinct clinical and immunologic phenotypes,\\u000a demonstrating a strong genotype-phenotype

Hans D. Ochs; Luigi D. Notarangelo

2004-01-01

168

An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation  

PubMed Central

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ?90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo.

Traub, Stephanie; Nikonova, Alexandra; Carruthers, Alan; Dunmore, Rebecca; Vousden, Katherine A.; Gogsadze, Leila; Hao, Weidong; Zhu, Qing; Bernard, Katie; Zhu, Jie; Dymond, Michael; McLean, Gary R.; Walton, Ross P.; Glanville, Nicholas; Humbles, Alison; Khaitov, Musa; Wells, Ted; Kolbeck, Roland; Leishman, Andrew J.; Sleeman, Matthew A.

2013-01-01

169

Demonstration and characterization of anti-human mitochondria autoantibodies in idiopathic hypoparathyroidism and in other conditions.  

PubMed Central

We studied 32 patients with idiopathic hypoparathyroidism (IHP), 19 patients with organ-specific autoimmune diseases (OSAD) without IHP, 50 normal controls and a known serum with anti-mitochondrial autoantibodies (AMA). Patients' sera were tested by the classical indirect immunofluorescent technique and by the indirect immunofluorescent complement fixation technique on unfixed cryostat sections of normal human parathyroid, pancreas, thyroid, stomach, kidney, and rat kidney. Five out of 32 patients with IHP, three out of 19 patients with OSAD without IHP and one out of 50 normal controls revealed a bright reactivity against oxyphil cells and a weak reactivity against chief cells of normal parathyroid. These sera also brightly reacted with mitochondria-rich cells and weakly with the remaining cells of only human tissues. The absorption of positive sera with human mitochondria completely abolished this positivity but the absorption with rat mitochondria failed to prevent this reaction. This reactivity was due to an anti-human mitochondrial autoantibody (AHMA) of IgG class. By non-competitive ELISA and Western blot we also demonstrated that every AHMA-positive serum mainly reacted against a human mitochondrial membrane-bound protein of approximate mol. wt. of 46 kd, while the AMA-positive serum reacted against different mitochondrial antigens. The present study shows that a specific parathyroid autoantibody was not detectable in patients with IHP. Images Fig. 3

Betterle, C; Caretto, A; Zeviani, M; Pedini, B; Salviati, C

1985-01-01

170

Follicular dendritic cells and human immunodeficiency virus infectivity  

NASA Astrophysics Data System (ADS)

LARGE amounts of human immunodeficiency virus (HIV) localize on follicular dendritic cells (FDC) in the follicles of secondary lymphoid tissues following viral infection1,2. During clinical latency, active viral infection occurs primarily at these sites3,4. As HIV on FDC is in the form of immune complexes5, some of which may be formed with neutralizing antibody, we investigated whether HIV on FDC is infectious. We report here that HIV on FDC is highly infectious. Furthermore, FDC can convert neutralized HIV into an infectious form even in the presence of a vast excess of neutralizing antibody. Thus FDC may provide a mechanism whereby HIV infection can continue in the presence of neutralizing antibody.

Heath, Sonya L.; Tew, J. Grant; Tew, John G.; Szakal, Andras K.; Burton, Gregory F.

1995-10-01

171

Humoral immune response to the entire human immunodeficiency virus envelope glycoprotein made in insect cells  

SciTech Connect

The human immunodeficiency virus envelope gene was expressed in insect cells by using a Baculovirus expression vector. The protein has an apparent molecular mass of 160 kDa, appears on the surface of infected insect cells, and does not appear to be cleaved to glycoproteins gp120 and gp41. Goats immunized with the 160-kDa protein have high titers of antibody that neutralizes virus infection as measured by viral gene expression or cell cytolysis. In addition, immune sera can block fusion of human immunodeficiency virus-infected cells in culture. Both neutralization and fusion-blocking activities are bound to and eluted from immobilized gp120.

Rusche, J.R.; Lynn, D.L.; Robert-Guroff, M.; Langlois, A.J.; Lyerly, H.K.; Carson, H.; Krohn, K.; Ranki, A.; Gallo, R.C.; Bolognesi, D.P.; Putney, S.D.

1987-10-01

172

Therapeutic Effect of Novel Anti-Human Fas Antibody HFE7A on Graft-versus-Host Disease Model  

Microsoft Academic Search

In order to evaluate anti-human Fas antibody, we have established a new graft-versus-host disease (GVHD) model wherein splenocytes of human Fas transgenic mice (hFas-TgM) were transferred to immune-deficient SCID mice. In this model, although host SCID cells are not activated by or responsive to graft hFas-TgM cells, graft hFas-TgM cells are activated by and responsive to host SCID cells and

Harumi Kuwahara; Yoshio Tani; Yukie Ogawa; Yasuhiro Takaichi; Akio Shiraishi; Masahiko Ohtsuki

2001-01-01

173

Directed evolution of an anti-human red blood cell antibody.  

PubMed

We have earlier described a haemagglutination-based assay for on-site detection of antibodies to HIV using whole blood. The reagent in this assay comprises of monovalent Fab fragment of an anti-human RBC antibody fused to immunodominant antigens of HIV-1 and HIV-2. In the present work, we describe a rational and systematic method for directed evolution of scFv and Fab antihuman RBC antibody fragments. Based on homology modeling and germline sequence alignments of antibodies, target residues in the anti-RBC MAb B6 sequence were identified for mutagenesis.A combinatorial library of 107 clones was constructed and subjected to selection on whole RBC under competitive binding conditions to identify several phage-displayed B6 scFv clones with improved binding as determined in an agglutination assay.Selected VL and VH sequences were shuffled to generate a second generation phage-displayed Fab library which on panning yielded Fab clones with several fold better binding than wild type. The mutants with better binding also displayed more Fab molecules per phage particle indicating improved in vivo folding which was also confirmed by their increased periplasmic secretion compared to the wild type. The mutant Fab molecules also showed superior characteristics in large scale production by in vitro folding of LC and Fd. The biophysical measurements involving thermal and chemical denaturation and renaturation kinetics clearly showed that two of the mutant Fab molecules possessed significantly improved characteristics as compared to the wild type B6 Fab.Structural modelling revealed that B6 Fab mutants had increased hydrogen bonding resulting in increased stability. Our approach provides a novel and useful strategy to obtain recombinant antibodies with improved characteristics. PMID:20069755

Gupta, Amita; Chaudhary, Vijay K; Bhat, Rajiv

2009-01-01

174

A monovalent anti-human CD28 domain antibody antagonist: preclinical efficacy and safety.  

PubMed

Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, we describe anti-human CD28 receptor antagonist domain Abs (dAbs) that are specific for human CD28. These dAbs are potent inhibitors of T cell activation, with an EC50 of 35 ± 14 ng/ml for inhibition of proliferation. The EC50 of 53 ± 11 ng/ml in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation. The anti-CD28 dAb is equipotent in the inhibition of CD80- and CD86-mediated T cell proliferation and does not interfere with CTLA-4-mediated downmodulation of CD86 expression on APCs. The anti-CD28 dAbs are monomeric and do not demonstrate any evidence of agonism or costimulatory activity. In cynomolgus monkeys, the anti-CD28 dAb demonstrated pharmacodynamic activity, as measured by the inhibition of a T cell-dependent Ab response, without evidence of T cell depletion or cytokine release. Furthermore, there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamic activity. Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases. PMID:24081989

Suchard, Suzanne J; Davis, Patricia M; Kansal, Selena; Stetsko, Dawn K; Brosius, Ruth; Tamura, James; Schneeweis, Lumelle; Bryson, James; Salcedo, Theodora; Wang, Haiqing; Yang, Zheng; Fleener, Catherine A; Ignatovich, Olga; Plummer, Christopher; Grant, Steven; Nadler, Steven G

2013-11-01

175

Directed evolution of an anti-human red blood cell antibody  

PubMed Central

We have earlier described a haemagglutination-based assay for on-site detection of antibodies to HIV using whole blood. The reagent in this assay comprises of monovalent Fab fragment of an anti-human RBC antibody fused to immunodominant antigens of HIV-1 and HIV-2. In the present work, we describe a rational and systematic method for directed evolution of scFv and Fab antihuman RBC antibody fragments. Based on homology modeling and germline sequence alignments of antibodies, target residues in the anti-RBC MAb B6 sequence were identified for mutagenesis. A combinatorial library of 107 clones was constructed and subjected to selection on whole RBC under competitive binding conditions to identify several phage-displayed B6 scFv clones with improved binding as determined in an agglutination assay. Selected VL and VH sequences were shuffled to generate a second generation phage-displayed Fab library which on panning yielded Fab clones with several fold better binding than wild type. The mutants with better binding also displayed more Fab molecules per phage particle indicating improved in vivo folding which was also confirmed by their increased periplasmic secretion compared to the wild type. The mutant Fab molecules also showed superior characteristics in large scale production by in vitro folding of LC and Fd. The biophysical measurements involving thermal and chemical denaturation and renaturation kinetics clearly showed that two of the mutant Fab molecules possessed significantly improved characteristics as compared to the wild type B6 Fab. Structural modelling revealed that B6 Fab mutants had increased hydrogen bonding resulting in increased stability. Our approach provides a novel and useful strategy to obtain recombinant antibodies with improved characteristics.

Bhat, Rajiv

2009-01-01

176

Characterization of a surrogate murine antibody to model anti-human CD3 therapies.  

PubMed

Fc-modified anti-human CD3? monoclonal antibodies (mAbs) are in clinical development for the treatment of autoimmune diseases. These next generation mAbs have completed clinical trials in patients with type-1 diabetes and inflammatory bowel disease demonstrating a narrow therapeutic window. Lowered doses are ineffective, yet higher pharmacologically-active doses cause an undesirable level of adverse events. Thus, there is a critical need for a return to bench research to explore ways of improving clinical outcomes. Indeed, we recently reported that a short course of treatment affords synergy, providing long-term disease amelioration when combining anti-mouse CD3 and anti-mouse tumor necrosis factor mAbs in experimental arthritis. Such strategies may widen the window between risk and benefit; however, to more accurately assess experimentally the biology and pharmacology, reagents that mimic the current development candidates were required. Consequently, we engineered an Fc-modified anti-mouse CD3? mAb, 2C11-Novi. Here, we report the functional characterization of 2C11-Novi demonstrating that it does not bind Fc?R in vitro and elicits little cytokine release in vivo, while maintaining classical pharmacodynamic effects (CD3-TCR downregulation and T cell killing). Furthermore, we observed that oral administration of 2C11-Novi ameliorated progression of remitting-relapsing experimental autoimmune encephalitis in mice, significantly reducing the primary acute and subsequent relapse phase of the disease. With innovative approaches validated in two experimental models of human disease, 2C11-Novi represents a meaningful tool to conduct further mechanistic studies aiming at exploiting the immunoregulatory properties of Fc-modified anti-CD3 therapies via combination therapy using parenteral or oral routes of administration. PMID:23751612

Dépis, Fabien; Hatterer, Eric; Ballet, Romain; Daubeuf, Bruno; Cons, Laura; Glatt, Sophie; Reith, Walter; Kosco-Vilbois, Marie; Dean, Yann

2013-01-01

177

Induction of antibody mediated neutralization in SIVmac239 by a naturally acquired V3 mutation  

PubMed Central

Achieving humoral immunity against human immunodeficiency virus (HIV) is a major obstacle in AIDS vaccine development. Despite eliciting robust humoral responses to HIV, exposed hosts rarely produce broadly neutralizing antibodies. The present study utilizes simian immunodeficiency virus (SIV) to identify viral epitopes that conferred antibody neutralization to clone SIV/17E-CL, an in vivo variant derived from neutralization resistant SIVmac239. Neutralization assays using rhesus macaque monoclonal antibodies were performed on viruses engineered to express single or multiple amino acid mutations. Results identified a single amino acid mutation, P334R, in the carboxy-terminal half of the V3 loop as a critical residue that induced neutralization while retaining normal glycoprotein expression on the surface of the virus. Furthermore, the R334 residue yielded neutralization sensitivity by antibodies recognizing diverse conformational and linear epitopes of gp120, suggesting that neutralization phenotype was a consequence of global structural changes of the envelope protein rather than a specific site epitope.

Faith, Seth A.; Wu, Yingyun; Kuhrt, David; Steckbeck, Jonathan D.; Craigo, Jodi K.; Clements, Janice E.; Cole, Kelly Stefano

2010-01-01

178

Space Flight Immunodeficiency  

NASA Technical Reports Server (NTRS)

The National Aeronautics and Space Administration (NASA) has had sufficient concern for the well-being of astronauts traveling in space to create the National Space Biomedical Research Institute (NSBRI), which is investigating several areas of biomedical research including those of immunology. As part of the Immunology, Infection, and Hematology Team, the co-investigators of the Space Flight Immunodeficiency Project began their research projects on April 1, 1998 and are now just into the second year of work. Two areas of research have been targeted: 1) specific immune (especially antibody) responses and 2) non-specific inflammation and adhesion. More precise knowledge of these two areas of research will help elucidate the potential harmful effects of space travel on the immune system, possibly sufficient to create a secondary state of immunodeficiency in astronauts. The results of these experiments are likely to lead to the delineation of functional alterations in antigen presentation, specific immune memory, cytokine regulation of immune responses, cell to cell interactions, and cell to endothelium interactions.

Shearer, William T.

1999-01-01

179

Anti-AIDS Agents 78 †. Design, Synthesis, Metabolic Stability Assessment, and Antiviral Evaluation of Novel Betulinic Acid Derivatives as Potent Anti-Human Immunodeficiency Virus (HIV) Agents  

PubMed Central

In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives, as well as seven novel 3,28-disubstituted BA analogs were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC50: 0.09 ?M), when compared to HIV entry inhibitors 3b (IC9564) and 4 (A43-D). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC50 values of 0.007 ?M and 0.006 ?M, respectively. These results are slightly better than that of bevirimat (2), which is currently in Phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates.

Qian, Keduo; Yu, Donglei; Chen, Chin-Ho; Huang, Li; Morris-Natschke, Susan L.; Nitz, Theodore J.; Salzwedel, Karl; Reddick, Mary; Allaway, Graham P.; Lee, Kuo-Hsiung

2009-01-01

180

Antiviral Drugs for Viruses Other Than Human Immunodeficiency Virus  

PubMed Central

Most viral diseases, with the exception of those caused by human immunodeficiency virus, are self-limited illnesses that do not require specific antiviral therapy. The currently available antiviral drugs target 3 main groups of viruses: herpes, hepatitis, and influenza viruses. With the exception of the antisense molecule fomivirsen, all antiherpes drugs inhibit viral replication by serving as competitive substrates for viral DNA polymerase. Drugs for the treatment of influenza inhibit the ion channel M2 protein or the enzyme neuraminidase. Combination therapy with Interferon-? and ribavirin remains the backbone treatment for chronic hepatitis C; the addition of serine protease inhibitors improves the treatment outcome of patients infected with hepatitis C virus genotype 1. Chronic hepatitis B can be treated with interferon or a combination of nucleos(t)ide analogues. Notably, almost all the nucleos(t) ide analogues for the treatment of chronic hepatitis B possess anti–human immunodeficiency virus properties, and they inhibit replication of hepatitis B virus by serving as competitive substrates for its DNA polymerase. Some antiviral drugs possess multiple potential clinical applications, such as ribavirin for the treatment of chronic hepatitis C and respiratory syncytial virus and cidofovir for the treatment of cytomegalovirus and other DNA viruses. Drug resistance is an emerging threat to the clinical utility of antiviral drugs. The major mechanisms for drug resistance are mutations in the viral DNA polymerase gene or in genes that encode for the viral kinases required for the activation of certain drugs such as acyclovir and ganciclovir. Widespread antiviral resistance has limited the clinical utility of M2 inhibitors for the prevention and treatment of influenza infections. This article provides an overview of clinically available antiviral drugs for the primary care physician, with a special focus on pharmacology, clinical uses, and adverse effects.

Razonable, Raymund R.

2011-01-01

181

Antiviral drugs for viruses other than human immunodeficiency virus.  

PubMed

Most viral diseases, with the exception of those caused by human immunodeficiency virus, are self-limited illnesses that do not require specific antiviral therapy. The currently available antiviral drugs target 3 main groups of viruses: herpes, hepatitis, and influenza viruses. With the exception of the antisense molecule fomivirsen, all antiherpes drugs inhibit viral replication by serving as competitive substrates for viral DNA polymerase. Drugs for the treatment of influenza inhibit the ion channel M(2) protein or the enzyme neuraminidase. Combination therapy with Interferon-? and ribavirin remains the backbone treatment for chronic hepatitis C; the addition of serine protease inhibitors improves the treatment outcome of patients infected with hepatitis C virus genotype 1. Chronic hepatitis B can be treated with interferon or a combination of nucleos(t)ide analogues. Notably, almost all the nucleos(t) ide analogues for the treatment of chronic hepatitis B possess anti-human immunodeficiency virus properties, and they inhibit replication of hepatitis B virus by serving as competitive substrates for its DNA polymerase. Some antiviral drugs possess multiple potential clinical applications, such as ribavirin for the treatment of chronic hepatitis C and respiratory syncytial virus and cidofovir for the treatment of cytomegalovirus and other DNA viruses. Drug resistance is an emerging threat to the clinical utility of antiviral drugs. The major mechanisms for drug resistance are mutations in the viral DNA polymerase gene or in genes that encode for the viral kinases required for the activation of certain drugs such as acyclovir and ganciclovir. Widespread antiviral resistance has limited the clinical utility of M(2) inhibitors for the prevention and treatment of influenza infections. This article provides an overview of clinically available antiviral drugs for the primary care physician, with a special focus on pharmacology, clinical uses, and adverse effects. PMID:21964179

Razonable, Raymund R

2011-10-01

182

78 FR 29755 - Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus...  

Federal Register 2010, 2011, 2012, 2013

...FDA-2013-N-0473] Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus...for public comment on human immunodeficiency virus...Patient-Focused Drug Development and HIV Cure...

2013-05-21

183

78 FR 46969 - Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus...  

Federal Register 2010, 2011, 2012, 2013

...FDA-2013-N-0473] Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus...meeting entitled ``Human Immunodeficiency Virus...Patient-Focused Drug Development and HIV Cure...

2013-08-02

184

Human immunodeficiency virus endocrinopathy  

PubMed Central

Human immunodeficiency virus (HIV) endocrinopathy encompasses a broad spectrum of disorders. Almost all the endocrine organs are virtually affected by HIV infection. HIV can directly alter glandular function. More commonly secondary endocrine dysfunction occurs due to opportunistic infections and neoplasms in immunocompromised state. The complex interaction between HIV infection and endocrine system may be manifested as subtle biochemical and hormonal perturbation to overt glandular failure. Antiretroviral therapy as well as other essential medications often result in adverse endocrinal consequences. Apart from adrenal insufficiency, hypogonadism, diabetes and bone loss, AIDS wasting syndrome and HIV lipodystrophy need special reference. Endocrinal evaluation should proceed as in other patients with suspected endocrine dysfunction. Available treatment options have been shown to improve quality of life and long-term mortality in AIDS patients.

Sinha, Uma; Sengupta, Nilanjan; Mukhopadhyay, Prasanta; Roy, Keshab Sinha

2011-01-01

185

Cryo-Electron Tomographic Structure of an Immunodeficiency Virus Envelope Complex In Situ  

Microsoft Academic Search

The envelope glycoprotein (Env) complexes of the human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate viral entry and are a target for neutralizing antibodies. The receptor binding surfaces of Env are in large part sterically occluded or conformationally masked prior to receptor binding. Knowledge of the unliganded, trimeric Env structure is key for an understanding of viral entry

Giulia Zanetti; John A. G Briggs; Kay Grünewald; Quentin J Sattentau; Stephen D Fuller

2006-01-01

186

ICON: the early diagnosis of congenital immunodeficiencies.  

PubMed

Primary immunodeficiencies are intrinsic defects in the immune system that result in a predisposition to infection and are frequently accompanied by a propensity to autoimmunity and/or immunedysregulation. Primary immunodeficiencies can be divided into innate immunodeficiencies, phagocytic deficiencies, complement deficiencies, disorders of T cells and B cells (combined immunodeficiencies), antibody deficiencies and immunodeficiencies associated with syndromes. Diseases of immune dysregulation and autoinflammatory disorder are many times also included although the immunodeficiency in these disorders are often secondary to the autoimmunity or immune dysregulation and/or secondary immunosuppression used to control these disorders. Congenital primary immunodeficiencies typically manifest early in life although delayed onset are increasingly recognized. The early diagnosis of congenital immunodeficiencies is essential for optimal management and improved outcomes. In this International Consensus (ICON) document, we provide the salient features of the most common congenital immunodeficiencies. PMID:24619621

Routes, John; Abinun, Mario; Al-Herz, Waleed; Bustamante, Jacinta; Condino-Neto, Antonio; De La Morena, Maria Teresa; Etzioni, Amos; Gambineri, Eleonora; Haddad, Elie; Kobrynski, Lisa; Le Deist, Francoise; Nonoyama, Shigeaki; Oliveira, Joao Bosco; Perez, Elena; Picard, Capucine; Rezaei, Nima; Sleasman, John; Sullivan, Kathleen E; Torgerson, Troy

2014-05-01

187

A novel anti-human ICOSL monoclonal antibody that enhances IgG production of B cells.  

PubMed

ICOSL, a newly identified member of the B7 superfamily, plays a major role in immune responses. In this study, a functional anti-human ICOSL monoclonal antibody (MAb) 3B3 was obtained and characterized by means of flow cytometry, Western blot, and competition assay. This MAb could specifically recognize a distinct epitope of the ICOSL molecule. As a functional antibody, MAb 3B3 could inhibit the proliferation of T lymphocytes stimulated by ICOSL-L929 transfectants. Furthermore, it could enhance IgG production of PWM-driven B cells. The results indicate that the ICOS-ICOSL signal is critically involved in specific humoral immunity. PMID:23607348

Chen, Jie; Wang, Fengming; Cai, Qiuping; Shen, Shuang; Chen, Youguo; Hao, Chao; Sun, Jing

2013-04-01

188

Humanization and Characterization of an Anti-Human TNF-? Murine Monoclonal Antibody  

PubMed Central

A murine monoclonal antibody, m357, showing the highly neutralizing activities for human tumor necrosis factor (TNF-?) was chosen to be humanized by a variable domain resurfacing approach. The non-conserved surface residues in the framework regions of both the heavy and light chain variable regions were identified via a molecular modeling of m357 built by computer-assisted homology modeling. By replacing these critical surface residues with the human counterparts, a humanized version, h357, was generated. The humanized h357 IgG1 was then stably expressed in a mammalian cell line and the purified antibody maintained the high antigen binding affinity as compared with the parental m357 based on a soluble TNF-? neutralization bioassay. Furthermore, h357 IgG1 possesses the ability to mediate antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity upon binding to cells bearing the transmembrane form of TNF-?. In a mouse model of collagen antibody-induced arthritis, h357 IgG significantly inhibited disease progression by intra-peritoneal injection of 50 µg/mouse once-daily for 9 consecutive days. These results provided a basis for the development of h357 IgG as therapeutic use.

Chiu, Wei-Chun; Lai, Ya-Ping; Chou, Min-Yuan

2011-01-01

189

Actin cytoskeletal defects in immunodeficiency  

PubMed Central

The importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin-related primary immunodeficiencies (PIDs). Studies of these PIDs have revealed a pivotal role for the actin cytoskeleton in almost all stages of immune system function, from hematopoiesis and immune cell development, through to recruitment, migration, intercellular and intracellular signaling, and activation of both innate and adaptive immune responses. The major focus of this review is the immune defects that result from mutations in the Wiskott-Aldrich syndrome gene (WAS), which have a broad impact on many different processes and give rise to clinically heterogeneous immunodeficiencies. We also discuss other related genetic defects and the possibility of identifying new genetic causes of cytoskeletal immunodeficiency.

Moulding, Dale A; Record, Julien; Malinova, Dessislava; Thrasher, Adrian J

2013-01-01

190

Broad neutralization coverage of HIV by multiple highly potent antibodies.  

PubMed

Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies. The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine. PMID:21849977

Walker, Laura M; Huber, Michael; Doores, Katie J; Falkowska, Emilia; Pejchal, Robert; Julien, Jean-Philippe; Wang, Sheng-Kai; Ramos, Alejandra; Chan-Hui, Po-Ying; Moyle, Matthew; Mitcham, Jennifer L; Hammond, Phillip W; Olsen, Ole A; Phung, Pham; Fling, Steven; Wong, Chi-Huey; Phogat, Sanjay; Wrin, Terri; Simek, Melissa D; Koff, Wayne C; Wilson, Ian A; Burton, Dennis R; Poignard, Pascal

2011-09-22

191

A case of transfusion-related acute lung injury induced by anti-human leukocyte antigen antibodies in acute leukemia  

PubMed Central

Transfusion-related acute lung injury (TRALI) is a noncardiogenic pulmonary edema that occurs during or within 6 hours after transfusion. Risk factors for TRALI, which is relatively common in critically ill patients, include recent surgery, hematologic malignancy, and sepsis. Here, we report a case of TRALI induced by anti-human leukocyte antigen (anti-HLA) class II antibodies (HLA-DR) occurring after transfusion of platelet concentrates in a patient with acute leukemia. Although most patients with TRALI show improvement within 48-96 hours, our patient's condition rapidly worsened, and he did not respond to supportive treatment. TRALI is a relatively common and serious adverse transfusion reaction that requires prompt diagnosis and management.

Jin, Sun Mi; Jang, Moon Ju; Huh, Ji Young; Park, Myoung Hee; Song, Eun Young

2012-01-01

192

Preparation and functional studies of hydroxyethyl chitosan nanoparticles loaded with anti-human death receptor 5 single-chain antibody  

PubMed Central

Objective To prepare hydroxyethyl chitosan nanoparticles loaded with anti-human death receptor 5 single-chain antibody, and study their characteristics, functions, and mechanisms of action. Materials and methods The anti-human death receptor 5 single-chain antibody was constructed and expressed. Protein-loaded hydroxyethyl chitosan nanoparticles were prepared, and their size, morphology, particle-size distribution and surface zeta potential were measured by scanning electron microscopy and laser particle-size analysis. Mouse H22 hepatocellular carcinoma cells were cultured, and growth inhibition was examined using the CellTiter-Blue cell-viability assay. Flow cytometry and Hoechst 33342 were employed to measure cell apoptosis. Kunming mice with H22 tumor models were treated with protein-loaded hydroxyethyl chitosan nanoparticles, and their body weight and tumor size were measured, while hematoxylin and eosin staining was used to detect antitumor effects in vivo and side effects from tumors. Results The protein-loaded hydroxyethyl chitosan nanoparticles had good stability; the zeta potential was ?24.2±0.205, and the dispersion index was 0.203. The inhibition of the protein-loaded hydroxyethyl chitosan nanoparticles on H22 growth was both time- and dose-dependent. Increased expressions of active caspase 8, active caspase 3, and BAX were detected following treatment. The average weight gain, tumor weight, and mean tumor volume of the protein and protein-loaded hydroxyethyl chitosan nanoparticle groups were significantly different (P<0.05) compared with the phosphate-buffered saline group. Conclusion The protein-loaded hydroxyethyl chitosan nanoparticles effectively suppressed tumor growth, indicating that nanotechnology has the potential for broad application in cancer therapy.

Yang, Jingjing; Huang, Xiaoping; Luo, Fanghong; Cheng, Xiaofeng; Cheng, Lianna; Liu, Bin; Chen, Lihong; Hu, Ruyi; Shi, Chunyan; Zhuang, Guohong; Yin, Ping

2014-01-01

193

Optimization of human immunodeficiency virus type 1 envelope glycoproteins with V1\\/V2 deleted, using virus evolution  

Microsoft Academic Search

The human immunodeficiency virus type 1 envelope glycoprotein (Env) complex is the principal focus of neutralizing antibody-based vaccines. The functional Env complex is a trimer consisting of six individual subunits: three gp120 molecules and three gp41 molecules. The individual subunits have proven unsuccessful as vaccines presumably because they do not resemble the functional Env complex. Variable domains and carbohydrates shield

Ilja Bontjer; Aafke Land; Dirk Eggink; Erwin Verkade; Kiki Tuin; Chris Baldwin; Georgios Pollakis; William A. Paxton; L. J. Braakman; Ben Berkhout; Rogier W. Sanders

2009-01-01

194

Conserved Sequence and Structural Elements in the HIV1 Principal Neutralizing Determinant  

Microsoft Academic Search

The principal neutralizing determinant (PND) of human immunodeficiency virus HIV-1 is part of a disulfide bridged loop in the third variable region of the external envelope protein, gp120. Analysis of the amino acid sequences of this domain from 245 different HIV-1 isolates revealed that the PND is less variable than thought originally. Conservation to better than 80 percent of the

Gregory J. Larosa; Joseph P. Davide; Kent Weinhold; Julie A. Waterbury; Albert T. Profy; John A. Lewis; Alphonse J. Langlois; Gordon R. Dreesman; R. Neal Boswell; Phillip Shadduck; L. Howard Holley; Martin Karplus; Dani P. Bolognesi; Thomas J. Matthews; Emilio A. Emini; Scott D. Putney

1990-01-01

195

Improved Breadth and Potency of an HIV1Neutralizing Human Single-chain Antibody by Random Mutagenesis and Sequential Antigen Panning  

Microsoft Academic Search

Several human monoclonal antibodies can neutralize a range of human immunodeficiency virus type 1 (HIV-1) primary isolates but their potency and related ability to suppress generation of HIV-1 escape mutants is significantly lower than the activity of antiretroviral drugs currently in clinical use. Recently, a human Fab, X5, was identified and found to neutralize primary isolates from different clades. Further

Mei-Yun Zhang; Yuuei Shu; Donna Rudolph; Ponraj Prabakaran; Aran F. Labrijn; Michael B. Zwick; Renu B. Lal; Dimiter S. Dimitrov

2004-01-01

196

Human Immunodeficiency Virus (HIV) Primary Infection  

MedlinePLUS

newsletter | contact Share | Human Immunodeficiency Virus (HIV) Primary Infection Information for adults A A A When HIV is first contracted, there may be ... 1–6 weeks following exposure to HIV (the human immunodeficiency virus). Chronic infection with this virus can ...

197

Pathogenesis of human immunodeficiency virus infection.  

PubMed Central

The lentivirus human immunodeficiency virus (HIV) causes AIDS by interacting with a large number of different cells in the body and escaping the host immune response against it. HIV is transmitted primarily through blood and genital fluids and to newborn infants from infected mothers. The steps occurring in infection involve an interaction of HIV not only with the CD4 molecule on cells but also with other cellular receptors recently identified. Virus-cell fusion and HIV entry subsequently take place. Following virus infection, a variety of intracellular mechanisms determine the relative expression of viral regulatory and accessory genes leading to productive or latent infection. With CD4+ lymphocytes, HIV replication can cause syncytium formation and cell death; with other cells, such as macrophages, persistent infection can occur, creating reservoirs for the virus in many cells and tissues. HIV strains are highly heterogeneous, and certain biologic and serologic properties determined by specific genetic sequences can be linked to pathogenic pathways and resistance to the immune response. The host reaction against HIV, through neutralizing antibodies and particularly through strong cellular immune responses, can keep the virus suppressed for many years. Long-term survival appears to involve infection with a relatively low-virulence strain that remains sensitive to the immune response, particularly to control by CD8+ cell antiviral activity. Several therapeutic approaches have been attempted, and others are under investigation. Vaccine development has provided some encouraging results, but the observations indicate the major challenge of preventing infection by HIV. Ongoing research is necessary to find a solution to this devastating worldwide epidemic. Images

Levy, J A

1993-01-01

198

Severe Viral Infections and Primary Immunodeficiencies  

PubMed Central

Patients with severe viral infections are often not thoroughly evaluated for immunodeficiencies. In this review, we summarize primary immunodeficiencies that predispose individuals to severe viral infections. Some immunodeficiencies enhance susceptibility to disease with a specific virus or family of viruses, whereas others predispose to diseases with multiple viruses in addition to disease with other microbes. Although the role of cytotoxic T cells in controlling viral infections is well known, a number of immunodeficiencies that predispose to severe viral diseases have recently been ascribed to defects in the Toll-like receptor–interferon signaling pathway. These immunodeficiencies are rare, but it is important to identify them both for prognostic information and for genetic counseling. Undoubtedly, additional mutations in proteins in the innate and adaptive arms of the immune system will be identified in the future, which will reveal the importance of these proteins in controlling infections caused by viruses and other pathogens.

Cohen, Jeffrey I.

2011-01-01

199

Probing Specific Interaction Forces Between Human IgG and Rat Anti-Human IgG by Self-Assembled Monolayer and Atomic Force Microscopy  

NASA Astrophysics Data System (ADS)

Interaction forces between biological molecules such as antigen and antibody play important roles in many biological processes, but probing these forces remains technically challenging. Here, we investigated the specific interaction and unbinding forces between human IgG and rat anti-human IgG using self assembled monolayer (SAM) method for sample preparation and atomic force microscopy (AFM) for interaction force measurement. The specific interaction force between human IgG and rat anti-human IgG was found to be 0.6-1.0 nN, and the force required for unbinding a single pair of human IgG and rat anti-human IgG was calculated to be 144 ± 11 pN. The results are consistent with those reported in the literatures. Therefore, SAM for sample preparation combined with AFM for interaction measurement is a relatively simple, sensitive and reliable technique to probe specific interactions between biological molecules such as antigen and antibody.

Lv, Zhengjian; Wang, Jianhua; Chen, Guoping; Deng, Linhong

2010-06-01

200

Preclinical evaluation of light-activatable, bispecific anti-human CD3 antibody conjugates as anti-ovarian cancer therapeutics  

PubMed Central

The administration of anti-CD3 antibodies, either unmodified or in bispecific formats, has been shown to kill tumors. However, their activity needs to be carefully controlled. We have approached this problem by inhibiting their anti-CD3 activity until it is required. Folated anti-human CD3 antibody bispecific conjugates were therefore synthesised in which the folate portion of the conjugates remained free to bind to folate receptor (FR) expressing cancer cells, whilst their anti-CD3 activity was reversibly inhibited. On irradiation with UV-A light, the T-cell binding activity of the anti-CD3 antibody can be restored only when and where it is required, i.e., adjacent to a tumor. Conjugate bound to FR expressed on normal tissues in other parts of the body remains inactive. This report describes the preclinical in vivo testing of these conjugates in transgenic mice whose T-cells express human CD3 molecules. When the ‘cloaked’ conjugates were reactivated in the region of the primary tumor, both primary tumor growth and liver metastasis were markedly reduced. That the deliberate targeting of T-cell activity locally to the primary tumor also resulted in reduced distant metastatic growth was a key finding. Light-activatable bispecific antibody conjugates similar to those described here offer a means to control T-cell targeting with a much higher degree of specificity to tumors because they minimize potentially dangerous and unwanted side effects in non-illuminated areas. The addition of light-specific targeting to the inherent tumor specific targeting of therapeutic antibody conjugates could result in the development of safer treatments for patients.

Dessi, John

2009-01-01

201

Cetuximab in combination with anti-human IgG antibodies efficiently down-regulates the EGF receptor by macropinocytosis  

SciTech Connect

The monoclonal antibody C225 (Cetuximab) blocks binding of ligand to the epidermal growth factor receptor (EGFR). In addition, it is known that incubation with C225 induces endocytosis of the EGFR. This endocytosis has previously been shown to be increased when C225 is combined with an additional monoclonal anti-EGFR antibody. However, the effects of antibody combinations on EGFR activation, endocytosis, trafficking and degradation have been unclear. By binding a secondary antibody to the C225-EGFR complex, we here demonstrate that a combination of antibodies can efficiently internalize and degrade the EGFR. Although the combination of antibodies activated the EGFR kinase and induced ubiquitination of the EGFR, the kinase activity was not required for internalization of the EGFR. In contrast to EGF-induced EGFR down-regulation, the antibody combination efficiently degraded the EGFR without initiating downstream proliferative signaling. The antibody-induced internalization of EGFR was found not to depend on clathrin and/or dynamin, but depended on actin polymerization, suggesting induction of macropinocytosis. Macropinocytosis may cause internalization of large membrane areas, and this could explain the highly efficient internalization of the EGFR induced by combination of antibodies. -- Highlight: Black-Right-Pointing-Pointer Cetuximab induced endocytosis of EGFR increases upon combination with anti-human IgG. Black-Right-Pointing-Pointer Antibody combination causes internalization of EGFR by macropinocytosis. Black-Right-Pointing-Pointer Antibody-induced internalization of EGFR is independent of EGFR kinase activity. Black-Right-Pointing-Pointer Antibody combination may have a zipper effect and cross-link EGFRs on neighboring cells.

Berger, Christian [Department of Pathology, Oslo University Hospital, Rikshospitalet, Post box 4950 Nydalen, 0424 Oslo (Norway)] [Department of Pathology, Oslo University Hospital, Rikshospitalet, Post box 4950 Nydalen, 0424 Oslo (Norway); Madshus, Inger Helene [Institute of Pathology, University of Oslo, Rikshospitalet, 0027 Oslo (Norway) [Institute of Pathology, University of Oslo, Rikshospitalet, 0027 Oslo (Norway); Department of Pathology, Oslo University Hospital, Rikshospitalet, Post box 4950 Nydalen, 0424 Oslo (Norway); Stang, Espen, E-mail: espsta@rr-research.no [Department of Pathology, Oslo University Hospital, Rikshospitalet, Post box 4950 Nydalen, 0424 Oslo (Norway)] [Department of Pathology, Oslo University Hospital, Rikshospitalet, Post box 4950 Nydalen, 0424 Oslo (Norway)

2012-12-10

202

ITER neutralizer modeling (abstract)  

NASA Astrophysics Data System (ADS)

In the neutralizer of the ITER Neutral Beam Injector, a 1 MeV-D- beam passes through an structure filled with D2 gas, where negative ions are mainly converted to fast D0 atoms. Once that the beam is neutralized no further optical correction is possible, i.e., transport from the neutralizer to the confinement chamber is ballistic. Because of this, the transport through the neutralizer determines ultimately the geometrical properties of the neutral beams. The ionization of the buffer gas (D2) filling the neutralizer induced by the D beam creates a rarefied and low temperature plasma (ionization degree ~10-3, electron temperature ~20 eV). This plasma can screen the electrostatic well of the D beam and, consequently, affect the properties of the extracted beam and the energy transport to the neutralizer walls. On the other hand, the plasma will eventually escape from the neutralizer and move back in the accelerator chain, toward the accelerating grids and the source. We present particle-in-cell simulations of the beam propagation and plasma formation through the neutralizer. Particle-particle and particle-wall collisions are treated using a Monte Carlo approach. Simulations show that the secondary plasma effectively screens the beam space charge preventing beam radial expansion due to Coulomb repulsion between beam ions. First results suggest that the current of plasma ions (D2+) into the accelerator would be of the order of I(D-)/100, with I(D-) the negative ion current.

Minea, T.; Lifschitz, A.; Maynard, G.; Katsonis, K.; Bretagne, J.; Simonin, A.

2008-02-01

203

Neutral particle beam intensity controller  

Microsoft Academic Search

A neutral beam intensity controller is provided for a neutral beam generator in which a neutral beam is established by accelerating ions from an ion source into a gas neutralizer. An amplitude modulated, rotating magnetic field is applied to the accelerated ion beam in the gas neutralizer to defocus the resultant neutral beam in a controlled manner to achieve intensity

Dagenhart; William K

1986-01-01

204

Purification, Characterization, and Immunogenicity of a Soluble Trimeric Envelope Protein Containing a Partial Deletion of the V2 Loop Derived from SF162, an R5Tropic Human Immunodeficiency Virus Type 1 Isolate  

Microsoft Academic Search

The envelope (Env) glycoprotein of human immunodeficiency virus type 1 (HIV-1) is the major target of neutralizing antibody responses and is likely to be a critical component of an effective vaccine against AIDS. Although monomeric HIV envelope subunit vaccines (gp120) have induced high-titer antibody responses and neutralizing antibodies against laboratory-adapted HIV-1 strains, they have failed to induce neutralizing antibodies against

Indresh K. Srivastava; Leonidas Stamatatos; Elaine Kan; Michael Vajdy; Ying Lian; Susan Hilt; Loic Martin; Claudio Vita; Ping Zhu; Kenneth H. Roux; Lucia Vojtech; David C. Montefiori; John Donnelly; Jeffrey B. Ulmer; Susan W. Barnett

2003-01-01

205

Phenotypic studies on recombinant human immunodeficiency virus type 1 (HIV1) containing CRF01_AE env gene derived from HIV1-infected patient, residing in central Thailand  

Microsoft Academic Search

Human immunodeficiency virus type 1 (HIV-1) env genes were cloned from blood samples of HIV-1-infected Thai patients, and 35 infectious CRF01_AE envelope glycoprotein (Env)-recombinant viruses were established. In this report, we examined the neutralization susceptibility of these viruses to human monoclonal antibodies, 2G12, IgG1 b12, 2F5 and 4E10, pooled patient plasma, coreceptor antagonists and fusion inhibitor, T-20. The neutralization susceptibility

Piraporn Utachee; Piyamat Jinnopat; Panasda Isarangkura-na-ayuthaya; U. Chandimal de Silva; Shota Nakamura; Uamporn Siripanyaphinyo; Nuanjun Wichukchinda; Kenzo Tokunaga; Teruo Yasunaga; Pathom Sawanpanyalert; Kazuyoshi Ikuta; Wattana Auwanit; Masanori Kameoka

2009-01-01

206

Characterization of Antibody Responses Elicited by Human Immunodeficiency Virus Type 1 Primary Isolate Trimeric and Monomeric Envelope Glycoproteins in Selected Adjuvants  

Microsoft Academic Search

We previously reported that soluble, stable YU2 gp140 trimeric human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein immunogens could elicit improved breadth of neutralization against HIV-1 isolates compared to monomeric YU2 gp120 proteins. In this guinea pig immunization study, we sought to extend these data and determine if adjuvant could quantitatively or qualitatively alter the neutralizing response elicited by trimeric

Y. Li; K. Svehla; N. L. Mathy; G. Voss; J. R. Mascola; R. Wyatt

2006-01-01

207

Disseminated cytomegalovirus infection in immunodeficient rhesus monkeys.  

PubMed Central

Rhesus monkeys experimentally infected with the lentivirus SIV/Delta become immunodeficient and often die of opportunistic infections. The most frequent of these is cytomegalovirus (CMV). The lesions due to reactivated CMV infection in 14 SIV-infected monkeys were reviewed. Changes due to CMV were observed in the brain, lung, lymph node, liver, spleen, small intestine, testicle, nerves, and arteries. Disseminated CMV infection in immunodeficient rhesus monkeys is a useful model for studying the pathogenesis, treatment, and prevention of similar infections in immunodeficient human beings. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8

Baskin, G. B.

1987-01-01

208

Antiretroviral Spermicide WHI-07 Prevents Vaginal and Rectal Transmission of Feline Immunodeficiency Virus in Domestic Cats  

PubMed Central

WHI-07 [5-bromo-6-methoxy-5,6-dihydro-3?-azidothymidine-5?-(p-bromophenyl)-methoxy alaninyl phosphate] is a novel dual-function aryl phosphate derivative of zidovudine with potent anti-human immunodeficiency virus (HIV) and spermicidal activities. WHI-07 was active against the feline immunodeficiency virus (FIV). This study evaluated whether topical application of WHI-07 as a single agent and in combination with an organometallic vanadium complex, vanadocene dithiocarbamate (VDDTC), via a nontoxic gel microemulsion can block vaginal as well as rectal transmission of feline AIDS (FAIDS) by chronically FIV-infected feline T cells in the natural host model. Genital transmission of FIV was monitored in recipient cats by the appearance of viral antibodies to FIV Gag proteins and by virus isolation of blood leukocytes as measured by FIV reverse transcriptase activity and FIV-specific PCR. Microbicidal activity was considered effective when the treated cats did not show evidence of FIV infection for up to 18 weeks postchallenge. An aggregate analysis of 46 specific-pathogen-free cats revealed that a single dose of the infected cell inoculum efficiently transmitted FIV infection when delivered into the vagina (100%) or rectum (66%). Pretreatment of the vagina or rectum with 2% WHI-07 alone or in combination with 0.25% VDDTC significantly (P = 0.004) protected cats from genital transmission by the highly infectious inoculum (7 million FIVBangston-infected feline T cells). Collectively, using the vaginal and rectal transmucosal model for FAIDS, our studies demonstrated that WHI-07 either alone or in combination with a vanadocene has clinical potential for the development of a dual-function anti-HIV microbicide for sexually active women.

D'Cruz, Osmond J.; Waurzyniak, Barbara; Uckun, Fatih M.

2004-01-01

209

Generation of anti-human DEC205/CD205 monoclonal antibodies that recognize epitopes conserved in different mammals  

PubMed Central

DEC205/CD205 is a C-type multilectin receptor, expressed highly in dendritic cells (DCs). Previous efforts to generate anti-human DEC205 (anti-hDEC205) monoclonal antibodies (mAbs) from mice immunized with subdomain proteins of hDEC205 resulted in a few mAbs. Recently, we expressed and utilized a full-length extracellular domain protein of hDEC205 to successfully generate 5 strong anti-hDEC205 mAbs from mice. In this study, DEC205 knockout (KO) mice were immunized with this full-length extracellular domain protein of hDEC205. One of the 3 immunized DEC205 KO mice was chosen for the highest anti-hDEC205 titer by flow cytometric analysis of serum samples on CHO cells stably expressing hDEC205 (CHO/hDEC205 cells) and used for hybridoma fusion. From a single fusion, more than 400 anti-hDEC205 hybridomas were identified by flow cytometric screen with CHO/hDEC205 cells, and a total of 115 hybridomas secreting strong anti-hDEC205 mAb were saved and named HD1 through HD115. To characterize in detail, 10 HD mAbs were chosen for superior anti-hDEC205 reactivity and further subjected to cloning and purification. Interestingly, out of those 10 chosen anti-hDEC205 HD mAbs, 5 mAbs were also strongly reactive to mouse DEC205 while 8 mAbs were found to stain DEC205+ DCs on monkey spleen sections. In addition, we also identified that HD83, one of the 10 chosen HD mAbs, stains DEC205+ DCs in rat spleen and lymph node. Therefore, by immunizing DEC205 KO mice with a full-length extracellular domain protein of hDEC205, we generated a large number of strong anti-hDEC205 mAbs many of which are cross-species reactive and able to visualize DEC205+ DCs in lymphoid tissues of other mammals.

Park, Chae Gyu; Rodriguez, Anthony; Ueta, Hisashi; Lee, Haekyung; Pack, Maggi; Matsuno, Kenjiro; Steinman, Ralph M.

2012-01-01

210

Inhibition of choriocarcinoma by Fe3O4-dextran-anti-?-human chorionic gonadotropin nanoparticles containing antisense oligodeoxynucleotide of heparanase  

PubMed Central

Objective To observe the influence of Fe3O4-dextran-anti-?-human chorionic gonadotropin (HCG) carrying heparanase (Hpa) antisense oligodeoxynucleotide (ASODN), via the invasion, proliferation, and Hpa expression of JEG-3 cell lines and inhibitory effect of transplanted choriocarcinoma tumor growth. Methods The different abilities of invasion and proliferation between transfected JEG-3 and untransfected JEG-3 were measured by Matrigel invasion assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in vitro. The effect of Hpa ASODN transfection on the expression of Hpa mRNA and protein was measured by reverse-transcription polymerase chain reaction and Western blot. The transplanted choriocarcinoma tumors were taken out to calculate the inhibitory effect on tumor growth of Hpa ASODN. Results In this study, we found that: (1) the invasive ability of JEG-3 cells was inhibited sufficiently (P < 0.05) after JEG-3 cells were transfected by Fe3O4-dextran-anti-?HCG carrying Hpa ASODN; (2) after JEG-3 cells were transfected by Fe3O4-dextran-anti-?HCG carrying Hpa ASODN at 48 and 72 hours, the proliferative ability of JEG-3 cells was inhibited sufficiently (P < 0.05); (3) the expression of Hpa mRNA and protein in JEG-3 cells was inhibited efficiently after JEG-3 cells were transfected by Fe3O4-dextran-anti-?HCG carrying Hpa ASODN (P < 0.05); and (4) Fe3O4-dextran-anti-?HCG carrying Hpa ASODN had an inhibitory effect on the transplanted choriocarcinoma tumor growth (P < 0.05) and was harmless on nude mice. Conclusion Fe3O4-dextran-anti-?HCG carrying Hpa ASODN weakened the invasive and proliferative ability of choriocarcinoma, with a significant inhibitory effect on the transplanted choriocarcinoma tumor. Therefore, Fe3O4-dextran-anti-?HCG carrying Hpa ASODN is an effective gene therapy, and Fe3O4-dextran-anti-?HCG nanoparticles are a harmless and effective gene vector.

Huining, Liu; Yi, Zhang; Dihong, Tang; Yifeng, Pan; Man, Xia; Ting, Yang; Jingting, Cai

2013-01-01

211

Gene Therapy for Primary Immunodeficiencies  

PubMed Central

Abstract For over 40 years, primary immunodeficiencies (PIDs) have featured prominently in the development and refinement of human allogeneic hematopoietic stem cell transplantation. More recently, ex vivo somatic gene therapy using autologous cells has provided remarkable evidence of clinical efficacy in patients without HLA-matched stem cell donors and in whom toxicity of allogeneic procedures is likely to be high. Together with improved preclinical models, a wealth of information has accumulated that has allowed development of safer, more sophisticated technologies and protocols that are applicable to a much broader range of diseases. In this review we summarize the status of these gene therapy trials and discuss the emerging application of similar strategies to other PIDs.

Rivat, Christine; Santilli, Giorgia; Gaspar, H. Bobby

2012-01-01

212

Autoimmunity in Common Variable Immunodeficiency  

PubMed Central

Common variable immunodeficiency (CVID) is the most common clinically significant primary immune defect. Although the hallmark of CVID is hypogammaglobulinemia, the intrinsic dysregulation of the immune system leads to defective T-cell activation and proliferation, as well as dendritic cell and cytokine defects. Although 70% to 80% of patients have had recurrent sinopulmonary infections, auto-immunity and inflammatory complications are also common. The most common autoimmune conditions are immune thrombocytopenic purpura and hemolytic anemia, but other autoimmune complications arise, including rheumatoid arthritis, pernicious anemia, primary biliary cirrhosis, thyroiditis, sicca syndrome, systemic lupus, and inflammatory bowel disease. Treatment of autoimmunity includes high-dose immunoglobulins, corticosteroids, selected immunosuppressants, and other immune modulators. This review focuses on autoimmune conditions associated with CVID, potential mechanisms of immune dysregulation, and therapeutic strategies.

Agarwal, Shradha; Cunningham-Rundles, Charlotte

2010-01-01

213

A DNA\\/MVA-based candidate human immunodeficiency virus vaccine for Kenya induces multi-specific T cell responses in rhesus macaques  

Microsoft Academic Search

The minimum requirement for candidate human immunodeficiency virus (HIV) vaccines to enter clinical evaluation in humans should be their demonstrable immunogenicity in non-human primates: induction of antibodies neutralizing pri- mary HIV isolates or elicitation of broad T cell- mediated immune responses. Here, we showed in rhesus macaques that the very same vaccines that had entered clinical trials in Oxford and

Edmund G.-T. Wee; Sandip Patel; Andrew J. McMichael

214

Learning about Severe Combined Immunodeficiency (SCID)  

MedlinePLUS

... Severe Combined Immunodeficiency (SCID) [rarediseases.info.nih.gov] Finding Reliable Health Information Online A listing of information and links for finding comprehensive genetics health information online. Top of page Last Updated: June ...

215

Decelerating Neutral Dipolar Molecules  

Microsoft Academic Search

It is experimentally demonstrated that a beam of neutral dipolar molecules can be efficiently decelerated with a time-varying electric field. A pulsed beam of neutral metastable CO molecules is slowed down from 225 m\\/s ( Ekin = 59 cm-1) to 98 m\\/s ( Ekin = 11 cm-1) upon passage through an array of 63 synchronously pulsed electric field stages.

Hendrick L. Bethlem; Giel Berden; Gerard Meijer

1999-01-01

216

Neutralizing Acids and Bases  

NSDL National Science Digital Library

Learners use their knowledge of color changes with red cabbage indicator to neutralize an acidic solution with a base and then neutralize a basic solution with an acid. Use this as a follow-up activity to the related activity, "Color Changes with Acids and Bases."

Kessler, James H.; Galvan, Patricia M.

2007-01-01

217

The Neutral Pentaquark  

Microsoft Academic Search

Using the principles of the Vortex Theory, it was discovered that when the gamma ray strikes a nucleon, the positively charged pentaquark [and the K^- meson] had to be created by the collision with neutron. This discovery further reveals that if the gamma ray strikes a proton it can create a Neutral Pentaquark [and a D^+ meson]. The neutral pentaquark

Russell Moon; Fabian Calvo; Victor Vasiliev

2006-01-01

218

Immunodeficiencies and Immunome: Diseases and Information Services  

Microsoft Academic Search

Essential human immunome is composed of about 900 genes and proteins. Primary immunodeficiencies (IDs) are a large and heterogenic\\u000a group of inherited disorders of the immune system. Since defects in any part of the adaptive or innate immune system can cause\\u000a disorders, numerous IDs have been detected. Immunodeficiency patients have increased susceptibility to recurrent and persistent,\\u000a even life-threatening infections. Other

Mauno Vihinen

219

Warts and All: HPV in Primary Immunodeficiencies  

PubMed Central

Infection with human papilloma virus (HPV) is almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy. It is also an underappreciated manifestation of primary immunodeficiency. Mutations in EVER1, EVER2, GATA2, CXCR4, and DOCK8 are typically associated with extensive HPV infections, whereas several other primary immune defects have severe HPV much less frequently. We review immunodeficiencies with severe HPV infections and the mechanisms underlying them.

Leiding, Jennifer W.; Holland, Steven M.

2012-01-01

220

Noncaseating granulomatous disease in common variable immunodeficiency.  

PubMed

Patients with common variable immunodeficiency (CVID) are occasionally recognized to have a concurrent noncaseating granulomatous disease. The granulomatous disease (GD) associated with CVID shares many clinical properties typical of sarcoidosis. Some investigators speculate that the GD-CVID is actually sarcoidosis that is expressed atypically because of the patient's immunodeficiency. Clinical differences, however, have led other investigators to speculate that the GD-CVID is a distinct "sarcoid-like" granulomatous process. PMID:10881789

Kanathur, N; Byrd, R P; Fields, C L; Roy, T M

2000-06-01

221

ITER neutralizer modeling (abstract)  

SciTech Connect

In the neutralizer of the ITER Neutral Beam Injector, a 1 MeV-D{sup -} beam passes through an structure filled with D{sub 2} gas, where negative ions are mainly converted to fast D{sup 0} atoms. Once that the beam is neutralized no further optical correction is possible, i.e., transport from the neutralizer to the confinement chamber is ballistic. Because of this, the transport through the neutralizer determines ultimately the geometrical properties of the neutral beams. The ionization of the buffer gas (D{sub 2}) filling the neutralizer induced by the D beam creates a rarefied and low temperature plasma (ionization degree {approx_equal}10{sup -3}, electron temperature {approx_equal}20 eV). This plasma can screen the electrostatic well of the D beam and, consequently, affect the properties of the extracted beam and the energy transport to the neutralizer walls. On the other hand, the plasma will eventually escape from the neutralizer and move back in the accelerator chain, toward the accelerating grids and the source. We present particle-in-cell simulations of the beam propagation and plasma formation through the neutralizer. Particle-particle and particle-wall collisions are treated using a Monte Carlo approach. Simulations show that the secondary plasma effectively screens the beam space charge preventing beam radial expansion due to Coulomb repulsion between beam ions. First results suggest that the current of plasma ions (D{sub 2}{sup +}) into the accelerator would be of the order of I(D{sup -})/100, with I(D{sup -}) the negative ion current.

Minea, T.; Lifschitz, A.; Maynard, G.; Katsonis, K.; Bretagne, J.; Simonin, A. [Laboratoire de Physique des Gaz et des Plasmas, Universite Paris Sud XI, 91405 Orsay Cedex (France); DRFC, CEA Cadarache, 13108 Saint-Paul lez Durance (France)

2008-02-15

222

History of Primary Immunodeficiency Diseases in Iran  

PubMed Central

Pediatric immunology came into sight in the second half of 20th century, when pediatricians and basic immunologists began to give attention to diagnosis and treatment of children with primary immunodeficiency diseases (PIDs). Understanding the genetic and mechanistic basis of PIDs provides unique insight into the functioning of the immune system. By progress in basic and clinical immunology, many infrastructural organizations and academic centers have been established in many countries worldwide to focus on training and research on the immune system and related disorders. Along with progress in basic and clinical immunology in the world, pediatric immunology had a good progress in Iran during the last 33-year period. Now, patients with PIDs can benefit from multidisciplinary comprehensive care, which is provided by clinical immunologists in collaboration with other specialists. Patients with history of recurrent and/or chronic infections suggestive of PIDs are evaluated by standard and research-based testing and receive appropriate treatment. The progress in PIDs can be described in three periods. Development of training program for clinical fellowship in allergy and immunology, multidisciplinary and international collaborative projects, primary immunodeficiency diseases textbooks, meetings on immunodeficiency disorders, improvement in diagnosis and treatment, and construction of Iranian primary immunodeficiency association, Students' research group for immunodeficiencies, Iranian primary immunodeficiency registry, and the immunological societies and centers were the main activities on PIDs during these years. In this article, we review the growth of modern pediatric immunology and PIDs status in Iran.

Aghamohammadi, Asghar; Moin, Mostafa; Rezaei, Nima

2010-01-01

223

Neutral particle beam intensity controller  

Microsoft Academic Search

A neutral beam generator is described wherein an energetic neutral particle beam is formed from a focused beam of ions accelerated along a beam axis into a neutralizer cell disposed about the beam axis, a neutral beam intensity controller. The controller consists of: a neutral particle beam dump disposed with a beam dump surface transverse to the beam axis downstream

Dagenhart

1986-01-01

224

Plasmas of Arbitrary Neutrality  

NASA Astrophysics Data System (ADS)

The physics of partially neutralized plasmas is largely unexplored, partly because of the difficulty of confining such plasmas. Plasmas are confined in a stellarator without the need for a plasma current, and regardless of the degree of neutralization. The Columbia Non-neutral Torus (CNT) is a stellarator dedicated to the study of non-neutral, and partially neutralized plasmas. This thesis describes the first systematic studies of plasmas of arbitrary neutrality. The degree of neutralization of the plasma can be parameterized through the quantity eta ? |ne - Z ni|/|ne + Z n i|. In CNT, eta can be varied continuously from pure electron (eta = 1) to quasi-neutral (eta = 0) by adjusting the neutral pressure in the chamber, which controls the volumetric ionization rate. Pure electron plasmas are in macroscopically stable equilibria, and have strong self electric potentials dictated by the emitter filament bias voltage on the magnetic axis. As eta decreases, the plasma potential decouples from the emitter, and spontaneous fluctuations begin to appear. Partially neutralized plasmas (10-3 < eta < 10-1) generally exhibit multi-mode oscillations in CNT. However, when magnetized ions are present, the electron-rich plasma oscillates at a single dominant mode (20 - 100 kHz). As the plasma approaches quasi-neutrality (eta < 10-5), it also reverts to single mode behavior (1 - 20 kHz). A parametric characterization of the single mode fluctuations detected in plasmas of arbitrary neutrality is presented in this thesis along with measurements of the spatial structure of the oscillations. The single mode fluctuations observed for eta ? 0.01 to 0.8 are identified as an ion resonant instability propagating close to the E x B velocity of the plasma. The experiments also show that these oscillations present a poloidal mode number m = 1, and a toroidal number n = 0, which is identical to the spatial structure of the diocotron instability in pure-toroidal traps, and implies that the ion-driven instability breaks parallel force balance and the conservation of poloidal flux in CNT. The low frequency oscillations detected in the quasi-neutral regime are a global instability convected by the E x B flow of the plasma. In this case, the mode aligns almost perfectly with the field lines, and presents a resonant m = 3 poloidal structure.

Sarasola Martin, Xabier

225

Chimeric Plant Virus Particles as Immunogens for Inducing Murine and Human Immune Responses against Human Immunodeficiency Virus Type 1  

Microsoft Academic Search

The high-yield expression of a neutralizing epitope from human immunodeficiency virus type 1 (HIV-1) on the surface of a plant virus and its immunogenicity are presented. The highly conserved ELDKWA epitope from glycoprotein (gp) 41 was expressed as an N-terminal translational fusion with the potato virus X (PVX) coat protein. The resulting chimeric virus particles (CVPs), purified and used to

CARLA MARUSIC; PAOLA RIZZA; LAURA LATTANZI; CAMILLO MANCINI; MASSIMO SPADA; FILIPPO BELARDELLI; EUGENIO BENVENUTO; IMERIO CAPONE

2001-01-01

226

Diagonal neutral currents  

Microsoft Academic Search

General conditions are derived for neutral currents to be diagonal in all quark fields. The solution is a generalization of the Glashow-Iliopoulos-Maiani scheme to many quark fields with two distinct charges. It is shown that the diagonality and universality of the neutral operator is preserved by leading terms of the single-loop diagrams. In contrast to the basic assumption of this

Emmanuel Paschos

1977-01-01

227

Genetics Home Reference: X-linked severe combined immunodeficiency  

MedlinePLUS

... PubMed Recent literature OMIM Genetic disorder catalog Conditions > X-linked severe combined immunodeficiency (often shortened to X- ... names Glossary definitions Reviewed May 2009 What is X-linked SCID? X-linked severe combined immunodeficiency (SCID) ...

228

Pathogenesis of human immunodeficiency virus infection and prospects for control.  

PubMed Central

In just six years after the initial description of the acquired immunodeficiency syndrome, much has been learned about the etiologic agent, the human immunodeficiency virus. The pathogenic mechanisms utilized by this virus to infect selectively and persistently T4+ lymphocytes and monocyte/macrophages, leading to immunodeficiency and neurologic dysfunction, are slowly becoming clear. Better understanding of the pathogenesis of human immunodeficiency virus infection is essential for the rational design of therapeutic and preventive strategies to combat this deadly virus.

Ho, D. D.; Kaplan, J. C.

1987-01-01

229

Gene therapy of primary T cell immunodeficiencies.  

PubMed

Gene therapy of severe combined immunodeficiencies has been proven to be effective to provide sustained correction of the T cell immunodeficiencies. This has been achieved for 2 forms of SCID, i.e SCID-X1 (?c deficiency) and adenosine deaminase deficiency. Occurrence of gene toxicity generated by integration of first generation retroviral vectors, as observed in the SCID-X1 trials has led to replace these vectors by self inactivated (SIN) retro(or lenti) viruses that may provide equivalent efficacy with a better safety profile. Results of ongoing clinical studies in SCID as well as in other primary immunodeficiencies, such as the Wiskott Aldrich syndrome, will be thus very informative. PMID:23583799

Fischer, Alain; Hacein-Bey-Abina, Salima; Cavazzana-Calvo, Marina

2013-08-10

230

Combined immunodeficiencies with nonfunctional T lymphocytes.  

PubMed

Immunodeficiencies with nonfunctional T cells comprise a heterogeneous group of conditions characterized by altered function of T lymphocytes in spite of largely preserved T cell development. Some of these forms are due to hypomorphic mutations in genes causing severe combined immunodeficiency. More recently, advances in human genome sequencing have facilitated the identification of novel genetic defects that do not affect T cell development, but alter T cell function and homeostasis. Along with increased susceptibility to infections, these conditions are characterized by autoimmunity and higher risk of malignancies. The study of these diseases, and of corresponding animal models, has provided fundamental insights on the mechanisms that govern immune homeostasis. PMID:24388215

Notarangelo, Luigi D

2014-01-01

231

Use of cytokine therapy in primary immunodeficiency.  

PubMed

Of the six cytokine therapies approved by the US Food and Drug Administration, five of them have been used in patients with primary immunodeficiency (PID). In some applications, clear benefits have been demonstrated, while in others, effects have been more marginal. The most compelling current applications of cytokine therapy in PID are those of granulocyte colony stimulating factor in severe congenital neutropenia and interferon gamma in chronic granulomatous disease. Despite encouraging results with interleukin-2 in common variable immunodeficiency and select other indications, its use in PID is not widespread. PMID:19449141

Roy-Ghanta, Sumita; Orange, Jordan S

2010-02-01

232

Oral Manifestations of Human Immunodeficiency Virus Infection  

PubMed Central

The AIDS epidemic continues. All health-care workers, including physicians and dental personnel, may be instrumental in recognizing risk factors associated with Acquired Immunodeficiency Syndrome (AIDS) and Human Immunodeficiency Virus (HIV) infection. Oral signs and symptoms of HIV infection may be the first presentation of the disease or may develop during the course of the disease and require management. Knowledge of the signs, symptoms and associated infections and tumours is needed to assist in recognition, diagnosis, and treatment. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6Figure 7Figure 8Figure 9Figure 10Figure 11Figure 12Figure 13

Epstein, Joel B.; Mathias, Richard G.

1988-01-01

233

Multi-subtype gp160 DNA immunization induces broadly neutralizing anti-HIV antibodies  

Microsoft Academic Search

A highly desirable feature for an human immunodeficiency virus type 1 (HIV-1) vaccine is the ability to induce broadly reactive anti-envelope antibodies that can neutralize primary HIV-1 isolates. Two immunizations with an HIV-1 envelope-encoding plasmid together with recombinant granulocyte–macrophage colony-stimulating factor (rGM-CSF) resulted in high antibody titers in mice. The antibody induction was further enhanced after immunization with genes encoding

E Rollman; J Hinkula; J Arteaga; B Zuber; A Kjerrström; M Liu; Britta Wahren; Karl Ljungberg

2004-01-01

234

Neutral particle lithography  

NASA Astrophysics Data System (ADS)

Neutral particle lithography (NPL) is a high resolution, proximity exposure technique where a broad beam of energetic neutral particles floods a stencil mask and transmitted beamlets transfer the mask pattern to resist on a substrate, such that each feature is printed in parallel, rather than in the serial manner of electron beam lithography. It preserves the advantages of ion beam lithography (IBL), including extremely large depth-of-field, sub-5 nm resist scattering, and the near absence of diffraction, yet is intrinsically immune to charge-related artifacts including line-edge roughness and pattern placement errors due to charge accumulation on the mask and substrate. In our experiments, a neutral particle beam is formed by passing an ion beam (e.g., 30 keV He+) through a high pressure helium gas cell (e.g., 100 mTorr) to convert the ions to energetic neutrals through charge transfer scattering. The resolution of NPL is generally superior to that of IBL for applications involving insulating substrates, large proximity gaps, and ultra-small features. High accuracy stepped exposures with energetic neutral particles, where magnetic or electrostatic deflection is impossible, have been obtained by clamping the mask to the wafer, setting the proximity gap with a suitable spacer, and mechanically inclining the mask/wafer stack relative to the beam. This approach is remarkably insensitive to vibration and thermal drift; nanometer scale image offsets have been obtained with +/-2 nm placement accuracy for experiments lasting over one hour. Using this nanostepping technique, linewidth versus dose curves were obtained, from which the NPL lithographic blur was determined as 4.4+/-1.4 nm (1sigma), which is 2-3 times smaller than the blur of electron beam lithography. Neutral particle lithography has the potential to form high density, periodic patterns with sub-10 nm resolution.

Craver, Barry Paul

235

Vaccination preserves CD4 memory T cells during acute simian immunodeficiency virus challenge  

PubMed Central

Acute simian immunodeficiency virus (SIV)/human immunodeficiency virus infection is accompanied by a massive destruction of CD4 memory T cells across all the tissue compartments. These early events set the course toward disease progression and immunodeficiency. Here, we demonstrate that prior vaccination reduces this destruction during acute SIV Mac251 infection, leading to better survival and long-term outcome. Systemic vaccination with a DNA-prime recombinant adenovirus boost regimen preserved memory CD4 T cells throughout the body. The vaccine regimen induced broad CD4 and CD8 T cell responses in all tissues examined and, importantly, induced antibodies that neutralized the primary isolate of SIV used for challenge. Finally, we demonstrate that the extent of preservation of the CD4 memory compartment during the acute phase provides a strong predictor for subsequent progression to death. Our data provide a mechanism to explain clinical observations that acute-phase viral loads predict long-term disease progression and underscore the need for interventions that protect against early destruction of CD4 memory T cells during acute infection.

Mattapallil, Joseph J.; Douek, Daniel C.; Buckler-White, Alicia; Montefiori, David; Letvin, Norman L.; Nabel, Gary J.; Roederer, Mario

2006-01-01

236

Neutralization sensitivity of HIV1 Env-pseudotyped virus clones is determined by co-operativity between mutations which modulate the CD4-binding site and those that affect gp120–gp41 stability  

Microsoft Academic Search

Adaptation of antibody neutralization-resistant human immunodeficiency virus type I (HIV-1) to growth in vitro generally results in the acquisition of a neutralization-sensitive phenotype, an alteration of viral growth kinetics, and an array of amino acid substitutions associated with these changes. Here we examine a panel of Env chimeras and mutants derived from these neutralization-resistant and -sensitive parental Envs. A range

Simon Beddows; Natalie N. Zheng; Carolina Herrera; Elizabeth Michael; Kelly Barnes; John P. Moore; Rod S. Daniels; Jonathan N. Weber

2005-01-01

237

Role of Human Immunodeficiency Virus (HIV) Type 1 Envelope in the Anti-HIV Activity of the Betulinic Acid Derivative IC9564  

PubMed Central

The betulinic acid derivative IC9564 is a potent anti-human immunodeficiency virus (anti-HIV) compound that can inhibit both HIV primary isolates and laboratory-adapted strains. However, this compound did not affect the replication of simian immunodeficiency virus and respiratory syncytial virus. Results from a syncytium formation assay indicated that IC9564 blocked HIV type 1 (HIV-1) envelope-mediated membrane fusion. Analysis of a chimeric virus derived from exchanging envelope regions between IC9564-sensitive and IC9564-resistant viruses indicated that regions within gp120 and the N-terminal 25 amino acids (fusion domain) of gp41 are key determinants for the drug sensitivity. By developing a drug-resistant mutant from the NL4-3 virus, two mutations were found within the gp120 region and one was found within the gp41 region. The mutations are G237R and R252K in gp120 and R533A in the fusion domain of gp41. The mutations were reintroduced into the NL4-3 envelope and analyzed for their role in IC9564 resistance. Both of the gp120 mutations contributed to the drug sensitivity. On the contrary, the gp41 mutation (R533A) did not appear to affect the IC9564 sensitivity. These results suggest that HIV-1 gp120 plays a key role in the anti-HIV-1 activity of IC9564.

Holz-Smith, Sonia L.; Sun, I-Chen; Jin, Lei; Matthews, Thomas J.; Lee, Kuo-Hsiung; Chen, Chin Ho

2001-01-01

238

Cross-reactivity of the anti-human D-dimer monoclonal antibody 1C9-6F10 to canine fibrin degradation products.  

PubMed

The cross-reactivity of the anti-human D-dimer antibody 1C9-6F10 to the canine D-dimer was evaluated by western blotting using purified canine fibrinogen, fibrin degradation products (XDPs) and plasma from a dog with suspected disseminated intravascular coagulation (DIC). The antibody cross-reacted with canine XDPs and plasma from the dog with suspected DIC. A latex agglutination assay using 1C9-6F10 measured the canine XDPs in dogs. In conclusion, the antibody 1C9-6F10 cross-reacted to the canine D-fragment with high specificity, but lower affinity compared with the human D-dimer. The latex agglutination assay using the 1C9-6F10 antibody was used to measure canine plasma D-dimer concentrations. PMID:23420644

Miura, Naoki; Furukawa, Makoto; Magari, Yasuo; Momoi, Yasuyuki

2013-07-31

239

STUDY OF THE ADSORPTION ON AND DESORPTION FROM POLYSTYRENE-HUMAN SERUM ALBUMIN CONJUGATES OF RABBIT ANTI-HUMAN SERUM ALBUMIN ANTIBODIES HAVING DIFFERENT SPECIFICITIES  

PubMed Central

An insoluble specific adsorbent for anti-human serum albumin antibodies was prepared by coupling human serum albumin (H.S.A.) to polystyrene by azo bonds. Rabbit anti-H.S.A. immune serum was passed through a column of the adsorbent. It was shown that different volumes of the immune serum were required for the saturation of the different determinant groups of H.S.A. by their corresponding antibodies. The elution of the anti-H.S.A. antibodies adsorbed on the column was achieved by passing successively through the column an acetate buffer pH 3.0 and a solution of 0.1 N HCl in 0.15 M NaCl. The antibodies were eluted in three different fractions, each of which was composed of ?-globulins only. These three fractions contained different proportions of antibodies of different specificities.

Webb, Tom; Lapresle, Claude

1961-01-01

240

Analysis of human and primate CD2 molecules by protein sequence and epitope mapping with anti-human CD2 antibodies.  

PubMed

A panel of anti-human CD2 monoclonal antibodies (mAb) and soluble human CD58 (LFA-3) were tested for binding to human peripheral blood mononuclear cells (PBMCs), recombinant human CD2 and mononuclear cells from Cynomolgus, Rhesus and African green monkey, Stump-tail, Pig-tail and Assamese macaque, Chimpanzee and Baboon. This analysis revealed that whilst some antibodies recognized all species, there were differential binding profiles with others. Three antibodies, MEDI-507, 6F10.3 and 4B2, recognized CD2 from human and Chimpanzee but not that from the other primates. We have cloned eight of the previously unknown primate CD2 molecules and report here their sequences for the first time. This analysis revealed that 12 amino acids formed a common set of residues in the extra cellular domain of human and Chimpanzee CD2. Using a "knock-in" mutagenesis approach starting with Baboon CD2, which does not bind MEDI-507, 6F10.3 and 4B2, we have identified three residues in the adhesion domain of human CD2 which are critical for its binding to these mAbs. These residues, N18, K55 and T59 define a region located outside of the previously described binding regions on CD2. Affinity measurements of the mutants revealed a variety of degrees of binding restoration for MEDI-507, 6F10.3 and 4B2, indicating that there are fine differences within a given epitope. Furthermore, the analysis of the competition of several of the anti-human CD2 antibodies with each other and CD58 demonstrated the existence of a continuum of overlapping epitopes on human CD2, which is in contrast to the commonly held belief that epitopes on human CD2 are clearly segregated. PMID:15302161

Damschroder, Melissa M; Kozhich, Alexander A; Woods, Robert M; Cheng, Li; Mullikin, Brian A; Wilson, Susan D; Ulbrandt, Nancy D; Bachy, Christine M; Wu, Herren; Suzich, JoAnn A; Kiener, Peter A; Dall'Acqua, William F; White, Wendy I

2004-08-01

241

Early diagnosis of severe combined immunodeficiency syndrome  

Microsoft Academic Search

Infants with severe combined immunodeficiency syndrome (SCIDS) have a greatly improved prognosis if diagnosed and treated before they develop overwhelming infection. Clinical and laboratory data on 45 patients with SCIDS were retrospectively reviewed to assess the value of absolute lymphocyte counts in making an early diagnosis. Ninety infants matched for age, sex, and presenting symptoms were used as controls. Thirteen

R A Hague; S Rassam; G Morgan; A J Cant

1994-01-01

242

Evaluation of primary immunodeficiency disease in children.  

PubMed

One in 2,000 children younger than 18 years is thought to have a primary immunodeficiency disease. Antibody, combined B-cell and T-cell, phagocytic, and complement disorders are the most common types. Children with these diseases tend to have bacterial or fungal infections with unusual organisms, or unusually severe and recurrent infections with common organisms. A family history of primary immunodeficiency disease is the strongest predictor of a person having this type of disease. When an immunodeficiency disease is suspected, initial laboratory screening should include a complete blood count with differential and measurement of serum immunoglobulin and complement levels. The presence of lymphocytopenia on complete blood count suggests a T-cell disorder, whereas a finding of neutropenia suggests a phagocytic disorder. Abnormal serum immunoglobulin levels suggest a B-cell disorder. Abnormalities on assay of the classic or alternative complement pathways suggest a complement disorder. If laboratory results are abnormal, or if clinical suspicion continues despite normal laboratory results, children should be referred for further evaluation. Human immunodeficiency virus infection should also be considered, and testing should be performed, if appropriate; this infection often clinically resembles a T-cell disorder. PMID:23939499

Reust, Carin E

2013-06-01

243

Cytokines in the treatment of primary immunodeficiency  

Microsoft Academic Search

Cytokines have great potential in the treatment of primary immunodeficiencies, which is just beginning to be realized. We discuss some general considerations in the use of cytokines in this setting, and review the clinical use of a number of cytokines. The best proven example to date is the use of interferon-? in chronic granulomatous disease, which significantly reduces infectious complications

Benjamin A. Kruskal; R. Alan B. Ezekowitz

1994-01-01

244

Women at Risk for Human Immunodeficiency Virus.  

ERIC Educational Resources Information Center

This article reports results from a survey among women at risk for contracting Human Immunodeficiency Virus (HIV) as well as transmitting it in a vertical (to offspring) and horizontal (sexual partner or intravenous [IV] drug usage) mode. Little is known about the extent of HIV knowledge, sexual behaviors, and IV drug usage for women at risk for…

Quadagno, David; And Others

245

Acquired immunodeficiency syndrome with subacute sclerosing panencephalitis.  

PubMed

A 7-year-old boy with acquired immunodeficiency syndrome, receiving antiretroviral drugs for 2 years, presented with a recent onset of myoclonic jerks and cognitive deterioration. On examination, he manifested myoclonic jerks once every 10-15 seconds. His electroencephalogram indicated periodic complexes, and his cerebrospinal fluid tested positive for measles antibodies. PMID:23044024

Gowda, Vykuntaraju K N; Sukanya, V; Shivananda

2012-11-01

246

Bleach Neutralizes Mold Allergens  

ERIC Educational Resources Information Center

Researchers at National Jewish Medical and Research Center have demonstrated that dilute bleach not only kills common household mold, but may also neutralize the mold allergens that cause most mold-related health complaints. The study, published in the Journal of Allergy and Clinical Immunology, is the first to test the effect on allergic…

Science Teacher, 2005

2005-01-01

247

Neutral particle beam intensity controller  

SciTech Connect

A neutral beam generator is described wherein an energetic neutral particle beam is formed from a focused beam of ions accelerated along a beam axis into a neutralizer cell disposed about the beam axis, a neutral beam intensity controller. The controller consists of: a neutral particle beam dump disposed with a beam dump surface transverse to the beam axis downstream of the neutralizer and having an opening therethrough for the passage of neutral particles focused along the beam axis; means for generating a magnetic field within the neutralizer perpendicular to the beam axis adjacent to the upstream end of the neutralizer; and control means operatively connected to the magnetic field generating means for selectively controlling the intensity of the magnetic field within the neutralizer in order to defocus a portion of the beam ions prior to neutralization in the neutralizer to direct the neutral particles generated from the defocused portion of the ion beam along paths which are intercepted by the beam dump surface of the beam dump, thereby controlling the intensity of neutral particles passing through the opening in the beam dump.

Dagenhart, W.K.

1986-06-24

248

IDR knowledge base for primary immunodeficiencies  

PubMed Central

Background The ImmunoDeficiency Resource (IDR) is a knowledge base for the integration of the clinical, biochemical, genetic, genomic, proteomic, structural, and computational data of primary immunodeficiencies. The need for the IDR arises from the lack of structured and systematic information about primary immunodeficiencies on the Internet, and from the lack of a common platform which enables doctors, researchers, students, nurses and patients to find out validated information about these diseases. Description The IDR knowledge base, first released in 1999, has grown substantially. It contains information for 158 diseases, both from a clinical as well as molecular point of view. The database and the user interface have been reformatted. This new IDR release has a richer and more complete breadth, depth and scope. The service provides the most complete and up-to-date dataset. The IDR has been integrated with several internal and external databases and services. The contents of the IDR are validated and selected for different types of users (doctors, nurses, researchers and students, as well as patients and their families). The search engine has been improved and allows either a detailed or a broad search from a simple user interface. Conclusion The IDR is the first knowledge base specifically designed to capture in a systematic and validated way both clinical and molecular information for primary immunodeficiencies. The service is freely available at http://bioinf.uta.fi/idr and is regularly updated. The IDR facilitates primary immunodeficiencies informatics and helps to parameterise in silico modelling of these diseases. The IDR is useful also as an advanced education tool for medical students, and physicians.

Samarghitean, Crina; Valiaho, Jouni; Vihinen, Mauno

2007-01-01

249

Feline immunodeficiency virus env gene evolution in experimentally infected cats.  

PubMed

Feline immunodeficiency virus (FIV), an immunosuppressive lentivirus found in cats worldwide, is studied to illuminate mechanisms of lentiviral pathogenesis and to identify key components of protective immunity. During replication, lentiviruses accumulate errors of nucleotide mis-incorporation due to the low-fidelity of reverse transcriptase and recombination between viral variants, resulting in the emergence of a complex viral "quasispecies". In patients infected with HIV-1, env sequences may vary by up to 10% and the detection of quasispecies with greater heterogeneity is associated with higher viral loads and reduced CD4+ T cell numbers [1], indicating that transmission of more complex quasispecies may lead to disease progression. However, little is known about how FIV evolves as disease progresses, or why some cats develop AIDS rapidly while disease progression is slow in others. The aim of this study was to determine whether disease progression may be governed by viral evolution and to examine the diversity of viral variants emerging following infection with an infectious molecular clone. The FIV env gene encoding the envelope glycoprotein (Env) was examined at early (12 weeks) and late (322 weeks) stages of FIV infection in two groups of cats infected experimentally with the FIV-GL8 molecular clone. Viral variants were detected within quasispecies in cats in the late stages of FIV infection that contained differing amino acid compositions in several variable loops of Env, some of which were identified as determinants of receptor usage and resistance to neutralization. Therefore these results indicate that the FIV env gene evolves during the course of infection, giving rise to variants that resist neutralization and likely lead to disease progression. PMID:19897254

Kraase, Martin; Sloan, Richard; Klein, Dieter; Logan, Nicola; McMonagle, Linda; Biek, Roman; Willett, Brian J; Hosie, Margaret J

2010-03-15

250

Role of CD4 endocytosis in human immunodeficiency virus infection.  

PubMed Central

We have analyzed the role of CD4 endocytosis in human immunodeficiency virus (HIV) entry by measuring the infection of HeLa cells expressing various CD4 constructs with endocytosis rates of between 0.2 and 30%/min in a quantitative infectious focus assay. For a number of laboratory-adapted HIV-1 and HIV-2 strains, the highest levels of infection were found on cells with very limited CD4 endocytosis, while cells with efficient CD4 uptake were only poorly infectable, suggesting that CD4 internalization is not required for HIV entry. This was confirmed in a modified assay involving prebinding of HIV-1LAI to HeLa-CD4 cells at 4 degrees C, synchronized virus entry during warming to 37 degrees C, and neutralization of virions remaining at the cell surface with anti-V3 loop antibodies. Warming cells in hypertonic medium inhibited CD4 endocytosis but did not affect the rate or the extent of infection. These studies confirm that HIV infection does not require endocytosis and that laboratory-adapted virus strains can enter HeLa-CD4 cells by fusion at the plasma membrane.

Pelchen-Matthews, A; Clapham, P; Marsh, M

1995-01-01

251

Neutral particle beam intensity controller  

DOEpatents

A neutral beam intensity controller is provided for a neutral beam generator in which a neutral beam is established by accelerating ions from an ion source into a gas neutralizer. An amplitude modulated, rotating magnetic field is applied to the accelerated ion beam in the gas neutralizer to defocus the resultant neutral beam in a controlled manner to achieve intensity control of the neutral beam along the beam axis at constant beam energy. The rotating magnetic field alters the orbits of ions in the gas neutralizer before they are neutralized, thereby controlling the fraction of neutral particles transmitted out of the neutralizer along the central beam axis to a fusion device or the like. The altered path or defocused neutral particles are sprayed onto an actively cooled beam dump disposed perpendicular to the neutral beam axis and having a central open for passage of the focused beam at the central axis of the beamline. Virtually zero therough 100% intensity control is achieved by varying the magnetic field strength without altering the ion source beam intensity or its species yield.

Dagenhart, William K. (Oak Ridge, TN)

1986-01-01

252

Human platelets inhibit liver fibrosis in severe combined immunodeficiency mice  

PubMed Central

AIM: To investigate the role of human platelets in liver fibrosis. METHODS: Severe combined immunodeficiency (SCID) mice were administered CCl4 and either phosphate-buffered saline (PBS group) or human platelet transfusions (hPLT group). Concentrations of hepatocyte growth factor (HGF), matrix metallopeptidases (MMP)-9, and transforming growth factor-? (TGF-?) in the liver tissue were compared between the PBS and the hPLT groups by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The effects of a human platelet transfusion on liver fibrosis included the fibrotic area, hydroxyproline content, and ?-smooth muscle actin (?-SMA) expression, which were evaluated by picrosirius red staining, ELISA, and immunohistochemical staining using an anti-mouse ?-SMA antibody, respectively. Phosphorylations of mesenchymal-epithelial transition factor (Met) and SMAD3, downstream signals of HGF and TGF-?, were compared between the two groups by Western blotting and were quantified using densitometry. Hepatocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Furthermore, the accumulation of human platelets in the liver 2 h after platelet transfusion was compared between normal and fibrotic livers by immunohistochemical staining using an anti-human CD41 antibody. RESULTS: The fibrotic area and hydroxyproline content in the liver were both significantly lower in the hPLT group when compared to the PBS group (fibrotic area, 1.7% ± 0.6% vs 2.5% ± 0.6%, P = 0.03; hydroxyproline content, 121 ± 26 ng/g liver vs 156 ± 47 ng/g liver, P = 0.04). There was less ?-smooth muscle actin staining in the hPLT group than in the PBS group (0.5% ± 0.1% vs 0.8% ± 0.3%, P = 0.02). Hepatic expression levels of mouse HGF and MMP-9 were significantly higher in the hPLT group than in the PBS group (HGF, 109 ± 13 ng/g liver vs 88 ± 22 ng/g liver, P = 0.03; MMP-9, 113% ± 7%/GAPDH vs 92% ± 11%/GAPDH, P = 0.04). In contrast, the concentration of mouse TGF-? in the liver tissue was significantly lower in the hPLT group than in the PBS group (22 ± 5 ng/g liver vs 39 ± 6 ng/g liver, P = 0.02). Phosphorylation of Met was more prevalent in the hPLT group than in the PBS group (37% ± 4%/GAPDH vs 20% ± 8%/GAPDH, P = 0.03). Phosphorylation of SMAD3 was weaker in the hPLT group than in the PBS group (60% ± 12%/GAPDH vs 84% ± 12%/GAPDH, P = 0.1), although this difference was not significant. Furthermore, a lower rate of hepatocyte apoptosis was observed in the hPLT group than in the PBS group (5.9% ± 1.7% vs 2.9% ± 2.1%, P = 0.02). Significant human platelet accumulation was observed in the fibrotic liver tissues, whereas few platelets accumulated in the normal liver. CONCLUSION: Human platelets inhibit liver fibrosis in SCID mice. Increased concentration of HGF in the liver suppresses hepatic stellate cell activation, induces MMPs, and inhibits hepatocyte apoptosis.

Takahashi, Kazuhiro; Murata, Soichiro; Fukunaga, Kiyoshi; Ohkohchi, Nobuhiro

2013-01-01

253

A comparative immunogenicity study in rabbits of disulfide-stabilized, proteolytically cleaved, soluble trimeric human immunodeficiency virus type 1 gp140, trimeric cleavage-defective gp140 and monomeric gp120  

Microsoft Academic Search

The human immunodeficiency virus type 1 (HIV-1) surface envelope glycoprotein (Env) complex, a homotrimer containing gp120 surface glycoprotein and gp41 transmembrane glycoprotein subunits, mediates the binding and fusion of the virus with susceptible target cells. The Env complex is the target for neutralizing antibodies (NAbs) and is the basis for vaccines intended to induce NAbs. Early generation vaccines based on

Simon Beddows; Michael Franti; Antu K. Dey; Marc Kirschner; Sai Prasad N. Iyer; Danielle C. Fisch; Thomas Ketas; Eloisa Yuste; Ronald C. Desrosiers; Per Johan Klasse; Paul J. Maddon; William C. Olson; John P.. Moore

2007-01-01

254

In vitro comparison of topical microbicides for prevention of human immunodeficiency virus type 1 transmission.  

PubMed

A standardized protocol was used to compare cellular toxicities and anti-human immunodeficiency virus type 1 (HIV-1) activities of candidate microbicides formulated for human use. The microbicides evaluated were cellulose acetate phthalate (CAP), Carraguard, K-Y plus nonoxynol-9 (KY-N9), PRO 2000 (0.5 and 4%), SPL7013 (5%), UC781 (0.1 and 1%), and Vena Gel, along with their accompanying placebos. Products were evaluated for toxicity on cervical and colorectal epithelial cell lines, peripheral blood mononuclear cells (PBMCs), and macrophages (MPhi) by using an ATP release assay, and they were tested for their effect on transepithelial resistance (TER) of polarized epithelial monolayers. Anti-HIV-1 activity was evaluated in assays for transfer of infectious HIV-1 from epithelial cells to activated PBMCs and for PBMC and MPhi infection. CAP, Carraguard, PRO 2000, SPL7013, and UC781 along with their placebos were 20- to 50-fold less toxic than KY-N9 and Vena Gel. None of the nontoxic product concentrations disrupted the TER. Transfer of HIV-1(Ba-L) from epithelial cells to PBMCs and PBMC and MPhi infection with laboratory-adapted HIV-1(Ba-L) and HIV-1(LAI) isolates were inhibited by all products except Carraguard, KY-N9, and Vena Gel. KY-N9, Vena Gel, and Carraguard were not effective in blocking PBMC infection with primary HIV-1(A), HIV-1(C), and HIV-1(CRF01-AE) isolates. The concordance of these toxicity results with those previously reported indicates that our protocol may be useful for predicting toxicity in vivo. Moreover, our systematic anti-HIV-1 testing provides a rational basis for making better informed decisions about which products to consider for clinical trials. PMID:15388443

Dezzutti, Charlene S; James, V Nicole; Ramos, Artur; Sullivan, Sharon T; Siddig, Aladin; Bush, Timothy J; Grohskopf, Lisa A; Paxton, Lynn; Subbarao, Shambavi; Hart, Clyde E

2004-10-01

255

Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms.  

PubMed Central

Studies of the mechanism of action of michellamine B, a novel anti-human immunodeficiency virus (HIV) alkaloid from the tropical plant Ancistrocladus korupensis, have revealed that the compound acts at two distinct stages of the HIV life cycle. The compound had no direct effect on HIV virions and did not block the initial binding of HIV to target cells. Postinfection time course studies revealed that the agent partially inhibited HIV-induced cell killing and syncytium formation when added up to 48 h following acute infection; however, viral reproduction was fully inhibited only when the compound was added immediately after infection. Time-limited treatments of HIV-infected cells revealed that michellamine B had to be present continuously to provide maximum antiviral protection. HIV replication in cells in which infection was already fully established or in chronically infected cells was unaffected by michellamine B. Biochemical studies showed that michellamine B inhibited the enzymatic activities of reverse transcriptases (RTs) from both HIV type 1 and HIV type 2 as well as two different nonnucleoside drug-resistant RTs with specific amino acid substitutions. In addition, human DNA polymerases alpha and beta were inhibited by the alkaloid. Michellamine B exerted a potent dose-dependent inhibition of cell fusion in two independent cell-based fusion assays. Thus, michellamine B acts both at an early stage of the HIV life cycle by inhibiting RT as well as at later stages by inhibiting cellular fusion and syncytium formation.

McMahon, J B; Currens, M J; Gulakowski, R J; Buckheit, R W; Lackman-Smith, C; Hallock, Y F; Boyd, M R

1995-01-01

256

Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors.  

PubMed Central

The observed in vitro and in vivo benefit of combination treatment with anti-human immunodeficiency virus (HIV) agents prompted us to examine the potential of resistance development when two protease inhibitors are used concurrently. Recombinant HIV-1 (NL4-3) proteases containing combined resistance mutations associated with BMS-186318 and A-77003 (or saquinavir) were either inactive or had impaired enzyme activity. Subsequent construction of HIV-1 (NL4-3) proviral clones containing the same mutations yielded viruses that were severely impaired in growth or nonviable, confirming that combination therapy may be advantageous. However, passage of BMS-186318-resistant HIV-1 (RF) in the presence of either saquinavir or SC52151, which represented sequential drug treatment, produced viable viruses resistant to both BMS-186318 and the second compound. The predominant breakthrough virus contained the G48V/A71T/V82A protease mutations. The clone-purified RF (G48V/A71T/V82A) virus, unlike the corresponding defective NL4-3 triple mutant, grew well and displayed cross-resistance to four distinct protease inhibitors. Chimeric virus and in vitro mutagenesis studies indicated that the RF-specific protease sequence, specifically the Ile at residue 10, enabled the NL4-3 strain with the triple mutant to grow. Our results clearly indicate that viral genetic background will play a key role in determining whether cross-resistance variants will arise. Images Fig. 1

Rose, R E; Gong, Y F; Greytok, J A; Bechtold, C M; Terry, B J; Robinson, B S; Alam, M; Colonno, R J; Lin, P F

1996-01-01

257

Neutral Transport in a Plasma.  

National Technical Information Service (NTIS)

A solution procedure for the neutral transport equation in plasma slab geometry is developed. Half-angle scalar fluxes, currents and averaged cross sections are introduced to provide a convenient and simple method of calculating the neutral energy distrib...

W. M. Stacey

1977-01-01

258

Neutral particle beam intensity controller  

DOEpatents

The neutral beam intensity controller is based on selected magnetic defocusing of the ion beam prior to neutralization. The defocused portion of the beam is dumped onto a beam dump disposed perpendicular to the beam axis. Selective defocusing is accomplished by means of a magnetic field generator disposed about the neutralizer so that the field is transverse to the beam axis. The magnetic field intensity is varied to provide the selected partial beam defocusing of the ions prior to neutralization. The desired focused neutral beam portion passes along the beam path through a defining aperture in the beam dump, thereby controlling the desired fraction of neutral particles transmitted to a utilization device without altering the kinetic energy level of the desired neutral particle fraction. By proper selection of the magnetic field intensity, virtually zero through 100% intensity control of the neutral beam is achieved.

Dagenhart, W.K.

1984-05-29

259

Neutral Particle Beam Intensity Controller.  

National Technical Information Service (NTIS)

The neutral beam intensity controller is based on selected magnetic defocusing of the ion beam prior to neutralization. The defocused portion of the beam is dumped onto a beam dump disposed perpendicular to the beam axis. Selective defocusing is accomplis...

W. K. Dagenhart

1984-01-01

260

Virus-Neutralizing Activity Mediated by the Fab Fragment of a Hemagglutinin-Specific Antibody Is Sufficient for the Resolution of Influenza Virus Infection in SCID Mice  

Microsoft Academic Search

Antibodies (Abs) contribute to the control of influenza virus infection in vivo by reducing progeny virus yield from infected cells (yield reduction (YR)) and by inhibiting progeny virus from spreading the infection to new host cells (virus neutralization (VN)). Previous studies showed that the infection could be resolved in severe combined immunodeficiency (SCID) mice by treatment with hemagglutinin (HA)-specific monoclonal

Krystyna Mozdzanowska; Jingqi Feng; Walter Gerhard

2003-01-01

261

Three-Dimensional Structure of Schistosoma Japonicum Glutathione S-Transferase Fused with a Six-Amino Acid Conserved Neutralizing Epitope of GP41 from HIV.  

National Technical Information Service (NTIS)

The 3-dimensional crystal structure of glutathione S-transferase (GST) of Schistosoma japonicum (Sj) fused with a conserved neutralizing epitope on gp41 (glycoprotein, 41 kDa) of human immunodeficiency virus type 1 (HIV-1) was determined at 2.5 A resoluti...

K. Lim J. X. Ho K. Keeling G. L. Gilliland X. Ji

1994-01-01

262

A recombinant live attenuated measles vaccine vector primes effective HLA-A0201-restricted cytotoxic T lymphocytes and broadly neutralizing antibodies against HIV1 conserved epitopes  

Microsoft Academic Search

Live attenuated measles vaccine (MV) could provide a safe and efficient pediatric vaccination vector to immunize children simultaneously against measles and human immunodeficiency virus type 1 (HIV-1). To evaluate the capacity of a vector derived from the certified Schwarz measles vaccine (MVSchw) to prime effective cytotoxic T cells (CTL) and broad neutralizing antibodies against HIV-1 conserved epitopes, we generated recombinant

Clarisse Lorin; Frédéric Delebecque; Valérie Labrousse; Lucie Da Silva; François Lemonnier; Michel Brahic; Frédéric Tangy

2005-01-01

263

Neutral beams for mirrors  

SciTech Connect

An important demonstration of negative ion technology is proposed for FY92 in the MFTF-..cap alpha..+T, an upgrade of the Mirror Fusion Test Facility at the Lawrence Livermore National Laboratory. This facility calls for 200-keV negative ions to form neutral beams that generate sloshing ions in the reactor end plugs. Three different beam lines are considered for this application. Their advantages and disadvantages are discussed.

Fink, J.H.

1983-08-31

264

Antihypertensive neutral lipid  

DOEpatents

The invention relates to the discovery of a class of neutral acetylated either-linked glycerolipids having the capacity to lower blood presure in warm-blooded animals. This physiological effect is structure sensitive requiring a long chain alkyl group at the sn-1 position and a short carbon chain acyl group (acetyl or propionyl) at the sn-2 position, and a hydroxyl group at the sn-3 position.

Snyder, F.L.; Blank, M.L.

1984-10-26

265

Antihypertensive neutral lipid  

DOEpatents

The invention relates to the discovery of a class of neutral acetylated ether-linked glycerolipids having the capacity to lower blood pressure in warm-blooded animals. This physiological effect is structure sensitive requiring a long chain alkyl group at the sn-1 position and a short carbon chain acyl group (acetyl or propionyl) at the sn-2 position, and a hydroxyl group at the sn-3 position.

Snyder, Fred L. (Oak Ridge, TN) [Oak Ridge, TN; Blank, Merle L. (Oak Ridge, TN) [Oak Ridge, TN

1986-01-01

266

Human\\/mouse radiation chimera generated from PBMC of B chronic lymphocytic leukemia patients with autoimmune hemolytic anemia produce anti-human red cell antibodies  

Microsoft Academic Search

Previous studies performed in our laboratory have shown that B-CLL cells are involved in the production of anti-red cell auto-antibodies, providing a possible mechanism for the auto-immune hemolytic anemia occurring during the course of B-CLL. In order to confirm this hypothesis, we attempted to transfer human B-CLL with AIHA to immunodeficient mice. Peripheral blood mononuclear cells (PBMC) from 11 B-CLL

H Marcus; A Shimoni; D Ergas; A Canaan; B Dekel; D Ben-David; M David; E Sigler; Y Reisner; A Berrebi

1997-01-01

267

Immunogenicity of a peptide from a major neutralising determinant of the feline immunodeficiency virus surface glycoprotein.  

PubMed

The third variable region (V3) of the feline immunodeficiency virus (FIV) surface glycoprotein is predicted to have similar physical properties to that of HIV and has been shown to contain immunodominant and neutralizing epitopes. Immunological characteristics of this region were investigated further using a peptide corresponding to the middle of the putative FIV V3 loop. The peptide was recognized in ELISA by sera from the majority of naturally FIV-infected cats, and absorbed a significant fraction of the virus neutralizing activity from a pool of sera of cats naturally infected with FIV, confirming the immunogenic nature of this region. A sheep immunized with an octameric form of the peptide (multiple antigenic peptide; MAP) in Freund's complete adjuvant generated neutralizing antibody to a higher titre than infected cats. However, immunization of cats with the same MAP in an acceptable adjuvant formulation (Quil A) induced antibody and cytotoxic T-cell responses to the immunizing peptides but only minimal neutralizing activity. These responses did not significantly alter the kinetics of infection or the proviral load after challenge with a homologous strain of FIV, compared with naive controls. While the potential efficacy of peptide vaccines to lentiviruses remains to be determined, this study shows that the immune response evoked may be highly dependent on the delivery and adjuvant regime used. PMID:8911003

Rigby, M A; Mackay, N; Reid, G; Osborne, R; Neil, J C; Jarrett, O

1996-08-01

268

The merits of neutral theory  

Microsoft Academic Search

Hubbell's neutral theory of biodiversity has challenged the classic niche-based view of ecological community structure. Although there have been many attempts to falsify Hubbell's theory, we argue that falsification should not lead to rejection, because there is more to the theory than neutrality alone. Much of the criticism has focused on the neutrality assumption without full appreciation of other relevant

David Alonso; Rampal S. Etienne; Alan J. McKane

2006-01-01

269

Neutral Particle Beam Intensity Controller.  

National Technical Information Service (NTIS)

A method is proposed in which an amplitude-modulated, rotating magnetic field is applied to an accelerated ion beam in a gas neutralizer to defocus the resultant neutral and ion beam in a controlled manner to control the intensity of the neutral beam alon...

W. K. Dagenhart

1988-01-01

270

Neutral particle beam intensity controller  

Microsoft Academic Search

A method is proposed in which an amplitude-modulated, rotating magnetic field is applied to an accelerated ion beam in a gas neutralizer to defocus the resultant neutral and ion beam in a controlled manner to control the intensity of the neutral beam along the beam axis at constant beam energy. Adjustments in the gas pressure determine the fraction of ions

Dagenhart

1988-01-01

271

Neutral particle beam intensity controller  

Microsoft Academic Search

The neutral beam intensity controller is based on selected magnetic defocusing of the ion beam prior to neutralization. The defocused portion of the beam is dumped onto a beam dump disposed perpendicular to the beam axis. Selective defocusing is occomplished by means of a magnetic field generator disposed about the neutralizer so that the field is transverse to the beam

W. K. Dagenhart

1984-01-01

272

Neutral particle beam intensity controller  

Microsoft Academic Search

A method is proposed in which an amplitude-modulated, rotating magnetic field is applied to an accelerated ion beam in a gas neutralizer to defocus the resultant neutral and ion beam in a controlled manner to control the intensity of the neutral beam along the beam axis at constant beam energy. Adjustments in the gas pressure determine the fraction of ions

W. K. Dagenhart

1989-01-01

273

[Correction of immune response using purified staphylococcal toxoid and likopid in the secondary immunodeficiency induced by Coxsackie virus B3].  

PubMed

The action of immunomodulators, purified staphylococcal toxoid (PST) and lycopid, on secondary immunodeficiency state developing during infection caused by Coxsackie virus B3 was studied. This defect was manifested by delayed hypersensitivity to sheep red blood cells (SRBC) and the suppression of neutralizing antibodies to poliomyelitis virus. Depending on the scheme of the experiment, PST normalized the defects of immune response to SRBC or poliovirus, increased suppression or showed no activity. Lycopid corrected the defects of humoral response to SRBC. The combination of PST and lycopid was found to produce no increase of suppression. The suggestion was made on the expediency of combination of two (and probably more) immunomodulators for increasing the efficiency of correction of secondary immunodeficiency. PMID:11871300

Semenova, I B; Vasil'eva, I G; Akatov, A K

2001-01-01

274

Dyschromia related to severe combined immunodeficiency.  

PubMed

Severe combined immunodeficiency includes a group of diseases characterized by different inherited immunological defects. A 4-month-old girl diagnosed with Omenn syndrome, a subtype of severe combined immunodeficiency presenting with generalized erythroderma, was referred to our hospital for an allogeneic stem cell transplantation. Days before transplantation, she developed hyperpigmented macules that increased in number in the following months. As the erythroderma resolved after transplantation, diffuse hypopigmentation was simultaneously noted together with the expansion of hyperpigmented lesions. Cutaneous biopsy samples were taken at different moments, showing features of Omenn syndrome at first, and 2 months later changes consistent with hypopigmentation and repigmentation were observed. Although pigmentary disorders are rarely described in this context, these must be taken into account as a possible alternative diagnosis to graft-versus-host disease and toxicoderma in immunosuppressed patients. PMID:23328788

Maldonado-Cid, Paola; Noguera-Morel, Lucero; Moreno-Alonso-de-Celada, Ricardo; De-Lucas-Laguna, Raúl; Feito-Rodríguez, Marta; Beato-Merino, Maria José; Casado-Jiménez, Mariano

2013-12-01

275

Immunogenetics: changing the face of immunodeficiency.  

PubMed

Tables 1 and 2 highlight the enormous advances that have been made in the definition of the molecular defects underlying primary immunodeficiencies in the past decade. The identification of SAP as the gene defective in XLP now completes the molecular bases of all the recognised X linked syndromes. Of the autosomally inherited syndromes, only the genes for DiGeorge syndrome, hyper-IgE, and perhaps most importantly, common variable immunodeficiency remain to be elucidated. The major clinical benefits of this information have primarily been in offering more accurate and rapid molecular diagnoses. The ability to make a molecular diagnosis also increases the options for earlier definitive treatments such as bone marrow transplantation and somatic gene therapy. Finally, as illustrated by the studies on the functions of WASP and the gamma c/JAK-3 pathway, identification of the gene defect is the first step to understanding the molecular pathogenesis of the immunological abnormalities. PMID:10767859

Jones, A M; Gaspar, H B

2000-01-01

276

Acquired immunodeficiency syndrome in African patients.  

PubMed

Between May 1979 and April 1983, 18 previously healthy African patients were hospitalized in Belgium with opportunistic infections (cryptococcosis, Pneumocystis carinii pneumonia, central-nervous-system toxoplasmosis, progressive cutaneous herpes simplex virus infection, disseminated cytomegalovirus infection, candidiasis, or cryptosporidiosis) or Kaposi's sarcoma, or with both. Ten of them died. During the same period five other patients were hospitalized with an illness consistent with a prodrome of the acquired immunodeficiency syndrome (chronic lymphadenopathy, fever, weight loss, and diarrhea). All patients tested had a marked decrease in helper T cells; an inversion of the normal ratio of helper to suppressor T cells, and a decreased or absent blastogenic response of lymphocytes to mitogens. Twenty patients had anergy. There was no evidence of an underlying immunosuppressive disease and no history of blood-product transfusion, homosexuality, or intravenous-drug abuse. This syndrome in patients originating in Central Africa is similar to the acquired immunodeficiency syndrome reported in American patients. PMID:6229701

Clumeck, N; Sonnet, J; Taelman, H; Mascart-Lemone, F; De Bruyere, M; Vandeperre, P; Dasnoy, J; Marcelis, L; Lamy, M; Jonas, C

1984-02-23

277

Ill thrift and juvenile llama immunodeficiency syndrome.  

PubMed

The problem of "ill thrift" or "failure to thrive" in juvenile llamas is widespread and relatively common in the continental United States. Juvenile llama immunodeficiency syndrome (JLIDS) is one of several causes of the problem and is the most common cause of ill thrift in juvenile llamas evaluated at Colorado State University's Veterinary Teaching Hospital. This article will review current knowledge of JLIDS and will briefly discuss other causes of ill thrift in juvenile llamas. PMID:7953965

Hutchison, J M; Garry, F

1994-07-01

278

Human Immunodeficiency Virus Infection and Pregnancy  

PubMed Central

The human immunodeficiency virus (HIV) epidemic is clearly one of the most serious health-care crises in the professional lives of contemporary physicians. It cannot be regarded as a curiosity to be dealt with by inner-city infectious-disease experts, but rather must be considered a problem for all health-care providers and a problem in which the obstetrician-gynecologist has a special role to play.

1994-01-01

279

Prognostic factors in acquired immunodeficiency syndrome  

Microsoft Academic Search

To identify prognostic factors in acquired immunodeficiency syndrome (AIDS), the authors studied an inception cohort of 45\\u000a patients in a non-endemic area (Group I). The probability of survival was 67% six months after the diagnosis of AIDS and 32%\\u000a at 12 months. As shown by multivariate Cox regression analysis, survivals were shorter (p<0.01) in patients 35 years old or\\u000a older

Jay D. Wenger; Christopher C. Whalen; Michael M. Lederman; Thomas J. Spech; John T. Carey; J. Walton Tomford; C. Seth Landefeld

1988-01-01

280

Is Neutral Humanitarianism Dead? Red Cross Neutrality: Walking the Tightrope of Neutral Humanitarianism  

Microsoft Academic Search

: Some have suggested that neutral humanitarianism is dead in the aftermath of the Cold War and 9\\/11. This article challenges the critical view called neo-humanitarianism and suggests that organizations such as the ICRC can carefully carve out an image of relative neutrality. This article argues that the difficulties associated with neutrality are not new and the ICRC has been

Barbara Ann Rieffer-Flanagan

2009-01-01

281

Is Neutral Humanitarianism Dead? Red Cross Neutrality: Walking the Tightrope of Neutral Humanitarianism  

Microsoft Academic Search

Some have suggested that neutral humanitarianism is dead in the aftermath of the Cold War and 9\\/11. This article challenges the critical view called neo-humanitarianism and suggests that organizations such as the ICRC can carefully carve out an image of relative neutrality. This article argues that the difficulties associated with neutrality are not new and the ICRC has been grappling

Barbara Ann Rieffer-Flanagan

2009-01-01

282

Problems of Prophylaxis of Secondary Immunodeficiency States.  

PubMed

An attempt is made in this paper to draw up some results of long-term studies conducted by the "Immunoprophylaxis" Center of RANS on such studies. The results of mass and individual studies among 250 thousand blue- and white-collar workers in Russian industrial enterprises are processed in the data bank of the Center, including an analysis of the immunological reactions of 30 thousand individuals studied. An analysis of the results shows that secondary immunodeficiency is encountered in 30% of the people occupied in industrial positions, in 40% of professional athletes and in more than 60% of the children studied. It should be emphasized that in enterprises where there is substantial excessive environmental harm, the frequency of development of immunodeficiency also exceeded the 60% mark. There are many reasons for the development of immunological deficiency and they depend on a large number of factors. Among them, in the first place, is the anthropogenic effect on the environment, which results in contamination of working zones, the earth, water and, as a consequence, food products, the use of which inevitably results in immunodepression. A special place in this problem is occupied by stress, which accompanies almost any professional activity. There is no doubt concerning the opinion that normal functioning of the immune system provides a sufficiently effective "interdiction" against the development of many diseases. Immune deficiency "opens the door" to illness. In other words, immunodeficiency is a detonator for the growth of a pathology. PMID:12687143

Pershin, Boris B.; Kuzmin, Sergey N.; Medvedev, Vladimir Ya.; Tolstov, Dmitry V.

1999-12-01

283

[HIV infection and acquired immunodeficiency syndrome].  

PubMed

On June 4, 1981, MMWR published a report about Pneumocystis carinii pneumonia in homosexual men in Los Angeles. This was the first published report. A years later, this disease was named acquired immunodeficiency syndrome (AIDS). In the following year, Montangier et al in France discovered the causative agent, which they called lymphadenopathy virus (LAV), now known as human immunodeficiency virus (HIV). In 1985, solid-phase enzymeimmunoassay for the detection of the antibody to HIV was developed. Since then, other new techniques for the identification of HIV infection have been become available. These include more sensitive methods (for example; polymerase chain reaction techniques). Although these techniques facilitate early and definite diagnosis of infection, these tests may fail to detect the antibody in sera during window period of infection or overdiagnose infection in sera contaminated with genes not related to HIV. Although preventing blood exposure is the primary means of preventing occupationally acquired human immunodeficiency virus (HIV) infection, appropriate post-exposure management is an important element of workplace safety. Information suggesting that zidovudine (ZDV) postexposure prophylaxis (PEP) may reduce the risk for HIV transmission after occupational exposure to HIV infected blood prompted a Public Health Service (PHS) interagency working group, with expert consultation, and recommendations on PEP and management of occupational exposure to HIV in relation to these findings were discussed. PMID:9170967

Takamatsu, J

1997-05-01

284

Attentiveness of pediatricians to primary immunodeficiency disorders  

PubMed Central

Background Primary immunodeficiency (PID) is a cluster of serious disorders that requires special alertness on the part of the medical staff for prompt diagnosis and management of the patient. This study explored PID knowledge and experience among pediatricians of wide educational backgrounds, practicing in the United Arab Emirates (UAE). Method A self-administered questionnaire was used to determine the competency of pediatricians in their knowledge of PID disorders. This study questionnaire included questions on PID signs and symptoms, syndromes associated with immunodeficiency, screening tests, interpreting laboratory tests and case management. The participants were 263 pediatricians of diverse education working in the 27 governmental hospitals in all regions of UAE. Results The overall performance of the pediatricians did not differ based on their age, gender, origin of certification, rank, or years of experience. Of the 50 questions, 20% of pediatricians answered correctly <60% of the questions, 76% answered correctly 60 to 79% of the questions, and 4% answered correctly ?80% of the questions. Seventeen of the 19 PID signs and symptoms were identified by 55 to 97%. Four of 5 syndromes associated with immunodeficiency were identified by 50 to 90%. Appropriate screening tests were chosen by 64 to 96%. Attention to the laboratory reference range values as function of patient age was notably limited. Conclusions There was a noteworthy deficiency in PID work-up. Therefore, implementing effective educational strategies is needed to improve the competency of pediatricians to diagnose and manage PID disorders.

2012-01-01

285

Immunological analysis in familial common variable immunodeficiency.  

PubMed Central

Immunological and genetic studies were performed in nine members from three generations of the family of a patient with common variable immunodeficiency (CVI). Two additional symptomatic members (mother and grandmother) had CVI. Among other six asymptomatic members, two had CVI and one had selective IgA deficiency. The proportions of monoclonal antibody defined total T cells (Leu 1+), helper phenotype (Leu 3+) suppressor phenotype (Leu 2+) T cells, natural killer cells (Leu 7+) and surface Ig+ B cells and proliferative response to phytohaemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM) and in mixed lymphocyte reaction (MLR) were comparable to controls. Addition of purified interleukin-2 (IL-2) resulted in augmentation of PHA-induced proliferation of T lymphocytes similar to that seen in the controls, however with IL-2 freshly isolated T cells in the absence of PHA demonstrated markedly increased proliferative response, suggesting the presence of in vivo activated T cells. Study of HLA phenotype did not reveal any linkage. This study demonstrates the genetic nature, possibly autosomal dominant inheritance, of common variable immunodeficiency; however the immunodeficiency is not linked to any specific HLA antigen.

Fuchs, H B; Slater, L; Novey, H; Ong, K; Gupta, S

1984-01-01

286

Mycobacterial disease, immunosuppression, and acquired immunodeficiency syndrome.  

PubMed Central

The mycobacteria are an important group of acid-fast pathogens ranging from obligate intracellular parasites such as Mycobacterium leprae to environmental species such as M. gordonae and M. fortuitum. The latter may behave as opportunistic human pathogens if the host defenses have been depleted in some manner. The number and severity of such infections have increased markedly with the emergence of the acquired immunodeficiency syndrome (AIDS) epidemic. These nontuberculous mycobacteria tend to be less virulent for humans than M. tuberculosis, usually giving rise to self-limiting infections involving the cervical and mesenteric lymph nodes of young children. However, the more virulent serovars of M. avium complex can colonize the bronchial and intestinal mucosal surfaces of healthy individuals, becoming virtual members of the commensal gut microflora and thus giving rise to low levels of skin hypersensitivity to tuberculins prepared from M. avium and M. intracellulare. Systemic disease develops when the normal T-cell-mediated defenses become depleted as a result of old age, cancer chemotherapy, or infection with human immunodeficiency virus. As many as 50% of human immunodeficiency virus antibody-positive individuals develop mycobacterial infections at some time during their disease. Most isolates of M. avium complex from AIDS patients fall into serotypes 4 and 8. The presence of these drug-resistant mycobacteria in the lungs of the AIDS patient makes their effective clinical treatment virtually impossible. More effective chemotherapeutic, prophylactic, and immunotherapeutic reagents are urgently needed to treat this rapidly increasing patient population.

Collins, F M

1989-01-01

287

Feline Immunodeficiency Virus in South America  

PubMed Central

The rapid emergence of AIDS in humans during the period between 1980 and 2000 has led to extensive efforts to understand more fully similar etiologic agents of chronic and progressive acquired immunodeficiency disease in several mammalian species. Lentiviruses that have gene sequence homology with human immunodeficiency virus (HIV) have been found in different species (including sheep, goats, horses, cattle, cats, and several Old World monkey species). Lentiviruses, comprising a genus of the Retroviridae family, cause persistent infection that can lead to varying degrees of morbidity and mortality depending on the virus and the host species involved. Feline immunodeficiency virus (FIV) causes an immune system disease in domestic cats (Felis catus) involving depletion of the CD4+ population of T lymphocytes, increased susceptibility to opportunistic infections, and sometimes death. Viruses related to domestic cat FIV occur also in a variety of nondomestic felids. This is a brief overview of the current state of knowledge of this large and ancient group of viruses (FIVs) in South America.

Teixeira, Bruno M.; Hagiwara, Mitika K.; Cruz, Juliano C. M.; Hosie, Margaret J.

2012-01-01

288

Allergic diseases in children with primary immunodeficiencies.  

PubMed

The aim of this study was to evaluate and compare the frequency of atopy and allergic disease in all groups of primary immunodeficiency (PID) patients. The study was done on 318 patients with PID between the ages of 6 months and 18 years. The patients and their parents were questioned regarding their histories of asthma and allergic disease. Within the study group, 82.4% of the patients had antibody deficiency, 10.4% combined immunodeficiency, 6.6% phagocyte number or function defect, and 0.6% complement deficiency. Patients with selective immunoglobulin (Ig)A deficiency had a more significant history of ever wheezing compared to those with IgG subclass deficiency (p=0.022). The frequency of current wheezing was higher in patients with antibody deficiency than in patients with combined immunodeficiency (p=0.049). In conclusion, patients with antibody deficiency, especially those with selective IgA deficiency, should be evaluated regarding asthma and allergic diseases if recurring respiratory symptoms are present. PMID:24827946

Ozcan, Celal; Metin, Ay?e; Erkoço?lu, Mustafa; Kocaba?, Can Naci

2014-01-01

289

Pathomorphology of humoral, cellular and combined primary immunodeficiencies  

Microsoft Academic Search

Histologic, immunohistologic and electron microscopic findings in three children with primary immunodeficiencies are reported. Classical X-linked infantile agammaglobulinemia Bruton was present in case 1 (?, aged 16 years), selective cellular immunodeficiency with thrombopenia in case 2 (?, aged 2 1\\/2 years) and non-lymphopenic severe combined immunodeficiency in case 3 (?, aged 1 3\\/4 years). At autopsy, all three cases exhibited

B. Heymer; D. Niethammer; R. Spanel; J. Galle; E. Kleihauer; O. Haferkamp

1977-01-01

290

Characterization of Human Immunodeficiency Virus Type 1 Monomeric and Trimeric gp120 Glycoproteins Stabilized in the CD4Bound State: Antigenicity, Biophysics, and Immunogenicity  

Microsoft Academic Search

The human immunodeficiency virus type 1 exterior gp120 envelope glycoprotein is highly flexible, and this flexibility may contribute to the inability of monomeric gp120 immunogens to elicit broadly neutralizing antibodies. We previously showed that an S375W modification of a critical interfacial cavity central to the primary receptor binding site, the Phe43 cavity, stabilizes gp120 into the CD4-bound state. However, the

Barna Dey; Marie Pancera; Krisha Svehla; Yuuei Shu; Shi-Hua Xiang; Jeffrey Vainshtein; Yuxing Li; Joseph Sodroski; Peter D. Kwong; John R. Mascola; Richard Wyatt

2007-01-01

291

Evaluating the immunogenicity of a disulfide-stabilized, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1  

Microsoft Academic Search

The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) complex comprises three gp120 exterior glycoproteins each noncovalently linked to a gp41 transmembrane glycoprotein. Monomeric gp120 proteins can elicit antibodies capable of neutralizing atypically sensitive test viruses in vitro, but these antibodies are ineffective against representative primary isolates and the gp120 vaccines failed to provide protection against HIV-1 transmission in

Simon Beddows; N. Schülke; Marc Kirschner; Kelly Barnes; Michael Franti; Elizabeth Michael; Thomas Ketas; Rogier W. Sanders; Paul J. Maddon; William C. Olson; John P. Moore

2005-01-01

292

Soluble Mimetics of Human Immunodeficiency Virus Type 1 Viral Spikes Produced by Replacement of the Native Trimerization Domain with a Heterologous Trimerization Motif: Characterization and Ligand Binding Analysis  

Microsoft Academic Search

The human immunodeficiency virus type 1 (HIV-1) exterior envelope glycoprotein, gp120, mediates binding to the viral receptors and, along with the transmembrane glycoprotein gp41, is a major target for neutralizing antibodies. We asked whether replacing the gp41 fusion\\/trimerization domain with a stable trimerization motif might lead to a more stable gp120 trimer that would be amenable to structural and immunologic

Marie Pancera; Jacob Lebowitz; Arne Schon; Ping Zhu; Ernesto Freire; Peter D. Kwong; Kenneth H. Roux; Joseph Sodroski; Richard Wyatt

2005-01-01

293

HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites.  

PubMed

The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization. PMID:12478295

Kwong, Peter D; Doyle, Michael L; Casper, David J; Cicala, Claudia; Leavitt, Stephanie A; Majeed, Shahzad; Steenbeke, Tavis D; Venturi, Miro; Chaiken, Irwin; Fung, Michael; Katinger, Hermann; Parren, Paul W I H; Robinson, James; Van Ryk, Donald; Wang, Liping; Burton, Dennis R; Freire, Ernesto; Wyatt, Richard; Sodroski, Joseph; Hendrickson, Wayne A; Arthos, James

2002-12-12

294

Pulsed field sample neutralization  

DOEpatents

An apparatus and method for alternating voltage and for varying the rate of extraction during the extraction of secondary particles, resulting in periods when either positive ions, or negative ions and electrons are extracted at varying rates. Using voltage with alternating charge during successive periods to extract particles from materials which accumulate charge opposite that being extracted causes accumulation of surface charge of opposite sign. Charge accumulation can then be adjusted to a ratio which maintains a balance of positive and negative charge emission, thus maintaining the charge neutrality of the sample.

Appelhans, Anthony D. (Idaho Falls, ID); Dahl, David A. (Idaho Falls, ID); Delmore, James E. (Idaho Falls, ID)

1990-01-01

295

Chimeric Plant Virus Particles as Immunogens for Inducing Murine and Human Immune Responses against Human Immunodeficiency Virus Type 1  

PubMed Central

The high-yield expression of a neutralizing epitope from human immunodeficiency virus type 1 (HIV-1) on the surface of a plant virus and its immunogenicity are presented. The highly conserved ELDKWA epitope from glycoprotein (gp) 41 was expressed as an N-terminal translational fusion with the potato virus X (PVX) coat protein. The resulting chimeric virus particles (CVPs), purified and used to immunize mice intraperitoneally or intranasally, were able to elicit high levels of HIV-1-specific immunoglobulin G (IgG) and IgA antibodies. Furthermore, the human immune response to CVPs was studied with severe combined immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL-SCID). hu-PBL-SCID mice immunized with CVP-pulsed autologous dendritic cells were able to mount a specific human primary antibody response against the gp41-derived epitope. Notably, sera from both normal and hu-PBL-SCID mice showed an anti-HIV-1-neutralizing activity. Thus, PVX-based CVPs carrying neutralizing epitopes can offer novel perspectives for the development of effective vaccines against HIV and, more generally, for the design of new vaccination strategies in humans.

Marusic, Carla; Rizza, Paola; Lattanzi, Laura; Mancini, Camillo; Spada, Massimo; Belardelli, Filippo; Benvenuto, Eugenio; Capone, Imerio

2001-01-01

296

Effects of Pharmacological Doses of Nandrolone Decanoate and Progressive Resistance Training in Immunodeficient Patients Infected with Human Immunodeficiency Virus  

Microsoft Academic Search

This nonplacebo-controlled, open label, randomized study was con- ducted to test the hypotheses that pharmacological doses of nan- drolone decanoate would increase lean body tissue, muscle mass, and strength in immunodeficient human immunodeficiency virus- infected men, and that these effects would be enhanced with pro- gressive resistance training (PRT). Thirty human immunodeficiency virus-positive men with fewer than 400 CD4 lymphocytes\\/mm3

FRED R. SATTLER; S. VICTORIA JAQUE; E. TODD SCHROEDER; CONNIE OLSON; MICHAEL P. DUBE; CARMEN MARTINEZ; WILLIAM BRIGGS; RICHARD HORTON

297

Protection in Macaques Immunized with HIV1 Candidate Vaccines Can Be Predicted Using the Kinetics of Their Neutralizing Antibodies  

Microsoft Academic Search

BackgroundA vaccine is needed to control the spread of human immunodeficiency virus type 1 (HIV-1). An in vitro assay that can predict the protection induced by a vaccine would facilitate the development of such a vaccine. A potential candidate would be an assay to quantify neutralization of HIV-1.Methods and FindingsWe have used sera from rhesus macaques that have been immunized

David Davis; Wim Koornstra; Daniella Mortier; Zahra Fagrouch; Ernst J. Verschoor; Jonathan L. Heeney; Willy M. J. M. Bogers

2011-01-01

298

Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome: Correlation but not Causation  

Microsoft Academic Search

AIDS is an acquired immunodeficiency syndrome defined by a severe depletion of T cells and over 20 conventional degenerative and neoplastic diseas es. In the U.S. and Europe, AIDS correlates to 95% with risk factors, such as about 8 years of promiscuous male homosexuality, intravenous drug use, or hemophilia. Since AIDS also correlates with antibody to a retrovirus, confirmed in

Peter H. Duesberg

1989-01-01

299

Neutrality and self-adaptation  

Microsoft Academic Search

Abstract. Neutral genotype-phenotype mappings can be observed in natural evo-lution and are often used in evolutionary computation. In this article, important aspects of such encodings are analyzed. First, it is shown that in the absence of external control neutrality allows a variation of the search distribution independent of phenotypic changes. In particular, neutrality is necessary for self-adaptation, which is used

Christian Igel; Marc Toussaint

2003-01-01

300

Update on the treatment of primary immunodeficiencies.  

PubMed

A general review of advances in the treatment of Primary Immunodeficiencies (PID) has been performed. Treatment with immunoglobulins is indicated in cases of humoral immunodeficiencies and in selected cases of combined immunodeficiencies. The use of intramuscular immunoglobulins in the treatment of PID was abandoned after obtaining the intravenous immunoglobulins, since these are much more effective and have fewer adverse effects. Now subcutaneous immunoglobulins are also available. Immunoglobulins help to keep the patients free of symptoms and infections as these substances are able to neutralise infectious agents, modulate and promote the immune response and favour phagocytosis. Adverse effects have been reported in 5-15 % of patients receiving IVIg, and patients with deficiencies of subclasses of IgG with IgA deficiency and/or anti-IgA antibodies are at risk of severe reactions. No severe adverse effects of subcutaneous immuneglobulins have been reported and the medication can be self-administered. The efficacy and safety of IVIg and SCIg are similar and SCIg administered at home is associated with better quality of life. Stem Cell Transplantation (SCT) in Primary Immunodeficiencies is aimed at restoring the number and/or function of lymphocytes or phagocytes. Matched, related or unrelated donors, or related haploidentical donors are selected. HLA class II mismatched unrelated donors are avoided owing to the risk of severe graft versus host disease (GVHD). Stem cells are obtained from bone marrow, cord blood or peripheral blood. Prophylactic immunossupression (as well as donor T lymphocyte depletion in haploidentical and unrelated donors) is performed to avoid or minimize GVHD. Less toxic "reduced intensity" protocols now exist for pre-transplantation conditioning, indicated to avoid graft rejection if there is residual T-lymphocyte immunity in the host. In the majority of Severe Combined Immunodeficiencies (SCID), SCT results in T lymphocytes graft and the antibody immunodeficiency persists in many cases. The results are better the earlier it is performed, with the absence of previous infections, and with the degree of matching. The patient must be maintained in a laminar flow room with broad anti-infectious prophylaxis and with the intravenous administration of gammaglobulin for a variable period. Many other complications can be expected. Gene therapy. Patients with PID are ideal candidates, as they are monogenic, the haematopoietic cells are easily obtained and virus replication is easy within them. Vectors (viruses) "infect" the stem cells of the patient's bone marrow, producing the transfection of the wild (healthy) gene in these cells. Encouraging results have been achieved in X-linked SCID as there are a number of patients who are considered "cured", although neoplastic processes have occurred due to the activation of proto-oncogenes close to the point of insertion of the external gene, using retroviruses as vectors; there are now trials with adenovirus, physical methods (direct injection...) and chemical methods (viral modification, artificial viruses...). Gene therapy has also been performed in patients with Chronic Granulomatous Disease and trials will improve in the future with changes in protocols used in oncology and infectious diseases. PMID:17923072

García, J M; Español, T; Gurbindo, M D; Casas C, C

2007-01-01

301

Dental treatment of children with severe combined immunodeficiency  

Microsoft Academic Search

The prolonged survival of children having primary and secondary immunodeFiciencies will require many of these youngsters to seek the attention of dentists. Two children with severe combined immunodeFiciency (SCID), a disease with profound abnormalities of both cellular and humoral immunity, are presented to illustrate how dental and oral lesions cause major difficulties in clinical management. The First child developed extensive

Ira N. Moyer; Roger H. Kobayashi; Mark L. Cannon; John F. Simon; Robert O. Cooley

1983-01-01

302

Infectious pathogens in pediatric patients with primary immunodeficiencies  

Microsoft Academic Search

Background and Purpose: Primary immunodeficiency diseases (PIDs) are rare disorders. Unusual infections often guide the initial investigation for immunodeficiency. Methods: In order to ascertain the organisms that lead to a predisposition for PIDs, we reviewed the charts of 92 children diagnosed with PIDs at the National Taiwan University Hospital between March 1984 and March 2004. Results: Pneumonia was diagnosed in

Shu-Hua Chang; Yao-Hsu Yang; Bor-Luen Chiang

303

Zidovudine Is Beneficial in Human Immunodeficiency Virus Associated Nephropathy  

Microsoft Academic Search

Human immunodeficiency virus associated nephropathy (Hivan) is a distinct renal disease described in patients infected with the human immunodeficiency virus (HIV). Hivan is characterized by a nephrotic syndrome, enlarged kidneys, a histologic finding of focal and segmental glomerulosclerosis, and a very rapid progression to end-stage renal disease (ESRD). No therapeutic intervention has been shown, in a prospective evaluation, to either

Onyekachi Ifudu; Sreepada Rao; Caridad C. Tan; Heidi Fleischman; Keith Chirgwin; Eli A. Friedman

1995-01-01

304

Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF)  

Microsoft Academic Search

The Immunodeficiency, Centromeric region instability, Facial anomalies syndrome (ICF) is a rare autosomal recessive disease described in about 50 patients worldwide and characterized by immunodeficiency, although B cells are present, and by characteristic rearrangements in the vicinity of the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16 and sometimes 9. Other variable symptoms of this probably under-diagnosed syndrome include

Melanie Ehrlich; Kelly Jackson; Corry Weemaes

2006-01-01

305

Matched unrelated bone marrow transplantation for combined immunodeficiency  

Microsoft Academic Search

Bone marrow transplantation (BMT) from siblings is the treatment of choice for severe combined immunodeficiency (SCID). The objective of this study was to evaluate the efficiency of BMT from matched unrelated donors (MUD) in congenital immunodeficiencies when a sibling donor is unavailable. Sixteen consecutive patients with SCID (n = 9) and CID (n = 7), were referred for an unrelated

I Dalal; B Reid; J Doyle; M Freedman; S Calderwood; F Saunders; CM Roifman

2000-01-01

306

Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies  

ClinicalTrials.gov

Immunologic Deficiency Syndromes; Chediak-Higashi Syndrome; Common Variable Immunodeficiency; Graft Versus Host Disease; X-Linked Lymphoproliferative Syndrome; Familial Erythrophagocytic Lymphohistiocytosis; Hemophagocytic Lymphohistiocytosis; X-linked Agammaglobulinemia; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; X-linked Hyper IgM Syndrome; Severe Combined Immunodeficiency; Leukocyte Adhesion Deficiency Syndrome; Virus-Associated Hemophagocytic Syndrome

2009-10-14

307

Orthopaedic surgery in hemophilic patients with human immunodeficiency virus.  

PubMed

Patients registered at the author's hemophilia center between 1982 and 1994 were studied to establish whether major orthopaedic surgical procedures accelerate the fall of CD4 lymphocyte counts of patients with hemophilia who are infected with the human immunodeficiency virus, and whether patients who had surgery had different rates of development of acquired immune deficiency syndrome or death when compared with patients who did not have surgery. The patients were divided into four groups: Group 1, 22 patients who were human immunodeficiency virus positive undergoing orthopaedic surgery; Group 2, 89 patients who were human immunodeficiency virus positive not undergoing orthopaedic surgery; Group 3, 18 patients who were human immunodeficiency virus negative undergoing orthopaedic surgery; and Group 4, 135 patients who were human immunodeficiency virus negative not undergoing orthopaedic surgery. There was no significant difference between the rates of decline of CD4 lymphocyte counts for patients who were human immunodeficiency virus positive who underwent surgery when compared with human immunodeficiency virus positive patients who did not undergo surgery, nor was there any significant difference between the two human immunodeficiency virus negative groups. There were no significant differences in the rate of development of acquired immune deficiency syndrome or mortality rates between patients who had surgery and those who did not. PMID:9345211

Phillips, A M; Sabin, C A; Ribbans, W J; Lee, C A

1997-10-01

308

Human cytomegalovirus infection is not increased in common variable immunodeficiency  

Microsoft Academic Search

It has been postulated that human cytomegalovirus (HCMV) infection may have a role in the pathogenesis of common variable immunodeficiency (CVID). Many patients have a lymphocyte phenotype similar to that seen in HCMV infection, HCMV mononucleosis may precipitate hypogammaglobulinaemia, and a previous small study of common variable immunodeficient patients reported a high rate of active HCMV infection. This study investigated

C. G. Mullighan; S. J. Read; A. G. Bird; J. B. Kurtz; H. M. Chapel; K. I. Welsh

1996-01-01

309

Chapter 27: Approach to primary immunodeficiency.  

PubMed

Primary immunodeficiency diseases (PID) are inherited defects of the innate or adaptive arms of the immune system that lead to an increase in the incidence, frequency, or severity of infections. There may be defects in the adaptive arm of the immune system that include combined immunodeficiency and antibody deficiency syndromes or by abnormalities in innate immunity such as disorders of phagocytes, the complement pathway, or Toll-Like receptor (TLR) mediated signaling. Recurrent sinopulmonary infections with encapsulated bacteria such as Haemophilus influenza type B or Streptococcus pneumoniae may be characteristic of an IgG antibody deficiency or dysfunction. Frequent viral, fungal, or protozoal infections may suggest T lymphocyte dysfunction. Multiple staphylococcal skin infections and fungal infections may imply neutrophil dysfunction or the hyper-IgE syndrome, and recurrent neisserial infection is a characteristic manifestation of late complement component (C5-9, or the membrane attack complex) defects. Recurrent viral or pyogenic bacterial infections often without the presence of a significant inflammatory response suggest a defect in TLR signaling. Mycobacterial infections are characteristic of defects in interleukin (IL)-12, interferon (IFN) gamma, or their receptors. Screening of newborns for T-cell lymphopenia using a polymerase chain reaction to amplify T-cell receptor excision circles (TRECs), which are formed when a T cell rearranges the variable region of its receptor, serves as a surrogate for newly synthesized naïve T cells. Because of very low numbers of TRECs, severe combined immunodeficiency, DiGeorge syndrome, and other causes of T-cell lymphopenia have been identified in newborns. PMID:22794700

Uzzaman, Ashraf; Fuleihan, Ramsay L

2012-01-01

310

Antigenicity and Immunogenicity of Transmitted/Founder, Consensus, and Chronic Envelope Glycoproteins of Human Immunodeficiency Virus Type 1  

PubMed Central

Human immunodeficiency virus type 1 (HIV-1) vaccine development requires selection of appropriate envelope (Env) immunogens. Twenty HIV-1 Env glycoproteins were examined for their ability to bind human anti-HIV-1 monoclonal antibodies (MAbs) and then used as immunogens in guinea pigs to identify promising immunogens. These included five Envs derived from chronically infected individuals, each representing one of five common clades and eight consensus Envs based on these five clades, as well as the consensus of the entire HIV-1 M group, and seven transmitted/founder (T/F) Envs from clades B and C. Sera from immunized guinea pigs were tested for neutralizing activity using 36 HIV-1 Env-pseudotyped viruses. All Envs bound to CD4 binding site, membrane-proximal, and V1/V2 MAbs with similar apparent affinities, although the T/F Envs bound with higher affinity to the MAb 17b, a CCR5 coreceptor binding site antibody. However, the various Envs differed in their ability to induce neutralizing antibodies. Consensus Envs elicited the most potent responses, but neutralized only a subset of viruses, including mostly easy-to-neutralize tier 1 and some more-difficult-to-neutralize tier 2 viruses. T/F Envs elicited fewer potent neutralizing antibodies but exhibited greater breadth than chronic or consensus Envs. Finally, chronic Envs elicited the lowest level and most limited breadth of neutralizing antibodies overall. Thus, each group of Env immunogens elicited a different antibody response profile. The complementary benefits of consensus and T/F Env immunogens raise the possibility that vaccines utilizing a combination of consensus and T/F Envs may be able to induce neutralizing responses with greater breadth and potency than single Env immunogens.

Tsao, Chun-Yen; Alam, S. Munir; Muldoon, Mark; Vandergrift, Nathan; Ma, Ben-Jiang; Lu, Xiaozhi; Sutherland, Laura L.; Scearce, Richard M.; Bowman, Cindy; Parks, Robert; Chen, Haiyan; Blinn, Julie H.; Lapedes, Alan; Watson, Sydeaka; Xia, Shi-Mao; Foulger, Andrew; Hahn, Beatrice H.; Shaw, George M.; Swanstrom, Ron; Montefiori, David C.; Gao, Feng; Haynes, Barton F.; Korber, Bette

2013-01-01

311

Screening for severe combined immunodeficiency in neonates.  

PubMed

Severe combined immunodeficiency (SCID) is a rare disease that severely affects the cellular and humoral immune systems. Patients with SCID present with recurrent or severe infections and often with chronic diarrhea and failure to thrive. The disease is uniformly fatal, making early diagnosis essential. Definitive treatment is hematopoietic stem cell transplantation, with best outcomes prior to 3.5 months of age. Newborn screening for SCID using the T-cell receptor excision circle assay has revolutionized early identification of infants with SCID or severe T-cell lymphopenia. PMID:24068875

Kelly, Brian T; Tam, Jonathan S; Verbsky, James W; Routes, John M

2013-01-01

312

Endemic mycosis complicating human immunodeficiency virus infection.  

PubMed Central

Persons infected with the human immunodeficiency virus are prone to the development of many fungal diseases. Normal hosts with intact immunity usually recover from infection by these less-invasive fungi. In persons with compromised T-cell-mediated immunity, however, widespread dissemination from a pulmonary focus occurs. In this review, we discuss the epidemiology, clinical manifestations, diagnosis, and treatment of the three major North American mycoses, histoplasmosis, blastomycosis, and coccidioidomycosis. In most cases, amphotericin B is the initial drug of choice, followed by one of the azoles for lifelong maintenance therapy.

Sarosi, G A; DAvies, S F

1996-01-01

313

[Human immunodeficiency virus (HIV): a review].  

PubMed

Since its discovery in 1983, a lot of knowledge about the human immunodeficiency virus (HIV) has been accumulated. Our paper gives a brief survey on what is known at present about the structure, molecular biology, and the cell tropism of this virus. We discuss its relationship to other lentiviruses as well as its possible origin; in addition, we refer to the immune response to HIV and its interactions with the infected host. We also briefly summarize the difficulties encountered in the attempts to produce a vaccine against HIV and highlight some promising approaches in the development of such a vaccine. PMID:2205059

Schulz, T F; Larcher, C; Dierich, M P

1990-07-01

314

[Human immunodeficiency virus infection - treatment beyond medication].  

PubMed

Human Immunodeficiency Virus (HIV) infection is presently considered a chronic disorder. Infected people need a thorough medical surveillance and chronic therapy, which affects families and other caregivers. Infected children are also affected by their parents' infection and by the stigma that is still associated with this particular illness. Regular meetings were organized for HIV infected children, their families and the health team with recreational and formative purposes. These meetings were evaluated in a strongly positive manner by all the intervenients. The goal to maintain these activities is proposed as a way of improving the follow-up and the prognosis of these children. PMID:21144321

Teixeira, Carla; Rodrigues, Paula; Cardoso, Cármen; Morais, Angélica; Sequeira, Fátima; Diz, Alcinda; Santos, M Carmo; Marques, Laura

2010-01-01

315

Human Immunodeficiency Virus and Pulmonary Arterial Hypertension  

PubMed Central

Human immunodeficiency virus- (HIV-) related pulmonary arterial hypertension (PAH) is a rare complication of HIV infection. The pathophysiology of HIV-related PAH is complex, with viral proteins seeming to play the major role. However, other factors, such as coinfection with other microorganisms and HIV-related systemic inflammation, might also contribute. The clinical presentation of HIV-related PAH and diagnosis is similar to other forms of pulmonary hypertension. Both PAH-specific therapies and HAART are important in HIV-related PAH management. Future studies investigating the pathogenesis are needed to discover new therapeutic targets and treatments.

Ali, Alaa M.

2013-01-01

316

Tumor uptake of radioiodinated anti-human pulmonary surfactant-associated protein monoclonal antibody pe10 in nude mice bearing human pulmonary adenocarcinoma in combination with an unlabeled preload  

Microsoft Academic Search

This study assessed the potential use of radioimmunoscintigraphy of pulmonary alveolar Type II cells tumor with the radiolabeled anti-human surfactant-associated protein (SP) monoclonal antibody (MAb) PE 10 in combination with preloads of unlabeled MAb. The in vitro binding of iodine-125 (125I)-labeled MAb PE 10 (1 ?g), which had a specific radioactivity of 400 MBq\\/mg, on human pulmonary papillary adenocarcinoma NCI-H441

Naoyuki Watanabe; Shuji Tanada; Noboru Oriuchi; E. Edmund Kim; Hajime Murata; Yasuhito Sasaki

2000-01-01

317

Porous silicon as a platform for immobilization of biotin anti-human IL6; rat IgG2a antibody onto p-type porous silicon via physical absorption method  

Microsoft Academic Search

Immobilization of biotin anti-human IL-6; rat IgG2a antibody onto porous silicon (PS) formed by an electrochemical anodization of p-type silicon surfaces has been reported. Chemical surface characterization by means of Fourier transformation infrared (FTIR) absorption spectroscopy, contact angle measurements and X-ray photoelectron spectroscopy (XPS), confirmed the efficiency of PS as entrapping template for the specific immobilization of IgG2a antibody via

M. Naddaf; A. Al-Mariri

318

Feline immunodeficiency virus: an interesting model for AIDS studies and an important cat pathogen.  

PubMed Central

The lentivirus feline immunodeficiency virus (FIV) is a widespread pathogen of the domestic cat that is mainly transmitted through bites, although other means of transmission are also possible. Its prevalence ranges from 1 to 10% in different cat populations throughout the world, thus representing a large reservoir of naturally infected animals. FIV resembles the human immunodeficiency virus (HIV) in many respects. Similarities include the structural features of the virion, the general organization and great variability of the genome, the life cycle in the infected host, and most importantly, the pathogenic potential. Infection is associated with laboratory signs of immunosuppression as well as with a large variety of superinfections, tumors, and neurological manifestations. Our understanding of FIV is steadily improving and is providing important clues to the pathogenesis of immunodeficiency-inducing lentiviruses. The cellular receptor for FIV is different from the feline equivalent of the human CD4 molecule used by HIV; nevertheless, the major hallmark of infection is a progressive loss of CD4+ T lymphocytes as in HIV infection. The mechanisms by which FIV escapes the host's immune responses are being actively investigated. FIV causes lysis of infected T cells and also appears to predispose these cells to apoptosis. Infection of macrophages and other cell types has also been documented. For reasons yet to be understood, antibody-mediated neutralization of fresh FIV isolates is very inefficient both in vitro and in vivo. Vaccination studies have provided some encouraging results, but the difficulties encountered appear to match those met in HIV vaccine development. FIV susceptibility to antiviral agents is similar to that of HIV, thus providing a valuable system for in vivo preclinical evaluation of therapies. It is concluded that in many respects FIV is an ideal model for AIDS studies.

Bendinelli, M; Pistello, M; Lombardi, S; Poli, A; Garzelli, C; Matteucci, D; Ceccherini-Nelli, L; Malvaldi, G; Tozzini, F

1995-01-01

319

Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti-human DEC205 monoclonal antibody  

PubMed Central

Protein vaccines for T-cell immunity are not being prioritized because of poor immunogenicity. To overcome this hurdle, proteins are being targeted to maturing dendritic cells (DCs) within monoclonal antibodies (mAbs) to DC receptors. To extend the concept to humans, we immunized human immunoglobulin-expressing mice with human DEC205 (hDEC205) extracellular domain. 3D6 and 3G9 mAbs were selected for high-affinity binding to hDEC205. In addition, CD11c promoter hDEC205 transgenic mice were generated, and 3G9 was selectively targeted to DCs in these animals. When mAb heavy chain was engineered to express HIV Gag p24, the fusion mAb induced interferon-?– and interleukin-2–producing CD4+ T cells in hDEC205 transgenic mice, if polynocinic polycytidylic acid was coadministered as an adjuvant. The T-cell response was broad, recognizing at least 3 Gag peptides, and high titers of anti-human immunoglobulin G antibody were made. Anti-hDEC205 also improved the cross-presentation of Gag to primed CD8+ T cells from HIV-infected individuals. In all tests, 3D6 and 3G9 targeting greatly enhanced immunization relative to nonbinding control mAb. These results provide preclinical evidence that in vivo hDEC205 targeting increases the efficiency with which proteins elicit specific immunity, setting the stage for proof-of-concept studies of these new protein vaccines in human subjects.

Cheong, Cheolho; Choi, Jae-Hoon; Vitale, Laura; He, Li-Zhen; Trumpfheller, Christine; Bozzacco, Leonia; Do, Yoonkyung; Nchinda, Godwin; Park, Sung Ho; Dandamudi, Durga Bhavani; Shrestha, Elina; Pack, Maggi; Lee, Han-Woong; Keler, Tibor

2010-01-01

320

Epidemiology of BK Virus in Renal Allograft Recipients: Identification of Steroid Maintenance Therapy and Rabbit Anti-Human Thymocyte Globulin Induction as Independent Risk Factors for BKV replication  

PubMed Central

BACKGROUND Identification of risk factors for BKV replication may improve transplant outcome. We investigated the impact of immunosuppressive drugs on the prevalence of BKV replication in recipients of human renal allografts. METHODS One hundred twenty renal allograft recipients were studied prospectively at one, three, and six months post-transplantation to identify risk factors for BKV replication. BKV replication was quantified by measurement of urinary cell BKV VP1 mRNA levels using BKV specific primers and TaqMan® probe in a real-time quantitative PCR assay. Levels of urinary cell mRNA for granzyme B, CD103 and TGF-?1 were measured to ascertain whether BKV replication is associated with an inflammatory signature. RESULTS The prevalence of BKV replication increased over time and was highest at six-months compared to 1 or 3 months post-transplantation (P<0.001). A logistic regression model analysis demonstrated that steroid maintenance therapy (odds ratio: 8.3, P= 0.003) and induction with rabbit anti-human thymocyte globulin (ATG) (odds ratio: 5.8, P= 0.008) were independent risk factors for BKV replication. Neither mycophenolate mofetil dose nor tacrolimus dose or trough levels were different between those with or without BKV replication. The development of acute rejection or anti-rejection treatment with methylprednisolone did not increase the risk of BKV replication. BKV replication was associated with heightened levels of urinary cell mRNA for granzyme B (P<0.002), CD103 (P<0.005) but not for TGF-?1 (P>0.05). CONCLUSIONS Steroid maintenance therapy and induction with ATG are independent risk factors for BKV replication in renal allograft recipients treated with tacrolimus and mycophenolate mofetil.

Dadhania, Darshana; Snopkowski, Catherine; Ding, Ruchuang; Muthukumar, Thangamani; Chang, Christina; Aull, Meredith; Lee, Jun; Sharma, Vijay K.; Kapur, Sandip; Suthanthiran, Manikkam

2013-01-01

321

Molecular basis of human immunodeficiency virus type 1 drug resistance: overview and recent developments.  

PubMed

The introduction of potent combination therapies in the mid-90s had a tremendous effect on AIDS mortality. However, drug resistance has been a major factor contributing to antiretroviral therapy failure. Currently, there are 26 drugs approved for treating human immunodeficiency virus (HIV) infections, although some of them are no longer prescribed. Most of the available antiretroviral drugs target HIV genome replication (i.e. reverse transcriptase inhibitors) and viral maturation (i.e. viral protease inhibitors). Other drugs in clinical use include a viral coreceptor antagonist (maraviroc), a fusion inhibitor (enfuvirtide) and two viral integrase inhibitors (raltegravir and elvitegravir). Elvitegravir and the nonnucleoside reverse transcriptase inhibitor rilpivirine have been the most recent additions to the antiretroviral drug armamentarium. An overview of the molecular mechanisms involved in antiretroviral drug resistance and the role of drug resistance-associated mutations was previously presented (Menéndez-Arias, L., 2010. Molecular basis of human immunodeficiency virus drug resistance: an update. Antiviral Res. 85, 210-231). This article provides now an updated review that covers currently approved drugs, new experimental agents (e.g. neutralizing antibodies) and selected drugs in preclinical or early clinical development (e.g. experimental integrase inhibitors). Special attention is dedicated to recent research on resistance to reverse transcriptase and integrase inhibitors. In addition, recently discovered interactions between HIV and host proteins and novel strategies to block HIV assembly or viral entry emerge as promising alternatives for the development of effective antiretroviral treatments. PMID:23403210

Menéndez-Arias, Luis

2013-04-01

322

Human immunodeficiency virus-1 vaccine design: where do we go now?  

PubMed

Numerous human immunodeficiency virus (HIV)-1 vaccines have been developed over the last three decades, but to date an effective HIV-1 vaccine that can be used for prophylactic or therapeutic purposes in humans has not been identified. The failures and limited successes of HIV-1 vaccines have highlighted the gaps in our knowledge with regard to fundamental immunity against HIV-1 and have provided insights for vaccine strategies that may be implemented for designing more effective HIV-1 vaccines in the future. Recent studies have shown that robust mucosal immunity, high avidity and polyfunctional T cells, and broadly neutralizing antibodies are important factors governing the induction of protective immunity against HIV-1. Furthermore, optimization of vaccine delivery methods for DNA or live viral vector-based vaccines, elucidating the immune responses of individuals who remain resistant to HIV-1 infections and also understanding the core immune responses mediating protection against simian immunodeficiency viruses (SIV) and HIV-1 in animal models following vaccination, are key aspects to be regarded for designing more effective HIV-1 vaccines in the future. PMID:20956986

Wijesundara, Danushka K; Jackson, Ronald J; Ramshaw, Ian A; Ranasinghe, Charani

2011-03-01

323

Net neutrality and investment incentives  

Microsoft Academic Search

This article analyzes the effects of net neutrality regulation on investment incentives for Internet service providers (ISPs) and content providers (CPs), and their implications for social welfare. Concerning the ISPs' investment incentives, we find that capacity expansion decreases the sale price of the priority right under the discriminatory regime. Thus, contrary to ISPs' claims that net neutrality regulations would have

Jay Pil Choi; Byung-Cheol Kim

2010-01-01

324

The delusions of net neutrality  

Microsoft Academic Search

Service providers argue that if net neutrality is not enforced, they will have sufficient incentives to build special high-quality channels that will take the Internet to the next level of its evolution. But what if they do get their wish, net neutrality is consigned to the dustbin, and they do build their new services, but nobody uses them? If the

Andrew Odlyzko

2008-01-01

325

Four nightmares for net neutrality  

Microsoft Academic Search

What is the economic substance behind net neutrality, the populist policy debate du jour? The authors assesses the basic economics behind net neutrality. To be sure, this debate has many arcane facets. For example, a couple years ago the FCC legally exempted US broadband firms - cable modem and DSL providers - from what are known as \\

Shane Greenstein

2006-01-01

326

Neutral theory and community ecology  

Microsoft Academic Search

I review the mathematical and biological aspects of Hubbell's (2001) neutral theory of species abundance for ecological communities, and clarify its historical connections with closely related approaches in population genetics. A selective overview of the empirical evidence for and against this theory is provided, with a special emphasis on tropical plant communities. The neutral theory predicts many of the basic

J. Chave

2004-01-01

327

NEUTRAL-BEAM INJECTION  

SciTech Connect

The emphasis in the preceding chapters has been on magnetic confinement of high temperature plasmas. The question of production and heating of such plasmas has been dealt with relatively more briefly. It should not be inferred, however, that these matters must therefore be either trivial or unimportant. A review of the history reveals that in the early days all these aspects of the controlled fusion problem were considered to be on a par, and were tackled simultaneously and with equal vigor. Only the confinement problem turned out to be much more complex than initially anticipated, and richer in challenge to the plasma physicist than the questions of plasma production and heating. On the other hand, the properties of high-temperature plasmas and plasma confinement can only be studied experimentally after the problems of production and of heating to adequate temperatures are solved. It is the purpose of this and the next chapter to supplement the preceding discussions with more detail on two important subjects: neutral-beam injection and radio-frequency heating. These are the major contenders for heating in present and future tokamak and mirror fusion experiments, and even in several proposed reactors. For neutral beams we emphasize here the technology involved, which has undergone a rather remarkable development. The physics of particle and energy deposition in the plasma, and the discussion of the resulting effects on the confined plasma, have been included in previous chapters, and some experimental results are quoted there. Other heating processes of relevance to fusion are mentioned elsewhere in this book, in connection with the experiments where they are used: i.e. ohmic heating, adiabatic compression heating, and alpha-particle heating in Chapter 3 by H.P. Furth; more ohmic heating in Chapter 7, and shock-implosion heating, laser heating, and relativistic-electron beam heating in Chapter 8, both by W. E. Quinn. These methods are relatively straightforward in their physics and their technology, or in any case they are considered to be adequately covered by these other authors.

Kunkel, W.B.

1980-06-01

328

Cellular Restriction Factors of Feline Immunodeficiency Virus  

PubMed Central

Lentiviruses are known for their narrow cell- and species-tropisms, which are determined by cellular proteins whose absence or presence either support viral replication (dependency factors, cofactors) or inhibit viral replication (restriction factors). Similar to Human immunodeficiency virus type 1 (HIV-1), the cat lentivirus Feline immunodeficiency virus (FIV) is sensitive to recently discovered cellular restriction factors from non-host species that are able to stop viruses from replicating. Of particular importance are the cellular proteins APOBEC3, TRIM5? and tetherin/BST-2. In general, lentiviruses counteract or escape their species’ own variant of the restriction factor, but are targeted by the orthologous proteins of distantly related species. Most of the knowledge regarding lentiviral restriction factors has been obtained in the HIV-1 system; however, much less is known about their effects on other lentiviruses. We describe here the molecular mechanisms that explain how FIV maintains its replication in feline cells, but is largely prevented from cross-species infections by cellular restriction factors.

Zielonka, Jorg; Munk, Carsten

2011-01-01

329

Combined Immunodeficiency Associated with DOCK8 Mutations  

PubMed Central

BACKGROUND Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown. METHODS We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase –polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry. RESULTS Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma –leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes. CONCLUSIONS Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency.

Zhang, Qian; Davis, Jeremiah C.; Lamborn, Ian T.; Freeman, Alexandra F.; Jing, Huie; Favreau, Amanda J.; Matthews, Helen F.; Davis, Joie; Turner, Maria L.; Uzel, Gulbu; Holland, Steven M.; Su, Helen C.

2010-01-01

330

Antibody cross-competition analysis of the human immunodeficiency virus type 1 gp120 exterior envelope glycoprotein.  

PubMed Central

Forty-six monoclonal antibodies (MAbs) able to bind to the native, monomeric gp120 glycoprotein of the human immunodeficiency virus type 1 (HIV-1) LAI (HXBc2) strain were used to generate a competition matrix. The data suggest the existence of two faces of the gp120 glycoprotein. The binding sites for the viral receptor, CD4, and neutralizing MAbs appear to cluster on one face, which is presumably exposed on the assembled, oligomeric envelope glycoprotein complex. A second gp120 face, which is presumably inaccessible on the envelope glycoprotein complex, contains a number of epitopes for nonneutralizing antibodies. This analysis should be useful for understanding both the interaction of antibodies with the HIV-1 gp120 glycoprotein and neutralization of HIV-1.

Moore, J P; Sodroski, J

1996-01-01

331

cDNA sequence and tissue distribution of canine Na-dependent neutral amino acid transporter 2 (ASCT 2).  

PubMed

A full-length cDNA sequence of canine Na-dependent neutral amino acid transporter (ASCT2) and its distribution were determined. The sequence was 2,090 bp long and was predicted to encode 544 amino acid polypeptides. The amino acid sequence deduced from canine ASCT2 showed 90% similarity to that of humans and mice. Northern blot analysis revealed ASCT2 expression in the kidney, heart, lung and muscles, and Western blot analysis using anti-human ASCT2 antiserum detected the bands at 60 and 65 kDa in membrane protein of the lung. RT-PCR analysis revealed ASCT2 expression in all the tissues examined. PMID:22785178

Ochiai, Hideharu; Onda, Ken; Ogihara, Kikumi; Naya, Yuko; Sugiyama, Hiroki; Maruo, Takuya

2012-11-01

332

Mutations in IRF8 and Human Dendritic Cell Immunodeficiency  

PubMed Central

Background The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in host defense against infections. Disseminated infection caused by BCG vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected individuals, the etiology of disseminated BCG disease is unexplained. Methods We investigated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, requiring hematopoietic stem cell transplantation. We also studied two otherwise healthy adults with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic cells compartments in these three persons and sequenced candidate genes, mutation of which could plausibly confer susceptibility to BCG disease. Results We detected two distinct disease-causing mutations affecting the transcriptional regulator IRF8. Both K108A and T80A mutations impair IRF8 transcriptional activity by disrupting IRF8 interaction with DNA. Mutation K108E was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. Mutation T80A was associated with an autosomal dominant milder immunodeficiency and a selective depletion of CD11c+ CD1c+ circulating dendritic cells. Conclusions These findings define a new class of human primary immunodeficiency, affecting the differentiation of mononuclear phagocytes. They also demonstrate that human IRF8 is critically required for the development of monocytes and dendritic cells and for anti-mycobacterial immunity.

Hambleton, Sophie; Salem, Sandra; Bustamante, Jacinta; Bigley, Venetia; Boisson-Dupuis, Stephanie; Azevedo, Joana; Fortin, Anny; Haniffa, Muzlifah; Ceron-Gutierrez, Lourdes; Bacon, Chris; Menon, Geetha; Trouillet, Celine; McDonald, David; Carey, Peter; Ginhoux, Florent; Alsina, Laia; Zumwalt, Timothy J; Kong, Xiaofei; Kumararatne, Dinakantha; Butler, Karina; Hubeau, Marjorie; Feinberg, Jacqueline; Al-Muhsen, Saleh; Cant, Andrew; Abel, Laurent; Chaussabel, Damien; Doffinger, Rainer; Talesnik, Eduardo; Grumach, Anete; Duarte, Alberto; Abarca, Katia; Moraes-Vasconcelos, Dewton; Burk, David; Berghuis, Albert; Geissmann, Frederic; Collin, Matthew; Casanova, Jean-Laurent; Gros, Philippe

2011-01-01

333

Hyperglycosylated Mutants of Human Immunodeficiency Virus (HIV) Type 1 Monomeric gp120 as Novel Antigens for HIV Vaccine Design  

PubMed Central

The ability to induce broadly neutralizing antibodies should be a key component of any forthcoming vaccine against human immunodeficiency virus type 1. One potential vaccine candidate, monomeric gp120, has generally failed to elicit such antibodies. We postulated that gp120 might be a better immunogen if it could be engineered to preferentially bind known broadly neutralizing antibodies. In a first study, we found that four alanine substitutions on the perimeter of the so-called Phe-43 cavity of gp120 could reduce binding of weakly neutralizing CD4-binding site antibodies (R. Pantophlet, E. O. Saphire, P. Poignard, P. W. H. I. Parren, I. A. Wilson, and D. R. Burton, J. Virol. 77:642-658, 2003), while slightly enhancing binding of the potent, broadly neutralizing antibody b12. In the present study, we sought to reduce or abolish the binding of a wider range of nonneutralizing antibodies, by incorporating extra N-glycosylation motifs at select positions into the hypervariable loops and the gp120 core. A hyperglycosylated mutant containing seven extra glycosylation sequons (consensus sequences) and the four alanine substitutions described above did not bind an extensive panel of nonneutralizing and weakly neutralizing antibodies, including a polyclonal immunoglobulin preparation (HIVIG) of low neutralizing potency. Binding of b12, at lowered affinity, and of four antibodies to the C1 and C5 regions was maintained. Removal of N- and C-terminal residues in the C1 and C5 regions, respectively, reduced or abolished binding of the four antibodies, but this also adversely affected b12 binding. The hyperglycosylated mutant and its analogues described here are novel antigens that may provide a new approach to eliciting antibodies with b12-like neutralizing properties.

Pantophlet, Ralph; Wilson, Ian A.; Burton, Dennis R.

2003-01-01

334

Biodegradation of neutralized sarin.  

PubMed

This research investigated the biotransformation of IMPA, the neutralization product of the nerve agent Sarin, by a microbial consortia. As mandated by the Chemical Weapons Convention signed by 132 countries in 1993, all chemical warfare agents are to be destroyed within ten years of ratification. Technologies must be developed to satisfy this commitment. This paper presents data from a biodegradation kinetics study and background information on the biological transformation of IMPA. Microbial transformation of organophosphate nerve agents and organophosphate pesticide intermediates can be incorporated into a treatment process for the fast and efficient destruction of these similar compounds. Sarin (isopropyl methylphosphonofluoridate), also known as GB, is one of several highly neurotoxic chemical warfare agents that have been developed over the past 50 to 60 years. Four mixed cultures were acclimated to the Sarin hydrolysis product, isopropyl methylphosphonic acid (IMPA). Two of these cultures, APG microorganisms and SX microorganisms, used IMPA as the sole phosphorus source. Extended exposure to IMPA improved the cultures' abilities to degrade IMPA to form methylphosphonic acid (MPA) and inorganic phosphate. The presence of free phosphate in the reactor suppressed the degradation of IMPA. IMPA did not inhibit either cultural consortia within the tested concentration range (0 to 1250 mg/L). The numax was 120.9 mg/L/day for the SX microorganisms and 118.3 mg/L/day for the APG microorganisms. Initial IMPA concentrations of 85 to 90 mg/L were degraded to nondetectable levels within 75 h. These results demonstrate the potential for biodegradation to serve as a complementary treatment process for the destruction of stockpiled Sarin. PMID:10397858

Zhang, Y; Autenrieth, R L; Bonner, J S; Harvey, S P; Wild, J R

1999-07-20

335

Observations After Human Immunodeficiency Virus Immunization and Challenge of Human Immunodeficiency Virus Seropositive and Seronegative Chimpanzees  

Microsoft Academic Search

Two human immunodeficiency virus (HIV)-seropositive chimpanzees (A-3 and A-86c) infected 4 yr earlier with HIV, along with one uninfected animal (A-36), were inoculated intramuscularly three times in a year with a gamma-irradiated gp120-depleted HIV immunogen in incomplete Freund's adjuvant. Both previously infected animals promptly developed an anamnestic humoral antibody response after the first dose, and the uninfected animal developed a

Clarence J. Gibbs Jr.; Robert Peters; Maneth Gravell; Bruce K. Johnson; Fred C. Jensen; Dennis J. Carlo; Jonas Salk

1991-01-01

336

DC-SIGN Interactions with Human Immunodeficiency Virus Type 1 and 2 and Simian Immunodeficiency Virus  

Microsoft Academic Search

Dendritic cells (DCs) efficiently bind and transmit human immunodeficiency virus (HIV) to cocultured T cells and so may play an important role in HIV transmission. DC-SIGN, a novel C-type lectin that is expressed in DCs, has recently been shown to bind R5 HIV type 1 (HIV-1) strains and a laboratory-adapted X4 strain. To characterize the interaction of DC-SIGN with primate

STEFAN POHLMANN; FREDERIC BARIBAUD; BENHUR LEE; GEORGE J. LESLIE; MELISSA D. SANCHEZ; KIRSTEN HIEBENTHAL-MILLOW; JAN MUNCH; FRANK KIRCHHOFF; ROBERT W. DOMS

2001-01-01

337

Acquired Immunodeficiency Syndrome (AIDS), Human Immunodeficiency Virus (HIV) Infection, and Dialysis  

Microsoft Academic Search

\\u000a A new disease, Acquired Immuno Deficiency Syndrome (AIDS) was identified in the early 1980’s, when it was observed that an\\u000a unusually high number of otherwise healthy gay men in San Francisco, developed Kaposi’s sarcoma, and pneumocystis carinii\\u000a pneumonia (1, 2). Before the discovery of Human Immunodeficiency Virus (HIV) as the causative agent, and refinements were made in various\\u000a serological methods

T. K. Sreepada Rao

338

Prolonged osteogenesis from human mesenchymal stem cells implanted in immunodeficient mice by using coralline hydroxyapatite incorporating rhBMP2 microspheres.  

PubMed

The local environment plays an important role in osteogenic tissue regeneration. Our previous studies have shown that xenogenic transplantation of human mesenchymal stem cells (hMSCs) alone into immunodeficient mice did not result in long-term bone formation. This study investigates whether bone formation can be prolonged by incorporating human mesenchymal stem cells in mineralized scaffolds together with controlled delivery of a growth factor, BMP2. A composite of coralline hydroxyapatite (CHA) with poly(lactic-co-glycolic acid) (PLGA)-encapsulated rhBMP2 was incorporated with hMSCs in vitro. After 2 weeks in vitro culture the constructs were implanted subcutaneously in CB17 scid beige mice and harvested 10 weeks after implantation. The mineralized tissues were stained by using a fluorescent marker, 5FAM-risedronate, followed by observation with fluorescence microscopy, histology, histomorphometry, mouse-anti-human vimentin immunohistochemistry, and scanning microscopy. The results showed that compared with control materials in which only fibrous tissue formed following implantation of coralline scaffolds, bone-like tissue formed within the CHA composite containing PLGA encapsulated rhBMP2 and hMSCs for up to 10 weeks after implantation. Human cells, identified by the human vimentin-specific monoclonal antibody were seen within the bone-like tissue. In conclusion, incorporation of hMSCs into CHA with controlled delivery of BMP showed prolonged bone formation in immunodeficient mice. Further research is required to optimize the growth factor delivery system and to understand the underlying cellular and molecular mechanisms involved. PMID:19322875

Fu, Kun; Xu, Qingguo; Czernuszka, Jan; McKenna, Charles E; Ebetino, Frank H; Russell, R Graham G; Triffitt, James T; Xia, Zhidao

2010-03-15

339

Genital mucosal transmission of simian immunodeficiency virus: animal model for heterosexual transmission of human immunodeficiency virus.  

PubMed Central

An animal model for the heterosexual transmission of human immunodeficiency virus (HIV) was developed by the application of simian immunodeficiency virus (SIV) onto the genital mucosas of both mature and immature, male and female rhesus macaques. Virus preparations were infused into the vaginal vaults or the urethras (males) of the animals through a soft plastic pediatric nasogastric feeding tube. The macaques that were infected by this route (six males and nine females) developed SIV-specific antibodies, and SIV was isolated from peripheral mononuclear cells of all seropositive animals. One male and one female infected by this route developed severe acquired immunodeficiency syndrome-like disease with retroviral giant-cell pneumonia. As few as two inoculations of cell-free SIV containing 50 50% tissue culture infective doses induced persistent viremia. Cell-free virus preparations were capable of producing infection by the genital route. Much higher doses of virus were required to transmit SIV by this route than are required for transmission by intravenous inoculation. Thus, it appears that the mucous membranes of the genital tract act as a barrier to SIV infection. Spermatozoa and seminal plasma were not required for the genital transmission of SIV. Rarely, SIV was recovered from mononuclear cells in semen and vaginal secretions. The SIV-rhesus macaque model is suitable for assessing the role of cofactors in heterosexual transmission of HIV and will be useful for testing the effectiveness of spermicides, pharmacologic agents, and vaccines in preventing the heterosexual transmission of HIV. Images

Miller, C J; Alexander, N J; Sutjipto, S; Lackner, A A; Gettie, A; Hendrickx, A G; Lowenstine, L J; Jennings, M; Marx, P A

1989-01-01

340

Translational Mini-Review Series on Immunodeficiency: Molecular defects in common variable immunodeficiency  

PubMed Central

OTHER ARTICLE PUBLISHED IN THIS MINI-REVIEW SERIES ON IMMUNODEFICIENCY Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review. Clin Exp Immunol 2007; 149: 10.1111/j.1365-2249.2007.03432.x Common variable immunodeficiency (CVID) is a primary immunodeficiency that typically affects adults and is characterized by abnormalities of quantative and qualitative humoral function that are heterogeneous in their immunological profile and clinical manifestations. The recent identification of four monogenic defects that result in the CVID phenotype also demonstrates that the genetic basis of CVID is highly variable. Mutations in the genes encoding the tumour necrosis factor (TNF) superfamily receptors transmembrane activator and calcium-modulating ligand interactor (TACI) and B cell activation factor of the TNF family receptor (BAFF-R), CD19 and the co-stimulatory molecule inducible co-stimulator molecule (ICOS) all lead to CVID and illustrate the complex interplay required to co-ordinate an effective humoral immune response. The molecular mechanisms leading to the immune defect are still not understood clearly and particularly in the case of TACI, where a number of heterozygous mutations have been found in affected individuals, the molecular pathogenesis of disease requires further elucidation. Together these defects account for perhaps 10–15% of all cases of CVID and it is highly likely that further genetic defects will be identified.

Bacchelli, C; Buckridge, S; Thrasher, A J; Gaspar, H B

2007-01-01

341

Neutral current interactions in MINOS  

SciTech Connect

The Main Injector Neutrino Oscillation Search (MINOS) long-baseline experiment has been actively collecting beam data since 2005, having already accumulated 3 x 10{sup 20} protons-on-target (POT). The several million neutrinos per year observed at the Near detector may improve the existing body of knowledge of neutrino cross-sections and the Near-Far comparison of the observed energy spectrum neutral current events constrains oscillations into sterile neutrinos. MINOS capabilities of observing neutral current neutrino events are described and the employed methodology for event selection is discussed, along with preliminary results obtained. An outlook on the expected neutral current related contributions from MINOS is also presented.

Sousa, Alexandre; /Oxford U.

2007-07-01

342

Protective immune responses induced by secretion of a chimeric soluble protein from a recombinant Mycobacterium bovis bacillus Calmette-Gu?rin vector candidate vaccine for human immunodeficiency virus type 1 in small animals.  

PubMed Central

A recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) vector-based vaccine that secretes the V3 principal neutralizing epitope of human immunodeficiency virus (HIV) could induce immune response to the epitope and prevent the viral infection. By using the Japanese consensus sequence of HIV-1, we successfully constructed chimeric protein secretion vectors by selecting an appropriate insertion site of a carrier protein and established the principal neutralizing determinant (PND)-peptide secretion system in BCG. The recombinant BCG (rBCG)-inoculated guinea pigs were initially screened by delayed-type hypersensitivity (DTH) skin reactions to the PND peptide, followed by passive transfer of the DTH by the systemic route. Further, immunization of mice with the rBCG resulted in induction of cytotoxic T lymphocytes. The guinea pig immune antisera showed elevated titers to the PND peptide and neutralized HIVMN, and administration of serum IgG from the vaccinated guinea pigs was effective in completely blocking the HIV infection in thymus/liver transplanted severe combined immunodeficiency (SCID)/hu or SCID/PBL mice. In addition, the immune serum IgG was shown to neutralize primary field isolates of HIV that match the neutralizing sequence motif by a peripheral blood mononuclear cell-based virus neutralization assay. The data support the idea that the antigen-secreting rBCG system can be used as a tool for development of HIV vaccines. Images Fig. 1

Honda, M; Matsuo, K; Nakasone, T; Okamoto, Y; Yoshizaki, H; Kitamura, K; Sugiura, W; Watanabe, K; Fukushima, Y; Haga, S

1995-01-01

343

Avian Influenza: Potential Impact on Sub-Saharan Military Populations with High Rates of Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome.  

National Technical Information Service (NTIS)

Several sub-Saharan militaries have large percentages of troops with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. With the arrival of avian influenza in Africa, the potential exists that some of those soldiers might also become i...

K. Nickell R. L. Feldman

2007-01-01

344

Oligonucleotides as inhibitors of human immunodeficiency virus.  

PubMed

Inhibition of human immunodeficiency virus (HIV) replication by oligonucleotides is a complex process and may be implemented by an array of antiviral mechanisms. These include inhibition of virus adsorption to the host cell, inhibition of transcription via antisense or as the result of triple helix formation, and inhibition of viral encoded enzymes such as reverse transcriptase and integrase. Since the particular mechanism of HIV inhibition depends on the oligonucleotide (ON) sequence and the ON chemical modifications, the design and synthesis of potent HIV inhibitors has been an important and rewarding focus of ON research. In this era of great concern that HIV may rapidly display resistance to any antiviral compound with one mechanism of viral inhibition, oligonucleotides are potentially attractive alternatives for therapy. Several ONs have entered clinical evaluation in AIDS patients. At present Zintevir, which inhibits both HIV adsorption and HIV integrase, is in phase I/II clinical trials. PMID:11713797

Field, A K

1999-06-01

345

Cardiovascular disease in human immunodeficiency virus.  

PubMed

With widespread access to high-quality medical care as in Australia, human immunodeficiency virus (HIV) is now considered a chronic, treatable condition, with a good life expectancy. The use of combined highly active antiretroviral therapy has enabled effective suppression of the virus, but has also been associated with increased cardiac morbidity and mortality. Over representation of traditional cardiac risk factors, such as hyperlipidaemia and diabetes, as well as an increased incidence of ischaemic and non-ischaemic heart disease is now considered a major concern of treatment with antiretroviral therapy. Therefore, a contemporary management strategy for patients with HIV must include active prevention and treatment of cardiovascular risk. This review will outline the complex interplay between HIV infection, antiretroviral drug regimens and accelerated cardiovascular disease, with a particular focus on screening, prevention and treatment options in a contemporary Australian HIV population. PMID:24754684

Cheruvu, S; Holloway, C J

2014-04-01

346

Acquired immunodeficiency syndrome: Ga-67 citrate imaging  

SciTech Connect

All gallium-67 citrate scans obtained in patients with acquired immunodeficiency syndrome (AIDS) at the Clinical Center, National Institutes of Health (Bethesda, Md.) were retrospectively analyzed and correlated with the results of bronchoscopy, chest radiography, and endoscopy. There were 164 scans of 95 patients. Twenty scans were from patients with Pneumocystis carinii pneumonia; 19 were abnormal, for a sensitivity of 95%. Ga-67 uptake tended to be less in patients receiving therapy for P. carinii pneumonia. Chest radiographs were normal at least initially in three patients with abnormal scans and P. carinii pneumonia. Unusually prominent colonic activity was associated with infection in some patients. No lesions of Kaposi sarcoma showed tracer uptake. Gallium scanning is useful for detecting P. carinii pneumonia and other opportunistic infections in patients with AIDS, but it is not useful for localizing Kaposi sarcoma.

Woolfenden, J.M.; Carrasquillo, J.A.; Larson, S.M.; Simmons, J.T.; Masur, H.; Smith, P.D.; Shelhamer, J.H.; Ognibene, F.P.

1987-02-01

347

Aging, human immunodeficiency virus, and bone health  

PubMed Central

Highly active antiretroviral therapy (HAART) has had a profound impact on improving the long-term prognosis for individuals infected with human immunodeficiency virus (HIV). HAART has been available for close to two decades, and now a significant number of patients with access to HAART are over the age of 50 years. Many clinical studies have indicated that HIV infection, as well as components of HAART, can increase the risk in these individuals to a variety of noninfectious complications, including a risk to bone health. There is a significant need for detailed mechanistic analysis of the aging, HIV-infected population regarding the risk of HIV infection and therapy in order to maintain bone health. Insights from basic mechanistic studies will help to shed light on the role of HIV infection and the components of HAART that impact bone health, and will help in identifying preventative countermeasures, particularly for individuals 50 years of age and older.

Mansky, Kim C

2010-01-01

348

Frequent Intratype Neutralization by Plasma Immunoglobulin A Identified in HIV Type 2 Infection  

PubMed Central

Abstract Human immunodeficiency virus type 2 (HIV-2) is less transmissible and less pathogenic compared to HIV-1 and, when matched for CD4+ T cell count, the plasma viral load in HIV-2-infected individuals is approximately one log lower than in HIV-1-infected individuals. The explanation for these observations is elusive, but differences in virus controlling immunity generated in the two infections may be contributing factors. In the present study, we investigated neutralization by immunoglobulin A (IgA), in parallel with IgG, purified from plasma of HIV-1, HIV-2, and HIV-1/HIV-2 dually (HIV-D) infected individuals. Neutralization was analyzed against HIV-1 and HIV-2 isolates using a plaque reduction assay. In HIV-2 infection, intratype-specific neutralization by IgA was frequently detected, although at a lesser magnitude then the corresponding IgG neutralizing titers. In contrast, neutralization by IgA could rarely be demonstrated in HIV-1 infection despite similar plasma IgA levels in both infections. In addition, IgA and IgG of HIV-D plasma neutralized the HIV-2 isolate more potently than the HIV-1 isolate, suggesting that the difference between neutralizing activity of plasma IgA and IgG depends on the virus itself. Taken together, these findings suggest that both IgA and IgG add to the potent intratype neutralizing activity detected in HIV-2 plasma, which may contribute to virus control in HIV-2 infection.

Mansson, Fredrik; Palm, Angelica A.; Vincic, Elzbieta; da Silva, Zacarias; Medstrand, Patrik; Norrgren, Hans; Fenyo, Eva Maria; Jansson, Marianne

2013-01-01

349

Autoimmune Cytopenias In Common Variable Immunodeficiency  

PubMed Central

Common variable immunodeficiency (CVID) is a humoral immunodeficiency whose primary diagnostic features include hypogammaglobulinemia involving two or more immunoglobulin isotypes and impaired functional antibody responses in the majority of patients. While increased susceptibility to respiratory and other infections is a common thread that binds a large cross-section of CVID patients, the presence of autoimmune complications in this immunologically and clinically heterogeneous disorder is recognized in up to two-thirds of patients. Among the autoimmune manifestations reported in CVID (20–50%; Chapel et al., 2008; Cunningham-Rundles, 2008), autoimmune cytopenias are by far the most common occurring variably in 4–20% (Michel et al., 2004; Chapel et al., 2008) of these patients who have some form of autoimmunity. Association of autoimmune cytopenias with granulomatous disease and splenomegaly has been reported. The spectrum of autoimmune cytopenias includes thrombocytopenia, anemia, and neutropenia. While it may seem paradoxical “prima facie” that autoimmunity is present in patients with primary immune deficiencies, in reality, it could be considered two sides of the same coin, each reflecting a different but inter-connected facet of immune dysregulation. The expansion of CD21 low B cells in CVID patients with autoimmune cytopenias and other autoimmune features has also been previously reported. It has been demonstrated that this unique subset of B cells is enriched for autoreactive germline antibodies. Further, a correlation has been observed between various B cell subsets, such as class-switched memory B cells and plasmablasts, and autoimmunity in CVID. This review attempts to explore the most recent concepts and highlights, along with treatment of autoimmune hematological manifestations of CVID.

Podjasek, Jenna C.; Abraham, Roshini S.

2012-01-01

350

Neutral Line in the Magnetotail.  

National Technical Information Service (NTIS)

A synoptic survey for the magnetotail neutral line and the associated plasma phenomena during substorms was studied to provide the observational basis for the nightside reconnection process. Observations made at different locations for different substorms...

A. Nishida

1973-01-01

351

Neutralizer for radioactive francium beam  

NASA Astrophysics Data System (ADS)

In order to trap francium atoms in a magneto-optical trap, a beam of singly charged francium ions must be neutralized and reduced to thermal energies. Vacuum requirements prevent the use of a gas-filled charge exchange cell. The simple alternative is to implant the ion beam into a hot catcher foil where the ions neutralize within the foil and then diffuse out. The fraction of ions which neutralize depends upon the work function of the foil and first ionization potential of the ion beam. In order to produce such a neutralizer several suitable materials were tested in a variety of different mechanical designs to determine the most effective and robust system.

Lipski, A. R.; Pearson, M. R.; Fliller, R. P.; Sprouse, G. D.

2004-03-01

352

Space Station Neutral External Environment.  

National Technical Information Service (NTIS)

Molecular contamination levels arising from the external induced neutral environment of the Space Station (Phase 1 configuration) were calculated using the MOLFLUX model. Predicted molecular column densities and deposition rates generally meet the Space S...

H. Ehlers L. Leger

1988-01-01

353

Neutral Particle Beam Popup Applications.  

National Technical Information Service (NTIS)

Popup neutral particle beams (NPBs) could have high leverage in discriminating decoyed threats. There is considerable leeway in the choice of platform parameters. For deuterium beams the number of platforms is modest for all energies. Hydrogen beams might...

G. H. Canavan

1991-01-01

354

Possible Eigenoscillations of Neutral Sheets.  

National Technical Information Service (NTIS)

A neutral sheet model with hyperbolic tangent equilibrium magnetic field and hyperbolic square secant density profiles is considered. It is shown that the equation for small oscillations takes the form of an eigenvalue oscillation problem. Computed eigenf...

W. A. Almeida J. M. da Costs E. G. Aruquipa J. P. Sudano

1974-01-01

355

Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120.  

PubMed Central

The bicyclams are a new class of anti-human immunodeficiency virus (anti-HIV) compounds targeted at viral entry. From marker rescue experiments, it appears that the envelope gp120 glycoprotein plays an important role in the anti-HIV activity of the bicyclams. Bicyclam-resistant strains contain a number of amino acid changes scattered over the V2 to V5 region of gp120. Experiments aimed at estimating the relative importance of particular amino acid changes with regard to the overall resistance pattern are described. The sequences of some partially bicyclam-resistant virus strains, obtained during the resistance development process, were analyzed, and the corresponding 50% effective concentrations were determined. Selected mutations observed in bicyclam-resistant strains were introduced in the wild-type background by site-directed mutagenesis. In addition, some amino acids were back-mutated to their wild-type counterparts in an otherwise JM3100-resistant strain. The sensitivities of these mutant viruses to bicyclams were determined. Construction of chimeric viruses, carrying the V3 loop of JM3100-resistant virus in a wild-type HIV type 1 HXB2 background, enabled us to investigate the importance of the mutations in the V3 loop of JM3100-resistant virus. From the results described in the report, it can be concluded that single amino acid substitutions do not influence the observed resistance to JM3100. Also, the mutations in the V3 loop are not sufficient to engender even a partially resistant phenotype. We postulate that the overall conformation of gp120 determines the degree of sensitivity or resistance of HIV strains to bicyclams.

De Vreese, K; Van Nerum, I; Vermeire, K; Anne, J; De Clercq, E

1997-01-01

356

Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120.  

PubMed

The bicyclams are a new class of anti-human immunodeficiency virus (anti-HIV) compounds targeted at viral entry. From marker rescue experiments, it appears that the envelope gp120 glycoprotein plays an important role in the anti-HIV activity of the bicyclams. Bicyclam-resistant strains contain a number of amino acid changes scattered over the V2 to V5 region of gp120. Experiments aimed at estimating the relative importance of particular amino acid changes with regard to the overall resistance pattern are described. The sequences of some partially bicyclam-resistant virus strains, obtained during the resistance development process, were analyzed, and the corresponding 50% effective concentrations were determined. Selected mutations observed in bicyclam-resistant strains were introduced in the wild-type background by site-directed mutagenesis. In addition, some amino acids were back-mutated to their wild-type counterparts in an otherwise JM3100-resistant strain. The sensitivities of these mutant viruses to bicyclams were determined. Construction of chimeric viruses, carrying the V3 loop of JM3100-resistant virus in a wild-type HIV type 1 HXB2 background, enabled us to investigate the importance of the mutations in the V3 loop of JM3100-resistant virus. From the results described in the report, it can be concluded that single amino acid substitutions do not influence the observed resistance to JM3100. Also, the mutations in the V3 loop are not sufficient to engender even a partially resistant phenotype. We postulate that the overall conformation of gp120 determines the degree of sensitivity or resistance of HIV strains to bicyclams. PMID:9420029

De Vreese, K; Van Nerum, I; Vermeire, K; Anné, J; De Clercq, E

1997-12-01

357

Building networks for immunodeficiency diseases and immunology training.  

PubMed

The RIKEN Research Center for Allergy and Immunology in Japan is reaching out regionally to the primary immunodeficiency disease community and internationally to graduate students and postdoctoral fellows. PMID:18711439

Burrows, Peter D; Fischer, Alain

2008-09-01

358

The Neonatal Fc Receptor (FcRn) Enhances Human Immunodeficiency Virus Type 1 (HIV-1) Transcytosis across Epithelial Cells  

PubMed Central

The mechanisms by which human immunodeficiency virus type 1 (HIV-1) crosses mucosal surfaces to establish infection are unknown. Acidic genital secretions of HIV-1-infected women contain HIV-1 likely coated by antibody. We found that the combination of acidic pH and Env-specific IgG, including that from cervicovaginal and seminal fluids of HIV-1-infected individuals, augmented transcytosis across epithelial cells as much as 20-fold compared with Env-specific IgG at neutral pH or non-specific IgG at either pH. Enhanced transcytosis was observed with clinical HIV-1 isolates, including transmitted/founder strains, and was eliminated in Fc neonatal receptor (FcRn)-knockdown epithelial cells. Non-neutralizing antibodies allowed similar or less transcytosis than neutralizing antibodies. However, the ratio of total:infectious virus was higher for neutralizing antibodies, indicating that they allowed transcytosis while blocking infectivity of transcytosed virus. Immunocytochemistry revealed abundant FcRn expression in columnar epithelia lining the human endocervix and penile urethra. Acidity and Env-specific IgG enhance transcytosis of virus across epithelial cells via FcRn and could facilitate translocation of virus to susceptible target cells following sexual exposure.

Gupta, Sandeep; Gach, Johannes S.; Becerra, Juan C.; Phan, Tran B.; Pudney, Jeffrey; Moldoveanu, Zina; Joseph, Sarah B.; Landucci, Gary; Supnet, Medalyn Jude; Ping, Li-Hua; Corti, Davide; Moldt, Brian; Hel, Zdenek; Lanzavecchia, Antonio; Ruprecht, Ruth M.; Burton, Dennis R.; Mestecky, Jiri; Anderson, Deborah J.; Forthal, Donald N.

2013-01-01

359

Tetherin upregulation in simian immunodeficiency virus-infected macaques.  

PubMed

Here we show that simian immunodeficiency virus (SIV) infection of rhesus macaques results in rapid upregulation of tetherin (BST-2 or CD317) on peripheral blood lymphocytes, including the CD4(+) CCR5(+) T cell targets of virus infection, with a peak of induction that coincides with peak alpha interferon (IFN-?) levels in plasma, and that tetherin remains above baseline levels throughout chronic infection. These observations are consistent with a role for tetherin in innate immunity to immunodeficiency virus infection. PMID:24109219

Rahmberg, Andrew R; Neidermyer, William J; Breed, Matthew W; Alvarez, Xavier; Midkiff, Cecily C; Piatak, Michael; Lifson, Jeffrey D; Evans, David T

2013-12-01

360

Tetherin Upregulation in Simian Immunodeficiency Virus-Infected Macaques  

PubMed Central

Here we show that simian immunodeficiency virus (SIV) infection of rhesus macaques results in rapid upregulation of tetherin (BST-2 or CD317) on peripheral blood lymphocytes, including the CD4+ CCR5+ T cell targets of virus infection, with a peak of induction that coincides with peak alpha interferon (IFN-?) levels in plasma, and that tetherin remains above baseline levels throughout chronic infection. These observations are consistent with a role for tetherin in innate immunity to immunodeficiency virus infection.

Rahmberg, Andrew R.; Neidermyer, William J.; Breed, Matthew W.; Alvarez, Xavier; Midkiff, Cecily C.; Piatak, Michael; Lifson, Jeffrey D.

2013-01-01

361

Computed tomography scan assessment of lung disease in primary immunodeficiencies  

Microsoft Academic Search

A wide spectrum of lung disease can complicate primary immunodeficiencies and early recognition influences management and\\u000a prognosis. Computed tomography (CT) especially high resolution computed tomography (HRCT) has been shown to detect lung disease\\u000a in adult immunodeficient patients often when the chest radiograph (CXR) is normal, but this has not been studied in children.\\u000a Twenty-five CT scans [10 HRCT] and CXRs

T. Newson; A. J. Chippindale; A. J. Cant

1999-01-01

362

The molecular basis of X-linked immunodeficiency disease  

Microsoft Academic Search

Summary The molecular bases of the X-linked immunodeficiency diseases remain largely undetermined. Two of the genes involved in these diseases have been isolated, namely the genes for X-linked chronic granulomatous disease and properdin deficiency, and substantial progress has now been made in identifying the genes which are defective in the other five diseases, Wiskott-Aldrich syndrome, X-linked severe combined immunodeficiency, X-linked

C. Kinnon; R. Levinsky

1992-01-01

363

Severe immunodeficiency disease induced by a defective murine leukaemia virus  

Microsoft Academic Search

DIFFERENT classes of retroviruses have been shown to induce immunodeficiency diseases in various animal species1. These animal models may provide an insight into our understanding of AIDS1-3 but, with the exception of one strain of feline leukaemia virus4, the determinants of pathogenicity have not yet been mapped to these viral genomes. The immunodeficiency-inducing feline leukaemia virus is replication-defective4, harbouring the

Douglas C. Aziz; Zaher Hanna; Paul Jolicoeur

1989-01-01

364

A new human immunodeficiency virus derived from gorillas.  

PubMed

We have identified a new human immunodeficiency virus in a Cameroonian woman. It is closely related to gorilla simian immunodeficiency virus (SIVgor) and shows no evidence of recombination with other HIV-1 lineages. This new virus seems to be the prototype of a new HIV-1 lineage that is distinct from HIV-1 groups M, N and O. We propose to designate it HIV-1 group P. PMID:19648927

Plantier, Jean-Christophe; Leoz, Marie; Dickerson, Jonathan E; De Oliveira, Fabienne; Cordonnier, François; Lemée, Véronique; Damond, Florence; Robertson, David L; Simon, François

2009-08-01

365

In vivo genetic variability of the human immunodeficiency virus type 2 V3 region.  

PubMed Central

The principal neutralizing epitope of the human immunodeficiency virus type 1 (HIV-1) lies between two invariant cysteines in the third variable region (V3) of the viral envelope (gp120), and its amino acid sequence varies among different HIV-1 isolates. HIV-2 carries an analogous amino acid sequence between two cysteines of the V3 regions, but its functional similarity with the HIV-1 principal neutralizing epitope is uncertain. We studied the degree of genetic variation of the HIV-2 V3 region in fresh blood samples from 12 HIV-2-seropositive individuals from Guinea-Bissau. Polymerase chain reaction was used to amplify viral fragments of 465 bp containing the V3 region from cellular DNA. Nucleotide sequence analysis of the entire envelope fragment from each patient revealed that the degree of variation among field isolates of HIV-2 is comparable to that observed in the analogous region of HIV-1. Most of the HIV-2 isolates studied were highly related, suggesting the existence of a limited number of different viral strains in the cohort studied. Thus, the HIV-2 and HIV-1 V3 regions vary to a similar degree and may also have analogous functions.

Boeri, E; Giri, A; Lillo, F; Ferrari, G; Varnier, O E; Ferro, A; Sabbatani, S; Saxinger, W C; Franchini, G

1992-01-01

366

Epitope Specificity of Human Immunodeficiency Virus-1 Antibody Dependent Cellular Cytotoxicity [ADCC] Responses  

PubMed Central

Antibody dependent cellular cytotoxicity [ADCC] has been suggested to play an important role in control of Human Immunodeficiency Virus-1 [HIV-1] viral load and protection from infection. ADCC antibody responses have been mapped to multiple linear and conformational epitopes within the HIV-1 envelope glycoproteins gp120 and gp41. Many epitopes targeted by antibodies that mediate ADCC overlap with those recognized by antibodies capable of virus neutralization. In addition, recent studies conducted with human monoclonal antibodies derived from HIV-1 infected individuals and HIV-1 vaccine-candidate vaccinees have identified a number of antibodies that lack the ability to capture primary HIV-1 isolates or mediate neutralizing activity, but are able to bind to the surface of infected CD4+ T cells and mediate ADCC. Of note, the conformational changes in the gp120 that may not exclusively relate to binding of the CD4 molecule are important in exposing epitopes recognized by ADCC responses. Here we discuss the HIV-1 envelope epitopes targeted by ADCC antibodies in the context of the potential protective capacities of ADCC.

Pollara, Justin; Bonsignori, Mattia; Moody, M. Anthony; Pazgier, Marzena; Haynes, Barton F; Ferrari, Guido

2013-01-01

367

Spacetime symmetries and neutral kaons  

NASA Astrophysics Data System (ADS)

In this work, CP and CPT violation in the neutral-meson systems is discussed. Emphasis is placed on the neutral kaons. Studies are performed demonstrating the symmetry-violating behavior of neutral mesons in classical analogue systems. Phenomena relevant to spacetime-symmetry breaking as seen in neutral mesons are considered. To demonstrate key features of spacetime-symmetry violations, classical oscillating systems are sought as analogue models for the neutral meson systems, Coupled oscillators with two degrees of freedom are considered. It is shown that some classical systems are insufficient to model spacetime-symmetry breaking in a natural way, No-go results are presented for undamped systems and for systems using two one-dimensional oscillators. A model of a two-dimensional oscillator with rheonomic constraints is given to parallel spontaneous T and CPT violation. Studies are presented of the physical phenomena involving CPT breaking in neutral mesons. CPT violation is investigated within the framework of a standard-model extension. This theoretical model assumes small CPT and Lorentz violation via spontaneous symmetry breaking in an underlying more fundamental theory. This standard-model extension contains a term testable only in neutral-meson systems. Some experimental methods are discussed using decays of unboosted correlated kaons to test the relevant parameter of the CPT-violating model. In the context of the standard-model extension, the CPT-violating phenomenological parameter depends on the momentum of the mesons as well as on sidereal time. Decay-rate asymmetries incorporating these features could test the parameters of the standard-model extension.

Roberts, Agnes

368

Characterization of Simian Immunodeficiency Virus SIVSM\\/Human Immunodeficiency Virus Type 2 Vpx Function in Human Myeloid Cells  

Microsoft Academic Search

Human immunodeficiency virus type 2 (HIV-2)\\/simian immunodeficiency virus SIVSM Vpx is incorporated into virion particles and is thus present during the early steps of infection, when it has been reported to influence the nuclear import of viral DNA. We recently reported that Vpx promoted the accumulation of full-length viral DNA following the infection of human monocyte-derived dendritic cells (DCs). This

Caroline Goujon; Vanessa Arfi; Thomas Pertel; Jeremy Luban; Julia Lienard; Dominique Rigal; Jean-Luc Darlix; Andrea Cimarelli

2008-01-01

369

Neutral and Non-Neutral Evolution of Drosophila Mitochondrial DNA  

PubMed Central

To test hypotheses of neutral evolution of mitochondrial DNA (mtDNA), nucleotide sequences were determined for 1515 base pairs of the NADH dehydrogenase subunit 5 (ND5) gene in the mitochondrial DNA of 29 lines of Drosophila melanogaster and 9 lines of its sibling species Drosophila simulans. In contrast to the patterns for nuclear genes, where D. melanogaster generally exhibits much less nucleotide polymorphism, the number of segregating sites was slightly higher in a global sample of nine ND5 sequences in D. melanogaster (s = 8) than in the nine lines of D. simulans (s = 6). When compared to variation at nuclear loci, the mtDNA variation in D. melanogaster does not depart from neutral expectations. The ND5 sequences in D. simulans, however, show fewer than half the number of variable sites expected under neutrality when compared to sequences from the period locus. While this reduction in variation is not significant at the 5% level, HKA tests with published restriction data for mtDNA in D. simulans do show a significant reduction of variation suggesting a selective sweep of variation in the mtDNA in this species. Tests of neutral evolution based on the ratios of synonymous and replacement polymorphism and divergence are generally consistent with neutral expectations, although a significant excess of amino acid polymorphism within both species is localized in one region of the protein. The rate of mtDNA evolution has been faster in D. melanogaster than in D. simulans and the population structure of mtDNA is distinct in these species. The data reveal how different rates of mtDNA evolution between species and different histories of neutral and adaptive evolution within species can compromise historical inferences in population and evolutionary biology.

Rand, D. M.; Dorfsman, M.; Kann, L. M.

1994-01-01

370

A Novel Antibody-Dependent Cellular Cytotoxicity Epitope in gp120 Is Identified by Two Monoclonal Antibodies Isolated from a Long-Term Survivor of Human Immunodeficiency Virus Type 1 Infection  

Microsoft Academic Search

Two monoclonal antibodies (MAbs), 42F and 43F, were isolated some 14 months apart from a single long-term survivor of human immunodeficiency virus type 1 (HIV-1) infection. These MAbs were found to be indistinguishable in terms of their isotypes, specificities, affinities, and biological activities. Both 42F and 43F directedsubstantialantibody-dependentcellularcytotoxicity(ADCC)againstcellsinfectedwithfourdivergent lab-adapted strains of HIV-1, but no neutralizing activity against these strains was

OSAMA ALSMADI; RUTH HERZ; ELLEN MURPHY; ABRAHAM PINTER; ANDSHERMAINE A. TILLEY

1997-01-01

371

A Conserved Tryptophan-Rich Motif in the Membrane-Proximal Region of the Human Immunodeficiency Virus Type 1 gp41 Ectodomain Is Important for Env-Mediated Fusion and Virus Infectivity  

Microsoft Academic Search

Mutations were introduced into the ectodomain of the human immunodeficiency virus type 1 (HIV-1) transmembrane envelope glycoprotein, gp41, within a region immediately adjacent to the membrane-spanning domain. This region, which is predicted to form an a-helix, contains highly conserved hydrophobic residues and is unusually rich in tryptophan residues. In addition, this domain overlaps the epitope of a neutralizing monoclonal antibody,

KARL SALZWEDEL; JOHN T. WEST; ERIC HUNTER

1999-01-01

372

Antibody-mediated enhancement of human immunodeficiency virus type 1 infectivity is determined by the structure of gp120 and depends on modulation of the gp120CCR5 interaction  

Microsoft Academic Search

In this study, we characterized the viral determinants of coreceptor usage in relation to susceptibility to antibody-mediated neutralization or enhancement of infectivity by using chimeras of three highly related human immunodeficiency virus type 1 (HIV-1) isolates of different phenotypes. We found that the V3 region was the main determinant of antibody-mediated enhancement and coreceptor specificity but that the overall structure

Christophe Guillon; Martin Schutten; Patrick H. M. Boers; Rob A. Gruters; Albert D. M. E. Osterhaus

2002-01-01

373

Gas cell neutralizers (Fundamental principles)  

SciTech Connect

Neutralizing an ion-beam of the size and energy levels involved in the neutral-particle-beam program represents a considerable extension of the state-of-the-art of neutralizer technology. Many different mediums (e.g., solid, liquid, gas, plasma, photons) can be used to strip the hydrogen ion of its extra electron. A large, multidisciplinary R and D effort will no doubt be required to sort out all of the ''pros and cons'' of these various techniques. The purpose of this particular presentation is to discuss some basic configurations and fundamental principles of the gas type of neutralizer cell. Particular emphasis is placed on the ''Gasdynamic Free-Jet'' neutralizer since this configuration has the potential of being much shorter than other type of gas cells (in the beam direction) and it could operate in nearly a continuous mode (CW) if necessary. These were important considerations in the ATSU design which is discussed in some detail in the second presentation entitled ''ATSU Point Design''.

Fuehrer, B.

1985-06-01

374

Neutral atom imaging mass spectrograph  

NASA Astrophysics Data System (ADS)

We describe a concept for an instrument to measure 2D space plasma distributions by remote sensing of neutral atoms. The instrument measures in one dimension, and from a spinning spacecraft one obtains 2D (line-of-sight) maps of the neutral flux. Because we want to employ this instrument for measurements in the magnetosphere, the main species of interest are neutral H and O atoms with kinetic energies ranging from about 10 eV to 1 keV. The instrument makes use of a low-work-function surface to convert neutral atoms efficiently to negative ions. The ions are then accelerated away from the surface and brought to an intermediate focus by a large aperture lens. After further acceleration, the ions are deflected by a spherical electrostatic analyzer into a time-of-flight mass spectrometer. Mass resolution of the device is sufficient to resolve H, D, He, and O. Energy and azimuth angle information are obtained by position imaging of the secondary electrons produced at the carbon foil. The large geometric factor combined with simultaneous angle-energy-mass measurement eliminates the need for cycling and provides the necessary high sensitivity for imaging at short time intervals. On a spinning spacecraft this instrument is capable of producing 2D maps of low- energy neutral atom fluxes.

Wurz, Peter; Aellig, Matthias R.; Bochsler, Peter A.; Ghielmetti, Arthur G.; Shelley, Edward G.; Fuselier, Stephen A.; Herrero, Federico A.; Smith, Mark F.; Stephen, Thomas S.

1995-08-01

375

Robust neutralizing antibodies elicited by HIV-1 JRFL envelope glycoprotein trimers in nonhuman primates.  

PubMed

Host cell-mediated proteolytic cleavage of the human immunodeficiency virus type 1 (HIV-1) gp160 precursor glycoprotein into gp120 and gp41 subunits is required to generate fusion-competent envelope glycoprotein (Env) spikes. The gp120-directed broadly neutralizing monoclonal antibodies (bNabs) isolated from HIV-infected individuals efficiently recognize fully cleaved JRFL Env spikes; however, nonneutralizing gp120-directed monoclonal antibodies isolated from infected or vaccinated subjects recognize only uncleaved JRFL spikes. Therefore, as an immunogen, cleaved spikes that selectively present desired neutralizing epitopes to B cells may elicit cross-reactive neutralizing antibodies. Accordingly, we inoculated nonhuman primates (NHPs) with plasmid DNA encoding transmembrane-anchored, cleaved JRFL Env or by electroporation (EP). Priming with DNA expressing soluble, uncleaved gp140 trimers was included as a comparative experimental group of NHPs. DNA inoculation was followed by boosts with soluble JRFL gp140 trimers, and control NHPs were inoculated with soluble JRFL protein trimers without DNA priming. In the TZM-bl assay, elicitation of neutralizing antibodies against HIV-1 tier 1 isolates was robust following the protein boost. Neutralization of tier 2 isolates was detected, but only in animals primed with plasmid DNA and boosted with trimeric protein. Using the more sensitive A3R5 assay, consistent neutralization of both clade B and C tier 2 isolates was detected from all regimens assessed in the current study, exceeding levels achieved by our previous vaccine regimens in primates. Together, these data suggest a potential advantage of B cell priming followed by a rest interval and protein boosting to present JRFL Env spikes to the immune system to better generate HIV-1 cross-clade neutralizing antibodies. PMID:24067980

Chakrabarti, Bimal K; Feng, Yu; Sharma, Shailendra Kumar; McKee, Krisha; Karlsson Hedestam, Gunilla B; Labranche, Celia C; Montefiori, David C; Mascola, John R; Wyatt, Richard T

2013-12-01

376

Robust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Nonhuman Primates  

PubMed Central

Host cell-mediated proteolytic cleavage of the human immunodeficiency virus type 1 (HIV-1) gp160 precursor glycoprotein into gp120 and gp41 subunits is required to generate fusion-competent envelope glycoprotein (Env) spikes. The gp120-directed broadly neutralizing monoclonal antibodies (bNabs) isolated from HIV-infected individuals efficiently recognize fully cleaved JRFL Env spikes; however, nonneutralizing gp120-directed monoclonal antibodies isolated from infected or vaccinated subjects recognize only uncleaved JRFL spikes. Therefore, as an immunogen, cleaved spikes that selectively present desired neutralizing epitopes to B cells may elicit cross-reactive neutralizing antibodies. Accordingly, we inoculated nonhuman primates (NHPs) with plasmid DNA encoding transmembrane-anchored, cleaved JRFL Env or by electroporation (EP). Priming with DNA expressing soluble, uncleaved gp140 trimers was included as a comparative experimental group of NHPs. DNA inoculation was followed by boosts with soluble JRFL gp140 trimers, and control NHPs were inoculated with soluble JRFL protein trimers without DNA priming. In the TZM-bl assay, elicitation of neutralizing antibodies against HIV-1 tier 1 isolates was robust following the protein boost. Neutralization of tier 2 isolates was detected, but only in animals primed with plasmid DNA and boosted with trimeric protein. Using the more sensitive A3R5 assay, consistent neutralization of both clade B and C tier 2 isolates was detected from all regimens assessed in the current study, exceeding levels achieved by our previous vaccine regimens in primates. Together, these data suggest a potential advantage of B cell priming followed by a rest interval and protein boosting to present JRFL Env spikes to the immune system to better generate HIV-1 cross-clade neutralizing antibodies.

Feng, Yu; Sharma, Shailendra Kumar; McKee, Krisha; Karlsson Hedestam, Gunilla B.; LaBranche, Celia C.; Montefiori, David C.; Mascola, John R.

2013-01-01

377

Absence of cytotoxic antibody to human immunodeficiency virus-infected cells in humans and its induction in animals after infection or immunization with purified envelope glycoprotein gp120  

SciTech Connect

The presence of antibody-dependent complement-mediated cytotoxicity (ACC) was assessed in humans and chimpanzees, which are capable of infection with human immunodeficiency virus isolate HTLV-IIIb, and examined in the goat after immunization with the major viral glycoprotein (gp120) of HTLV-IIIb. In infected humans no antibody mediating ACC was observed regardless of the status of disease. Even healthy individuals with high-titer, broadly reactive, neutralizing antibodies has no ACC. In contrast, chimpanzees infected with HTLV-IIIb, from whom virus could be isolated, not only had neutralizing antibody but also antibodies broadly reactive in ACC, even against distantly related human immunodeficiency virus isolates, as well as against their own reisolated virus. In the goat, the gp120 of HTLV-IIIb induced a highly type-specific response as measured by both ACC and flow cytofluorometry of live infected H9 cells. Normal human cells were not subject to ACC by animal anti-HTLV-III gp120-specific sera. Induction of ACC and neutralizing antibody were closely correlated in the animal experimental models but not in humans. The presence of ACC in gp120-inoculated goats and HTLV-III-infected chimpanzees represent a qualitative difference that may be important in the quest for the elicitation of a protective immunity in humans.

Nara, P.L.; Robey, W.G.; Gonda, M.A.; Carter, S.G.; Fischinger, P.J.

1987-06-01

378

Solids formation on filtrate neutralization  

SciTech Connect

The Separations Technology Laboratory was requested to study what happens when a filtrate solution, which will be a F B-Line product, is neutralized with sodium hydroxide. The primary concern was the formation of solids that could cause damage in pump seals, resulting in their failure. The results of these experiments indicate that under process conditions, granular, crystalline sodium fluoride will be produced by rapid neutralization of the filtrate solution with 50% NaOH plus a 25 volume percent excess. Postprecipitation of sodium oxalate-sodium fluoride and its accumulation can occur over a three-week storage period of the neutralized filtrate. Such solids could pose operational problems from pump seal abrasion and potential failure caused by them.

Holcomb, H.P.

1988-05-26

379

How I treat severe combined immunodeficiency.  

PubMed

Severe combined immunodeficiency (SCID) arises from different genetic defects associated with lymphocyte development and function and presents with severe infections. Allogeneic hematopoietic stem cell transplantation is an extremely effective way of restoring immunity in these individuals. Numerous multicenter studies have identified the factors determining successful outcome, and survival for SCID has shown great improvement. Advances in understanding the genetic basis of disease also mean that we increasingly tailor transplant protocols to the specific SCID form. Wherever possible, we attempt to transplant SCID patients without the use of cytoreductive conditioning, but it is clear that this is only successful for specific SCID forms and, although survival is good, in specific patients there are ongoing humoral defects. We aim to use matched related and unrelated donors (including cord blood) whenever possible and have limited the use of mismatched haploidentical donors. The development of autologous hematopoietic stem cell gene therapy provides another treatment of the X-linked and adenosine deaminase-deficient forms of SCID, and we discuss how we have integrated gene therapy into our treatment strategy. These developments together with the advent of universal newborn screening for SCID should allow for a highly favorable outcome for this otherwise lethal condition. PMID:24113871

Gaspar, H Bobby; Qasim, Waseem; Davies, E Graham; Rao, Kanchan; Amrolia, Persis J; Veys, Paul

2013-11-28

380

Enhancement after feline immunodeficiency virus vaccination.  

PubMed

Cats were vaccinated with one of the three preparations: purified feline immunodeficiency virus (FIV) incorporated into immune stimulating complexes (ISCOMs), recombinant FIV p24 ISCOMs, or a fixed, inactivated cell vaccine in quil A. Cats inoculated with the FIV ISCOMs or the recombinant p24 ISCOMs developed high titres of antibodies against the core protein p24 but had no detectable antibodies against the env protein gp120 or virus neutralising antibodies. In contrast, all of the cats inoculated with the fixed, inactivated cell vaccine developed anti-env antibodies and four of five had detectable levels of neutralising antibody. However, none of the vaccinated cats were protected from infection after intraperitoneal challenge with 20 infectious units of FIV. Indeed there appeared to be enhancement of infection after vaccination as the vaccinated cats become viraemic sooner than the unvaccinated controls, and 100% of the vaccinated cats became viraemic compared with 78% of the controls. The mechanism responsible for this enhancement remains unknown. PMID:1337397

Hosie, M J; Osborne, R; Reid, G; Neil, J C; Jarrett, O

1992-12-01

381

Common Variable Immunodeficiency: Etiological and Treatment Issues  

PubMed Central

One of the great advances in clinical medicine was the recognition of the pleomorphism of the immune response and the multiple afferent and efferent limbs of antigen processing and responsiveness. A significant contribution to this understanding was derived from studies of human immunodeficiency states, including both inherited and acquired syndromes. Amongst these syndromes, one of the most common, and least understood, is common variable immune deficiency (CVID). CVID is a syndrome that leads to a reduction in serum immunoglobulins and complications including recurrent infections. Management includes immunoglobulin replacement therapy; however, patients with CVID are at risk for complications of exogenous immunoglobulin administration as well as CVID-associated diseases such as autoimmune processes and malignancies. To assess the current state of knowledge in the field, we performed a literature review of a total of 753 publications covering the period of 1968 until 2008. From this list, 189 publications were selected for discussion. In this review, we demonstrate that while the molecular basis of CVID in many cases remains incompletely understood, significant strides have been made and it is now clear that there is involvement of several pathways of immune activation, with contributions from both T and B cells. Furthermore, despite the current gaps in our knowledge of the molecular pathogenesis of the syndrome, there have been dramatic advances in management that have led to improved survival and significantly reduced morbidity in affected patients.

Deane, Sean; Selmi, Carlo; Naguwa, Stanley M.; Teuber, Suzanne S.; Gershwin, M. Eric

2009-01-01

382

Immunodeficiency as a factor in lymphomagenesis.  

PubMed

The human immune system has evolved multiple cellular and humoral defense mechanisms against the lymphotropic virus, EBV. NK cells, suppressor T-cells, cytotoxic K-cells, memory T-cells, and humoral immune responses usually subdue the virus into latency. Individuals with immune deficiency are at great risk of developing immunoregulatory disturbances and lymphoproliferative diseases when confronted by EBV. The infection of B-cells by EBV provokes a marked activation of immunoregulatory T-cells and requires restoration of immune homeostasis during convalescence. This is accomplished with difficulty in an individual with significant immune defects. The X-linked lymphoproliferative syndrome is an exemplary model for studying EBV in immune deficient individuals. Boys with XLP can develop acquired agammaglobulinemia, aplastic anemia, chronic or fatal IM, and a variety of B-cell malignant lymphomas following infection by the virus. We have identified multiple immune defects in the patients and progressive immunoregulatory disturbances following infection by the virus. Other patients with immune deficiency syndromes, i.e., ataxia telangiectasia or the renal transplant recipient, are also at increased risk for developing EBV-induced lymphoproliferative diseases. Moreover, certain families are at increased risk for EBV-associated malignancies, especially those with a triad of manifestations (i.e., autoimmunity, immunodeficiency, and lymphoma). Chromosomal breakage as seen in patients with ataxia telangiectasia may predispose to leukemogenesis. Immunoregulatory defects are also probably predisposing factors to lymphomagenesis. Both inherited and acquired defects can render persons vulnerable to leukemia and lymphoma. PMID:6330665

Purtilo, D T; Sakamoto, K

1984-01-01

383

Inhibitors of human immunodeficiency virus integrase.  

PubMed Central

In an effort to further extend the number of targets for development of antiretroviral agents, we have used an in vitro integrase assay to investigate a variety of chemicals, including topoisomerase inhibitors, antimalarial agents, DNA binders, naphthoquinones, the flavone quercetin, and caffeic acid phenethyl ester as potential human immunodeficiency virus type 1 integrase inhibitors. Our results show that although several topoisomerase inhibitors--including doxorubicin, mitoxantrone, ellipticines, and quercetin--are potent integrase inhibitors, other topoisomerase inhibitors--such as amsacrine, etoposide, teniposide, and camptothecin--are inactive. Other intercalators, such as chloroquine and the bifunctional intercalator ditercalinium, are also active. However, DNA binding does not correlate closely with integrase inhibition. The intercalator 9-aminoacridine and the polyamine DNA minor-groove binders spermine, spermidine, and distamycin have no effect, whereas the non-DNA binders primaquine, 5,8-dihydroxy-1,4-naphthoquinone, and caffeic acid phenethyl ester inhibit the integrase. Caffeic acid phenethyl ester was the only compound that inhibited the integration step to a substantially greater degree than the initial cleavage step of the enzyme. A model of 5,8-dihydroxy-1,4-naphthoquinone interaction with the zinc finger region of the retroviral integrase protein is proposed. Images Fig. 2

Fesen, M R; Kohn, K W; Leteurtre, F; Pommier, Y

1993-01-01

384

[Variability of human immunodeficiency virus type 1].  

PubMed

The variability of human immunodeficiency virus type 1 (HIV-1) is very high. To date, three distinct lineages of HIVs, type 1 group M, type 1 group O and type 2 are described, suggesting at least three different zoonotic infections. HIV-1 group M is responsible for the global epidemic of AIDS. At least ten subtypes of HIV-1 group M, labelled A through J, have been discovered. Viral sequences from both the gag and the env gene, particularly a part of gp 120 referred to as the V3 region have been used to identify subtypes of HIV-1 group M. The nucleotide distance between viruses of different subtypes is on average 30% for the env gene. The various subtypes are geographically distributed throughout the world. Some of the subtypes were identified as recombinant or mosaic viruses. The existence of different subtypes of HIV-1 have major implication for vaccination. They may also influence the diagnosis of HIV infection. To date, it is unclear whether subtypes of HIV-1 differ with respect to transmissibility or pathogenicity. PMID:10572662

Brun-Vézinet, F; Damond, F; Simon, F

1999-01-01

385

The many faces of common variable immunodeficiency  

PubMed Central

Common variable immunodeficiency (CVID) is a rare immune deficiency characterized by low levels of serum IgG, IgA, and/or IgM, with a loss of Ab production. The diagnosis is most commonly made in adults between the ages of 20 and 40 years, but both children and much older adults can be found to have this immune defect. The range of clinical manifestations is broad, including acute and chronic infections, inflammatory and autoimmune diseases, and an increased incidence of cancer and lymphoma. For all of these reasons, the disease phenotype is both heterogeneous and complex. In the past few years, data from large patient registries have revealed that both selected laboratory markers and clinical phenotyping may aid in separating groups of subjects into biologically relevant categories. CVID consists of 2 phenotypes, 1 in which infections are the characteristic and another in which impressive inflammatory and/or hematologic complications also develop, including lymphadenopathy, splenomegaly, autoimmune cytopenias, enteropathy, and/or and granulomatous disease. These phenotypes appear to be stable, are related to immunologic and inflammatory markers, and are predictive of outcomes. This review outlines current understanding about this syndrome based on studies of large cohorts, highlighting the evaluation and treatment of complications and, in particular, the autoimmune and inflammatory conditions that affect these patients.

Cunningham-Rundles, Charlotte

2014-01-01

386

Immunodeficiency and laser magnetic therapy in urology  

NASA Astrophysics Data System (ADS)

The importance of immunodeficiency problem has increased last time not only due to AIDS appearance, but also to a great extent as a result of the development and active practical use of the methods of immunology parameters investigations. Al great pharmaceutical firms are organizing the process of creating the drugs, influencing on the different phases of immunity, but unfortunately, the problem of their adverse effect and connected complications is till today a milestone. A great number of investigations, proving a good effect of laser-magnetic therapy concerning immune system have been done today. There is, in particular, changing of blood counts and immunologic tests after intravenous laser irradiation of blood. Intravenous laser irradiation of blood results in increasing of lymphocytes, T-immuno stimulation, stabilization of t-lymphocyte subpopulation, increasing of t-lymphocyte helper activity and decreasing of suppressor one.Under this laser action number of circulating immune complexes is decreased, and blood serum bactericide activity and lisozyme number are increased.

Maati, Moufagued; Rozanov, Vladimir V.; Avdoshin, V. P.

1996-11-01

387

Pediatric Selective IgM Immunodeficiency  

PubMed Central

Objective. Limited information exists on features of pediatric Selective IgM immunodeficiency (SIgMID). Previously published pediatric cases and 2 new cases are reviewed. Methods. English literature from PubMed and references from relevant articles were reviewed. Previously reported cases and 2 new cases from an allergy/immunology practice were analyzed. Results. Forty-nine reported cases of SIgMID presented with respiratory infections (77.6%), gastrointestinal disease (16.3%), skin disease (12.2%), and meningitis (8.2%). Mean serum IgM level was 16.5 ± 13.8 mg/dL. Two patients were identified with SIgMID among 6300 active pediatric patients (0.03%) presenting with asthma, vasomotor rhinitis, and recurrent respiratory infections. In the 51 cases reported, none developed lymphoproliferative disease nor evolved into panhypogammaglobulinemia; four fatalities were reported. Conclusions. The prevalence of SIgMID in our pediatric population was 0.03%. In general, respiratory infections are the common comorbid conditions. Death and autoimmune disease are uncommon complications of pediatric SIgMID.

Goldstein, Marc F.; Goldstein, Alex L.; Dunsky, Eliot H.; Dvorin, Donald J.; Belecanech, George A.; Shamir, Kfir

2008-01-01

388

Gastrointestinal Manifestations of the Acquired Immunodeficiency Syndrome  

PubMed Central

In addition to abnormalities in systemic immune function, patients with the acquired immunodeficiency syndrome (AIDS) and the pre-AIDS syndromes have significant abnormalities in the distribution of T-cell subsets in the intestinal tract. Such immune deficits predispose such patients to opportunistic infections and tumors, many of which involve the gastrointestinal tract. For example, Candida albicans often causes stomatitis and esophagitis. Intestinal infections with parasites (Cryptosporidium, Isospora belli, Microsporidia) or bacteria (Mycobacterium avium-intracellulare) are associated with severe diarrhea and malabsorption, whereas viruses like cytomegalovirus and herpes simplex virus cause mucosal ulcerations. Clinically debilitating chronic diarrhea develops in many AIDS patients for which no clear cause can be identified. Enteric pathogens like Salmonella and Campylobacter can be associated with bacteremias. Kaposi's sarcoma and lymphoma involving the intestinal tract are now well-recognized complications of AIDS. Although AIDS is not associated with a pathognomonic liver lesion, opportunistic infections and Kaposi's sarcoma or lymphoma may involve the liver. ImagesFigure 3.Figure 4.Figure 5.Figure 6.Figure 7.

Rodgers, Vance D.; Kagnoff, Martin F.

1987-01-01

389

A "tongue" of neutral composition  

NASA Astrophysics Data System (ADS)

Both the thermosphere and the ionosphere react to forcing from the magnetospherically imposed ion convection pattern. A twin-celled, neutral convection pattern is set up that normally follows the ion convection pattern; however, unlike the ionosphere, the thermosphere takes a considerable time to react to geomagnetic forcing. In solar maximum conditions this reaction time can take 1-3 h. The close relationship between the ion and neutral winds suggests that other features may exist in the high-latitude thermosphere that have counterparts in the high-latitude ionosphere. Two possible examples of these counterparts are tongues and patches. In this study, we use a thermosphere-ionosphere nested grid (TING) model simulation of the Bastille Day storm to determine whether such features can occur and whether they can, in turn, affect the ionosphere. We draw the following conclusions: (1) there is a "tongue" of neutral composition, which is formed in much the same way that the tongue of ionization is; (2) the neutral "tongue" is formed when parcels of air, which are rich in O/N2, are drawn from the dayside by the antisunward winds associated with the neutral convection pattern and transported across the polar cap towards the night side auroral oval; (3) this O/N2-rich air can only be transported from a small region on the dayside due to the geometry of the transport, so the neutral "tongue" is narrow like the ion tongue; (4) this neutral "tongue" tends to be weaker than the ion tongue, it extends a shorter distance across the polar cap and it takes longer to form; (5) the formation of the tongue of ionization is affected by the "leakage" of air that contains high concentrations of molecular species into the daytime middle latitudes, which, through recombination, results in a region of low electron densities in the dayside middle latitudes; (6) this region of the ionosphere, which is ion-poor, cannot produce flux tubes that can advect across the polar cap with the high ion densities that are needed to produce a strong tongue of ionization; (7) when enough time has elapsed to allow a neutral "tongue" to form in conjunction with the tongue of ionization, the latter becomes both stronger and longer, but causality in this relationship has not been established.

Burns, A. G.; Wang, W.; Killeen, T. L.; Solomon, S. C.

2004-10-01

390

Sequential injection immunoassay for human bone morphogenic protein-7 using an immunoreactor immobilized with anti-human bone morphogenic protein-7 antibody--CdSe/ZnS quantum dot conjugates.  

PubMed

The detection of human bone morphogenic protein-7 (BMP-7) was achieved using a sequential injection immunoassay (SIIA) system. The SIIA system is based on the binding between BMP-7 and anti-human BMP-7 (AbBMP7)-CdSe/ZnS quantum dot (QD) conjugates immobilized onto a glass disk or an optical fiber, using fluorescence detection at excitation and emission wavelengths of 470 nm and 580 nm, respectively. The AbBMP7-QD conjugates were prepared by conjugating anti-human BMP-7 antibody (AbBMP7) to hydrophilic CdSe/ZnS core/shell quantum dots (QDs). The SIIA system was fully automated using software written in the LabVIEW™ development environment. The analytical performance of the SIIA system was characterized with a number of variables such as carrier flow rate and elution buffer. Under partially optimized operating conditions, the SIIA system had a linear calibration graph at up to 10.0 ng mL(-1) BMP-7 (R(2)?0.975) and a sample frequency of two samples per hour. The SIIA system with an optical fiber immunosensor was used to detect and quantify BMP-7 in spiked real samples obtained from a biological process with recoveries in the range of 95-102%. PMID:23790295

Kim, Chun-Kwang; Duong, Hong Dinh; Rhee, Jong Il

2013-07-01

391

The Selection of Low Envelope Glycoprotein Reactivity to Soluble CD4 and Cold during Simian-Human Immunodeficiency Virus Infection of Rhesus Macaques  

PubMed Central

Envelope glycoprotein (Env) reactivity (ER) describes the propensity of human immunodeficiency virus type 1 (HIV-1) Env to change conformation from the metastable unliganded state in response to the binding of ligands (antibodies and soluble CD4 [sCD4]) or incubation in the cold. To investigate Env properties that favor in vivo persistence, we inoculated rhesus macaques with three closely related CCR5-tropic simian-human immunodeficiency viruses (SHIVs) that differ in ER to cold (ERcold) and ER to sCD4 (ERsCD4); these SHIVs were neutralized by antibodies equivalently and thus were similar in ERantibody. All three SHIVs achieved high levels of acute viremia in the monkeys without alteration of their Env sequences, indicating that neither ERcold nor ERsCD4 significantly influences the establishment of infection. Between 14 and 100 days following infection, viruses with high ERcold and ERsCD4 were counterselected. Remarkably, the virus variant with low ERcold and low ERsCD4 did not elicit a neutralizing antibody response against the infecting virus, despite the generation of high levels of anti-Env antibodies in the infected monkeys. All viruses that achieved persistent viremia escaped from any autologous neutralizing antibodies and exhibited low ERcold and low ERsCD4. One set of gp120 changes determined the decrease in ERcold and ERsCD4, and a different set of gp120 changes determined resistance to autologous neutralizing antibodies. Each set of changes contributed to a reduction in Env-mediated entry. During infection of monkeys, any Env replication fitness costs associated with decreases in ERcold and ERsCD4 may be offset by minimizing the elicitation of autologous neutralizing antibodies.

McGee, Kathleen; Haim, Hillel; Korioth-Schmitz, Birgit; Espy, Nicole; Javanbakht, Hassan; Letvin, Norman

2014-01-01

392

21 CFR 610.46 - Human immunodeficiency virus (HIV) âlookbackâ requirements.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 2013-04-01 false Human immunodeficiency virus (HIV) âlookbackâ...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS GENERAL...Communicable Disease Agents § 610.46 Human immunodeficiency virus (HIV)...

2013-04-01

393

AIDS (Acquired Immunodeficiency Syndrome): Information on Global Dimensions and Possible Impacts.  

National Technical Information Service (NTIS)

The fact sheet provides information on (1) the impact of the Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS) on world population and demographics and (2) the likely effects of AIDS on Zaire. Because scientists lack importa...

1987-01-01

394

DYNAMIC EFFECTS OF NETWORK NEUTRALITY  

Microsoft Academic Search

At the heart of the network neutrality debate is a challenging institutional design problem: the selection of a regime to govern the relations between the stakeholders in the complex value net of advanced communication services, most importantly between platform operators and providers of applications and content. How it is resolved will have far-reaching effects on the future evolution of communication

Johannes M. Bauer

2007-01-01

395

Net neutrality: A user's guide  

Microsoft Academic Search

Net neutrality is a complex issue that has generated intense levels of political discussion in the United States, but which has yet to attract significant attention from regulators in the UK. Nevertheless, the question of whether network operators should be prevented from blocking or prioritising certain network traffic or traffic from particular sources is a significant one for a wide range

Paul Ganley; Ben Allgrove

2006-01-01

396

Net Neutrality... Seriously this Time  

Microsoft Academic Search

The net neutrality debate began a few years ago, prematurely, with overheated rhetoric about potential disasters for the Internet but little in the way of real threats requiring immediate government action. Beginning around May 2007, one of the largest ISPs in the US, Comcast, began a program of discriminatory blocking of certain Internet communications protocols. The blocking has focused on

Daniel J. Weitzner

2008-01-01

397

The Economics of Net Neutrality  

Microsoft Academic Search

Robert Hahn and Scott Wallsten argue that mandating net neutrality, like most other forms of price regulation, is poor policy; instead, the government should focus on creating competition in the broadband market by liberalizing more spectrum and reducing entry barriers created by certain local regulations.

Robert W. Hahn; Scott Wallsten

2006-01-01

398

Net Neutrality Paradox: Regulator's Dilemma  

Microsoft Academic Search

Internet has emerged as a disruptive force for the conventional communication model. Internet evolution as the most effective communication medium paved the way for convergent communication services and new business models. The growing incidents of internet service discrimination (1) and service Blockade (2) has once again revived the debate of resolving the old issue of Network neutrality (3). The recent

Khalid Rafique; Chunhui Yuan; Muhammad Saeed

2011-01-01

399

MSFC Skylab neutral buoyancy simulator  

NASA Technical Reports Server (NTRS)

The use of a neutral buoyancy simulator for developing extravehicular activity systems and for training astronauts in weightless activities is discussed. The construction of the facility and the operations are described. The types of tests and the training activities conducted in the simulator are reported. Photographs of the components of the simulator and actual training exercises are included.

1974-01-01

400

Low energy neutral atom imaging  

SciTech Connect

Energetic neutral atom (ENA) and low energy neutral atom (LENA) imaging of space plasmas are emerging new technology which promises to revolutionize the way we view and understand large scale space plasma phenomena and dynamics. ENAs and LENAs are produced in the magnetosphere by charge exchange between energetic and plasma ions and cold geocoronal neutrals. While imaging techniques have been previously developed for observing ENAs, with energies above several tens of keV, most of the ions found in the terrestrial magnetosphere have lower energies. We recently suggested that LENAs could be imaged by first converting the neutrals to ions and then electrostatically analyzing them to reject the UV background. In this paper we extend this work to examine in detail the sensor elements needed to make an LENA imager. These elements are (1) a biased collimator to remove the ambient plasma ions and electrons and set the azimuthal field-of-view; (2) a charge modifier to convert a portion of the incident LENAs to ions; (3) an electrostatic analyzer to reject UV light and set the energy passband; and (4) a coincidence detector to measure converted LENAs while rejecting noise and penetrating radiation. We also examine the issue of LENA imager sensitivity and describe ways of optimizing sensitivity in the various sensor components. Finally, we demonstrate in detail how these general considerations are implemented by describing one relatively straightforward design based on a hemispherical electrostatic analyzer.

McComas, D.J.; Funsten, H.O.; Gosling, J.T.; Moore, K.R.; Thomsen, M.F.

1992-05-01

401

Low energy neutral atom imaging  

SciTech Connect

Energetic neutral atom (ENA) and low energy neutral atom (LENA) imaging of space plasmas are emerging new technology which promises to revolutionize the way we view and understand large scale space plasma phenomena and dynamics. ENAs and LENAs are produced in the magnetosphere by charge exchange between energetic and plasma ions and cold geocoronal neutrals. While imaging techniques have been previously developed for observing ENAs, with energies above several tens of keV, most of the ions found in the terrestrial magnetosphere have lower energies. We recently suggested that LENAs could be imaged by first converting the neutrals to ions and then electrostatically analyzing them to reject the UV background. In this paper we extend this work to examine in detail the sensor elements needed to make an LENA imager. These elements are (1) a biased collimator to remove the ambient plasma ions and electrons and set the azimuthal field-of-view; (2) a charge modifier to convert a portion of the incident LENAs to ions; (3) an electrostatic analyzer to reject UV light and set the energy passband; and (4) a coincidence detector to measure converted LENAs while rejecting noise and penetrating radiation. We also examine the issue of LENA imager sensitivity and describe ways of optimizing sensitivity in the various sensor components. Finally, we demonstrate in detail how these general considerations are implemented by describing one relatively straightforward design based on a hemispherical electrostatic analyzer.

McComas, D.J.; Funsten, H.O.; Gosling, J.T.; Moore, K.R.; Thomsen, M.F.

1992-01-01

402

Neutral models for patchy landscapes  

Microsoft Academic Search

The landscapes currently studied in ecology are either “discontinuous” (category-based or patch-based), as in the case of mosaics of agricultural units, or of more “continuous” type (raster lattices), as used for representing elevation or other ecological gradients. The main landscape models either involve explicit processes or are neutral, recreating spatial patterns in the absence of studied processes (using statistical rules).

C. Gaucherel; D. Fleury; D. Auclair; P. Dreyfus

2006-01-01

403

Neutralization kinetics for polonium-218  

SciTech Connect

In a well-defined experimental system the neutralization of polonium-218 ions was investigated as a function of the physical and chemical properties of the controlled composition atmosphere. The diffusion coefficient of polonium-218 under various concentrations of trace gas NO/sub 2/ in nitrogen was measured. The mobilities of Po/sup +/ and PoO/sub 2//sup +/ are determined by combining experimental results with a computer model of the system. Three neutralization mechanisms were individually studied. The small-ion recombination rate has been found to be proportional to the square root of radon concentration. The electron-scavenging mechanism is responsible for the neutralization of Po/sup +/ in NO/sub 2/ or H/sub 2/O in nitrogen. When PoO/sub 2//sup +/ is formed, the electron-transfer mechanism dominates the neutralization process. The electron is transferred to PoO/sub 2//sup +/ from molecules with lower ionization potentials. The ionization molecules with lower ionization potentials. The ionization potential of PoO/sub 2//sup +/ is also determined to be 10.44 +/- 0.05 eV.

Chu, K.D.; Hopke, P.K.

1988-06-01

404

LBL neutralized beam focusing experiment  

SciTech Connect

An intense neutralized Cs/sup +1/ beam has been focused by an electrostatic polarization field induced by a solenoidal magnetic field of 10-25 gauss. This report describes the experiment and compares the results with the predictions of an analytic linearized fluid model and a particle-in-cell simulation which treats the motion of the warm electrons in detail.

Krafft, G.A.; Kim, C.H.; Smith, L.

1985-05-01

405

Neutral Current Interactions in MINOS  

NASA Astrophysics Data System (ADS)

The Main Injector Neutrino Oscillation Search (MINOS) long baseline experiment has been actively taking beam data since 2005, having already accumulated 2.6E20 protons-on-target. MINOS uses the most powerful neutrino beam currently in operation measured in two locations: a Near detector at Fermilab, close to beam production, and a Far detector, 735 km downstream, in Northern Minnesota. Although the measurement of neutrino oscillations is the primary goal of MINOS, relevant contributions can be extracted from studies of neutral current neutrino interactions in the detectors. The several million neutrinos per year observed at the Near detector may improve the existing body of knowledge of neutrino cross-sections and the Near-Far comparison of the observed energy spectrum neutral current events constrains oscillations into sterile neutrinos. This poster outlines the MINOS capabilities of observing neutral current neutrino events, describes the employed methodology for event selection and shows preliminary results obtained. An outlook on the expected neutral current related contributions from MINOS is also presented.

Sousa, Alexandre

406

Dynamics of ultracold neutral plasma  

NASA Astrophysics Data System (ADS)

For an ultracold neutral plasma produced by photoionzation of laser-cooled heavy particles, initial expansion behavior was studied with classical molecular dynamics. To investigate huge particle sets under open boundary condition, the TREE method has been implemented and Rydberg states of low quantum number were studied. We also examined the degree of ion correlation.

Collins, Lee; Jeon, Byoungseon; Kress, Joel; Gronbech-Jensen, Niels

2007-03-01

407

CPT symmetry and neutral kaons  

Microsoft Academic Search

We discuss the accuracy of CPT invariance tests in the neutral kaon decays. The possible CPT non-invariance is parametrized by amplitudes of two types: (i) CP violating, but T conserving, and (ii) T violating, but CP conserving. It is shown that the experimental data are consistent with CPT symmetry essentially within two standard deviations. The source of this not quite

V. V. Barmin; V. G. Barylov; I. V. Chuvilo; G. V. Davidenko; V. S. Demidov; A. G. Dolgolenko; A. G. Meshkovsky; L. B. Okun; V. A. Shebanov; M. Baldo-Ceolin; E. Calimani; S. Ciampolillo; F. Mattioli; G. Miari; A. Sconza

1984-01-01

408

Possible transmission of human immunodeficiency virus-1 infection from an elite controller to a patient who progressed to acquired immunodeficiency syndrome: a case report  

PubMed Central

Introduction Most individuals infected with human immunodeficiency virus-1, in the absence of antiretroviral therapy, exhibit persistent virus replication and declining CD4+ cell numbers, and progress to acquired immunodeficiency syndrome within 10?years of infection. Elite controllers are rare individuals with human immunodeficiency virus-1 infection who can maintain undetectable plasma virus levels and remain asymptomatic without antiretroviral therapy. It has been proposed that elite controllers benefit from being infected with attenuated human immunodeficiency virus-1 variants. Case presentation A 31-year-old African woman presented with human immunodeficiency virus-1 infection during pregnancy and was diagnosed with acquired immunodeficiency syndrome. Subsequently, her husband, a 31-year-old African man, was tested and found to be seropositive for human immunodeficiency virus-1. His plasma human immunodeficiency virus-1 ribonucleic acid level was found to be below the limit of detection of the clinical assay. Conclusion This report provides evidence for the first described case of human immunodeficiency virus-1 infection possibly transmitted from an elite controller to a patient who progressed to acquired immunodeficiency syndrome. This observation strengthens the case against avirulence as a mechanism that protects elite controllers.

2012-01-01

409

A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies  

PubMed Central

A desirable but as yet unachieved property of a human immunodeficiency virus type 1 (HIV-1) vaccine candidate is the ability to induce broadly neutralizing antibodies (bNAbs). One approach to the problem is to create trimeric mimics of the native envelope glycoprotein (Env) spike that expose as many bNAb epitopes as possible, while occluding those for non-neutralizing antibodies (non-NAbs). Here, we describe the design and properties of soluble, cleaved SOSIP.664 gp140 trimers based on the subtype A transmitted/founder strain, BG505. These trimers are highly stable, more so even than the corresponding gp120 monomer, as judged by differential scanning calorimetry. They are also homogenous and closely resemble native virus spikes when visualized by negative stain electron microscopy (EM). We used several techniques, including ELISA and surface plasmon resonance (SPR), to determine the relationship between the ability of monoclonal antibodies (MAbs) to bind the soluble trimers and neutralize the corresponding virus. In general, the concordance was excellent, in that virtually all bNAbs against multiple neutralizing epitopes on HIV-1 Env were highly reactive with the BG505 SOSIP.664 gp140 trimers, including quaternary epitopes (CH01, PG9, PG16 and PGT145). Conversely, non-NAbs to the CD4-binding site, CD4-induced epitopes or gp41ECTO did not react with the trimers, even when their epitopes were present on simpler forms of Env (e.g. gp120 monomers or dissociated gp41 subunits). Three non-neutralizing MAbs to V3 epitopes did, however, react strongly with the trimers but only by ELISA, and not at all by SPR and to only a limited extent by EM. These new soluble trimers are useful for structural studies and are being assessed for their performance as immunogens.

Sanders, Rogier W.; Derking, Ronald; Cupo, Albert; Julien, Jean-Philippe; Yasmeen, Anila; de Val, Natalia; Kim, Helen J.; Blattner, Claudia; de la Pena, Alba Torrents; Korzun, Jacob; Golabek, Michael; de los Reyes, Kevin; Ketas, Thomas J.; van Gils, Marit J.; King, C. Richter; Wilson, Ian A.; Ward, Andrew B.; Klasse, P. J.; Moore, John P.

2013-01-01

410

A next-generation cleaved, soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies.  

PubMed

A desirable but as yet unachieved property of a human immunodeficiency virus type 1 (HIV-1) vaccine candidate is the ability to induce broadly neutralizing antibodies (bNAbs). One approach to the problem is to create trimeric mimics of the native envelope glycoprotein (Env) spike that expose as many bNAb epitopes as possible, while occluding those for non-neutralizing antibodies (non-NAbs). Here, we describe the design and properties of soluble, cleaved SOSIP.664 gp140 trimers based on the subtype A transmitted/founder strain, BG505. These trimers are highly stable, more so even than the corresponding gp120 monomer, as judged by differential scanning calorimetry. They are also homogenous and closely resemble native virus spikes when visualized by negative stain electron microscopy (EM). We used several techniques, including ELISA and surface plasmon resonance (SPR), to determine the relationship between the ability of monoclonal antibodies (MAbs) to bind the soluble trimers and neutralize the corresponding virus. In general, the concordance was excellent, in that virtually all bNAbs against multiple neutralizing epitopes on HIV-1 Env were highly reactive with the BG505 SOSIP.664 gp140 trimers, including quaternary epitopes (CH01, PG9, PG16 and PGT145). Conversely, non-NAbs to the CD4-binding site, CD4-induced epitopes or gp41ECTO did not react with the trimers, even when their epitopes were present on simpler forms of Env (e.g. gp120 monomers or dissociated gp41 subunits). Three non-neutralizing MAbs to V3 epitopes did, however, react strongly with the trimers but only by ELISA, and not at all by SPR and to only a limited extent by EM. These new soluble trimers are useful for structural studies and are being assessed for their performance as immunogens. PMID:24068931

Sanders, Rogier W; Derking, Ronald; Cupo, Albert; Julien, Jean-Philippe; Yasmeen, Anila; de Val, Natalia; Kim, Helen J; Blattner, Claudia; de la Peña, Alba Torrents; Korzun, Jacob; Golabek, Michael; de Los Reyes, Kevin; Ketas, Thomas J; van Gils, Marit J; King, C Richter; Wilson, Ian A; Ward, Andrew B; Klasse, P J; Moore, John P

2013-09-01

411

Medical management of human immunodeficiency virus infection  

PubMed Central

The human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome (AIDS) pandemic has pervasive effects on culture, economics, policy, and human development. All organs can be affected by complications of HIV/AIDS, including the eye. When sufficient resources are available and widespread antiretroviral resistance does not exist, the four available classes of antiretroviral agents - nucleoside/ nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors - can be combined to provide highly active antiretroviral therapy (HAART). For many (not all) patients, HAART converts an inexorably fatal disease into a chronic disease with a fairly good prognosis. Use of HAART often induces partial immune recovery, which has predominantly beneficial effects on ocular complications of AIDS. However, HAART-induced immune recovery sometimes results in immune recovery inflammatory syndromes, such as immune recovery uveitis. Use of HAART is the single most useful intervention for most patients with ocular complications of AIDS. However, specific ocular therapy is also critical to avoid blindness in the early months before immune recovery can occur, or if HAART is unavailable. Increasing availability of HAART worldwide shows great promise to alleviate one of the world?s greatest plagues. However, predictable secular trends in the AIDS epidemic make it likely that the number of cases of ocular complications of AIDS will increase substantially before they decrease. Ophthalmologists worldwide should be familiar with the diagnosis and management of cytomegalovirus retinitis - the most common ocular complication of AIDS - and should establish partnerships with physicians who are able to provide HAART. Research is needed to determine the optimal approach for managing cytomegalovirus retinitis in resource- constrained settings.

2008-01-01

412

Generation and characterization of severe combined immunodeficiency rats.  

PubMed

Severe combined immunodeficiency (SCID) mice, the most widely used animal model of DNA-PKcs (Prkdc) deficiency, have contributed enormously to our understanding of immunodeficiency, lymphocyte development, and DNA-repair mechanisms, and they are ideal hosts for allogeneic and xenogeneic tissue transplantation. Here, we use zinc-finger nucleases to generate rats that lack either the Prkdc gene (SCID) or the Prkdc and Il2rg genes (referred to as F344-scid gamma [FSG] rats). SCID rats show several phenotypic differences from SCID mice, including growth retardation, premature senescence, and a more severe immunodeficiency without "leaky" phenotypes. Double-knockout FSG rats show an even more immunocompromised phenotype, such as the abolishment of natural killer cells. Finally, xenotransplantation of human induced pluripotent stem cells, ovarian cancer cells, and hepatocytes shows that SCID and FSG rats can act as hosts for xenogeneic tissue grafts and stem cell transplantation and may be useful for preclinical testing of new drugs. PMID:22981234

Mashimo, Tomoji; Takizawa, Akiko; Kobayashi, Junya; Kunihiro, Yayoi; Yoshimi, Kazuto; Ishida, Saeko; Tanabe, Koji; Yanagi, Ami; Tachibana, Asato; Hirose, Jun; Yomoda, Jun-ichiro; Morimoto, Shiho; Kuramoto, Takashi; Voigt, Birger; Watanabe, Takeshi; Hiai, Hiroshi; Tateno, Chise; Komatsu, Kenshi; Serikawa, Tadao

2012-09-27

413

Immunodeficiency due to chylous dysplasia: diagnostic and therapeutic considerations.  

PubMed

Among primary immunodeficiencies, common variable immunodeficiency (CVID) is defined by an impaired production of immunoglobulins characterized by low levels of plasma immunoglobulins and an altered antibody response. The case reported here was initially interpreted as a CVID. A 20 year old male suffered from diarrhea, weight loss, and malnutrition. Accurate diagnostic assessment uncovered a protein-losing enteropathy. Conventional oil contrast lymphangiography accurately documented the underlying problem and established the appropriate therapeutic approach. The operation consisted of multiple antigravitational ligatures of dilated and incompetent chylous vessels and chylous vessel-mesenteric vein microanastomoses. Serum albumin and leukocyte counts normalized by 1 week after operation and remained stable with time. There were no more episodes of diarrhea, and the patient regained weight. Accurate diagnostic assessment and particularly lymphangiography may be necessary to properly define difficult cases of immunodeficiency due to intestinal protein loss and to plan a corrective therapeutic functional approach. PMID:23057150

Campisi, C C; Spinaci, S; Lavagno, R; Larcher, L; Boccardo, F; Santi, P; Campisi, C

2012-06-01

414

[Combined immunodeficiency with cutaneous manifestations associated with DOCK8 mutation].  

PubMed

Different primary immunodeficiencies present increased levels of IgE and cutaneous infections of viral etiology. We report a case of a 2 y, 8 m old boy with combined immunodeficiency, dermatitis and disseminated molluscum contagiosum. The patient presented high titers of IgE, eosinophilia and pronounced TCD8 lymphopenia. Impaired proliferation assays and abnormal antibody response to vaccination were found. Normal results of ZAP-70 protein, NK function, and HLA I levels, to test quantitatives and functional defects of cytotoxic cells, lead us to suspect a mutation in DOCK8 gene. Positive result in molecular study together with clinical and immunology features in the patient confirmed the diagnosis of this new immunodeficiency, being to the authors' knowledge the first case recorded in a paediatric hospital in our country. PMID:24955914

Cantisano, Claudio; Díaz, Héctor; Balbaryski, Jeanette; Oleastro, Matías; Quiroz, Héctor; Gaddi, Eduardo

2014-08-01

415

Late Onset Combined Immunodeficiency Presenting with Recurrent Pneumocystis jiroveci Pneumonia  

PubMed Central

Late onset combined immunodeficiency (LOCID) is a recently described variant of common variable immunodeficiency (CVID), involving adult patients presenting with opportunistic infections and/or low CD4+ lymphocyte counts. A 36-year-old male with unremarkable past medical history presented with fever, respiratory failure, and lymphocytopenia. He was found to have Pneumocystis jiroveci pneumonia (PJP), subsequently complicated by recurrent hospital-acquired Pseudomonas aeruginosa pneumonia and immune reconstitution phenomena, attributed to restoration of immunoglobulin levels. Clinicians should be aware of LOCID, which could be confused with HIV infection/AIDS or idiopathic CD4 lymphocytopenia. In the English bibliography there is only one case report, where PJP was the initial presentation of CVID (that case would probably be classified as LOCID). Phenomena of immune reconstitution are described in various settings, including primary immunodeficiency, manifesting as temporary clinical and radiologic deterioration and leading to misperceptions of therapeutic failure and/or presence of alternative/additional diagnoses.

Baraboutis, Ioannis G.; Karnesis, Lazaros

2014-01-01

416

Vaccine-associated paralytic poliomyelitis in immunodeficient children, Iran, 1995-2008.  

PubMed

To determine the prevalence of vaccine-associated paralytic poliomyelitis (VAPP) in immunodeficient infants, we reviewed all documented cases caused by immunodeficiency-associated vaccine-derived polioviruses in Iran from 1995 through 2008. Changing to an inactivated polio vaccine vaccination schedule and introduction of screening of neonates for immunodeficiencies could reduce the risk for VAPP infection. PMID:20587188

Shahmahmoodi, Shohreh; Mamishi, Setareh; Aghamohammadi, Asghar; Aghazadeh, Nessa; Tabatabaie, Hamideh; Gooya, Mohammad Mehdi; Zahraei, Seyed Mohsen; Mousavi, Taha; Yousefi, Maryam; Farrokhi, Kobra; Mohammadpour, Masoud; Ashrafi, Mahmoud Reza; Nategh, Rakhshandeh; Parvaneh, Nima

2010-07-01

417

Primary Immunodeficiency in Iran: First Report of the National Registry of PID in Children and Adults  

Microsoft Academic Search

Epidemiological studies have shown wide geographical and racial variation in the prevalence and patterns of immunodeficiency disorders. To determine the frequency of primary immunodeficiencies (PID) in Iran, the Iranian Primary Immunodeficiency Registry (IPIDR) was organized in 1999. We extracted the patient’s data, by using a uniform questionnaire from their hospital records. The diagnosis of patients was based on WHO criteria.

Asghar Aghamohammadi; Mosafa Moein; Abolhasan Farhoudi; Zahra Pourpak; Nima Rezaei; Kamran Abolmaali; Masoud Movahedi; Mohammad Gharagozlou; Bahram Mir Saeid Ghazi; Maryam Mahmoudi; Davoud Mansouri; Saba Arshi; Naser Javaher Trash; Hedayatallah Akbari; Roya Sherkat; Reza Farid Hosayni; Ahmad Hashemzadeh; Iraj Mohammadzadeh; Reza Amin; Sara Kashef; Abdalvahab Alborzi; Abdallah Karimi; Hosaynali Khazaei

2002-01-01

418

Immunodeficiency-associated Vaccine-Derived Poliovirus Type 3 in Infant, South Africa, 2011  

PubMed Central

Patients with primary immunodeficiency are prone to persistently excrete Sabin-like virus after administration of live-attenuated oral polio vaccine and have an increased risk for vaccine-derived paralytic polio. We report a case of type 3 immunodeficiency-associated vaccine-derived poliovirus in a child in South Africa who was born with X-linked immunodeficiency syndrome.

Muthambi, Vongani; Schoub, Barry D.

2012-01-01

419

Human monoclonal antibodies that neutralize vaccine and wild-type poliovirus strains.  

PubMed

An essential requirement for eradication of poliomyelitis is the elimination of circulating vaccine derived polioviruses (cVDPV) and polioviruses excreted by chronically infected individuals with immunodeficiencies (iVDPV). As part of a post-eradication risk management strategy, a human monoclonal antibody (mAb) therapeutic could play a role in halting excretion in asymptomatic carriers and could be used, in combination with vaccines and antiviral drugs, to protect polio-exposed individuals. Cross-neutralizing mAbs may be particularly useful, as they would reduce the number of mAbs needed to create a comprehensive PV therapeutic. We cloned a panel of IgG mAbs from OPV-vaccinated, IPV-boosted healthy subjects. Many of the mAbs had potent neutralizing activities against PV wild-type (WT) and Sabin strains, and two of the mAbs, 12F8 and 1E4, were significantly cross-reactive against types 1 and 2 and types 1 and 3, respectively. Mapping the binding epitopes using strains resistant to neutralization (escape mutants) suggested that cross-specific PV binding epitopes may primarily reside within the canyon region, which interacts with the cellular receptor molecule CD155 and the cross-neutralizing chimpanzee/human mAb, A12. Despite their close proximity, the epitopes for the 12F8 and 1E4 mAbs on Sabin 1 were not functionally identical to the A12 epitope. When tested together, 12F8 and 1E4 neutralized a diverse panel of clinically relevant PV strains and did not exhibit interference. Virus mutants resistant to the anti-poliovirus drug V-073 were also neutralized by the mAbs. The 12F8 and 1E4 mAbs may suitable for use as anti-PV therapeutics. PMID:24824031

Puligedda, Rama Devudu; Kouiavskaia, Diana; Adekar, Sharad P; Sharma, Rashmi; Devi Kattala, Chandana; Rezapkin, Gennady; Bidzhieva, Bella; Dessain, Scott K; Chumakov, Konstantin

2014-08-01

420

Persistent cryptosporidiosis in horses with severe combined immunodeficiency.  

PubMed Central

Cryptosporidial infections were established in five young foals with severe combined immunodeficiency following oral administration of 10(8) Cryptosporidium parvum oocysts. All foals shed oocysts (average of 8 x 10(6) t