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Sample records for cytomegalovirus infection implications

  1. Cytomegalovirus (CMV) infection

    MedlinePlus

    CMV mononucleosis; Cytomegalovirus; CMV; Human cytomegalovirus; HCMV ... infection is spread by: Blood transfusions Organ transplants ... viruses remain in your body for the rest of your life. If your ...

  2. Enhanced cytomegalovirus infection in human trabecular meshwork cells and its implication in glaucoma pathogenesis

    PubMed Central

    Choi, Jin A; Kim, Ju-Eun; Noh, Seung-Jun; Kyoung Kim, Eun; Park, Chan Kee; Paik, Soon-Young

    2017-01-01

    Cytomegalovirus (CMV) is one of the infectious causes of hypertensive anterior uveitis, which is characterized by recurrent episodes of elevated intraocular pressure (IOP) and mild anterior uveitis. Despite the potentially vision-threatening complications of this disease, the underlying mechanisms remain largely undefined. We aimed to investigate whether human trabecular meshwork (TM) cells, the key cell type that regulates IOP, could support CMV replication, as well as demonstrate the relevant pathological changes in TM. When human TM cells were infected with CMV AD169, immediate early antigens were detected 1 day post-infection (dpi); cytopathic changes including rounding, a ballooned appearance with disorganization, and a decreased number of stress fibers were noted in TM cells. The marked increase in viral DNA accumulation was observed most notably at 5 and 7 dpi, suggesting that the active viral infection in human TM cells could be the key mechanism underlying the elevation of IOP in anterior viral uveitis. Notably, CMV infection enhanced the production of transforming growth factor (TGF)-β1, an upstream molecule that increases the resistance of the outflow pathway in human TM cells. The increase of TGF-β1 was countervailed by additional treatment with corticosteroids. Our results provide a pathogenic mechanism for IOP elevation in viral anterior uveitis. PMID:28240260

  3. Neurological Consequences of Cytomegalovirus Infection

    MedlinePlus

    ... an uninfected person, but the virus can also pass from mother to fetus during pregnancy. × Definition Cytomegalovirus ( ... an uninfected person, but the virus can also pass from mother to fetus during pregnancy. View Full ...

  4. Rare Presentations of Cytomegalovirus Infection in Renal Allograft Recipients

    PubMed Central

    Ardalan, Mohammadreza

    2012-01-01

    Cytomegalovirus is the most common viral infection after kidney transplantation. Clinical presentations of cytomegalovirus infection range from asymptomatic infection to organ-specific involvement. Most symptomatic infections manifest as fever and cytopenia. The gastrointestinal tract is the most common site of tissue-invasive infection, often presenting as diarrhea or gastrointestinal bleeding. Gastrointestinal obstruction, perforation, thrombosis of large gastrointestinal veins, splenic artery thrombosis, and pancreatitis are rare gastrointestinal presentations of cytomegalovirus infection. Renal-allograft ureteral stricture and skin involvement are other rare presentations of cytomegalovirus infection. hemophagocytic syndrome, thrombotic microangiopathy, adrenal insufficiency, and renal allograft artery stenosis are other rare symptoms of cytomegalovirus infection. PMID:23573461

  5. Congenital cytomegalovirus infection – An update

    PubMed Central

    Friedman, Smadar; Ford-Jones, E Lee

    1999-01-01

    Cytomegalovirus is estimated to be the leading infectious cause of nonheriditary sensorneural loss and a significant cause of mental retardation. Approximately 1% of newborn infants are congenitally infected with the virus. This review summarizes recent developments concerning this infection, including clinical outcome, risk factors for aquisition diagnosis and therapy. PMID:20212987

  6. Congenital cytomegalovirus infection: Clinical presentation, epidemiology, diagnosis and prevention

    PubMed Central

    van Zuylen, Wendy J; Hamilton, Stuart T; Naing, Zin; Hall, Beverly; Shand, Antonia

    2014-01-01

    Cytomegalovirus is the most common congenital infection causing serious disease in infants. It is the leading infectious cause of sensorineural hearing loss and neurodevelopmental disability in developed countries. Despite the clinical importance of congenital cytomegalovirus, surveys show there is limited awareness and knowledge in the medical and general community about congenital cytomegalovirus infection. This article reviews the clinical features, global epidemiology, transmission and risk factors for cytomegalovirus infections. It also highlights several major advances made in recent years in the diagnosis and prevention of cytomegalovirus infection during pregnancy. Although research is ongoing, no therapy is currently proven to prevent or treat maternal, fetal or neonatal cytomegalovirus infection. Education of women regarding hygiene measures can help prevent cytomegalovirus infection and are currently the best strategy to prevent congenital cytomegalovirus disease. PMID:27512442

  7. Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model.

    PubMed

    Slavuljica, Irena; Kveštak, Daria; Huszthy, Peter Csaba; Kosmac, Kate; Britt, William J; Jonjić, Stipan

    2015-03-01

    Congenital human cytomegalovirus infection is a leading infectious cause of long-term neurodevelopmental sequelae, including mental retardation and hearing defects. Strict species specificity of cytomegaloviruses has restricted the scope of studies of cytomegalovirus infection in animal models. To investigate the pathogenesis of congenital human cytomegalovirus infection, we developed a mouse cytomegalovirus model that recapitulates the major characteristics of central nervous system infection in human infants, including the route of neuroinvasion and neuropathological findings. Following intraperitoneal inoculation of newborn animals with mouse cytomegalovirus, the virus disseminates to the central nervous system during high-level viremia and replicates in the brain parenchyma, resulting in a focal but widespread, non-necrotizing encephalitis. Central nervous system infection is coupled with the recruitment of resident and peripheral immune cells as well as the expression of a large number of pro-inflammatory cytokines. Although infiltration of cellular constituents of the innate immune response characterizes the early immune response in the central nervous system, resolution of productive infection requires virus-specific CD8(+) T cells. Perinatal mouse cytomegalovirus infection results in profoundly altered postnatal development of the mouse central nervous system and long-term motor and sensory disabilities. Based on an enhanced understanding of the pathogenesis of this infection, prospects for novel intervention strategies aimed to improve the outcome of congenital human cytomegalovirus infection are proposed.

  8. Thrombosis associated with acute cytomegalovirus infection: a narrative review

    PubMed Central

    Sherman, Shany; Eytan, Ori

    2014-01-01

    Thrombosis associated with acute cytomegalovirus infection has been reported many times in the literature since the mid 1980s – mainly in case reports and in small case series, but also in four controlled studies. Still, many physicians are unaware of this association although acute cytomegalovirus infection diagnosis in a thrombosis patient may warrant antiviral therapy and may affect anticoagulation therapy duration. Accordingly, the clinical characteristics of patients with thrombosis and acute cytomegalovirus infection are reviewed, and the current knowledge concerning this unique association is presented herein. We believe it is time to add acute cytomegalovirus infection to the list of thrombosis triggers. PMID:25624857

  9. Murine cytomegalovirus infection of cultured mouse embryos.

    PubMed Central

    Tsutsui, Y.; Naruse, I.

    1987-01-01

    Isolated mouse whole embryos of 7.5 days' gestation were infected with murine cytomegalovirus (MCMV) and cultured in pure rat serum. Although the MCMV infection had little effect on the survival and development of the embryos during 3 days of cultivation, immunohistochemical analysis of their serial sections using monoclonal antibody showed MCMV-infected cells in various portions of the embryos. This monoclonal antibody, when tested with the use of infected cultured mouse fibroblasts, reacted with nuclear antigen within 2 hours after infection and also reacted with nuclear inclusions in the late phase of infection. The viral antigen-positive cells detected by the monoclonal antibody were present in almost all of the ectoplacental cone and the yolk sac and in about 82% of the embryos. In the embryos, antigen-positive cells were frequently observed in the epithelium of the digestive tracts, endothelial cells of the blood vessels, and the mesodermal cells. In some of the embryos, viral antigen-positive cells were clearly observed in a small percentage of the blood cells. These findings indicate that blood cells, in addition to cell migration during embryogenesis, may play an important role in transmission of infectious virus into the embryos. Mouse whole embryo culture infected with MCMV can provide a model for the study of cellular tropism related to congenital infection by cytomegalovirus. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:3034066

  10. Strongyloides Hyperinfection Syndrome Combined with Cytomegalovirus Infection

    PubMed Central

    Alsaeed, Mohammed; Ballool, Sulafa; Attia, Ashraf

    2016-01-01

    The mortality in Strongyloides hyperinfection syndrome (SHS) is alarmingly high. This is particularly common in bone marrow, renal, and other solid organ transplant (SOT) patients, where figures may reach up to 50–85%. Immunosuppressives, principally corticosteroids, are the primary triggering factor. In general, the clinical features of Strongyloides stercoralis hyperinfection are nonspecific; therefore, a high index of suspicion is required for early diagnosis and starting appropriate therapy. Although recurrent Gram-negative sepsis and meningitis have been previously reported, the combination of both cytomegalovirus (CMV) and strongyloidiasis had rarely been associated. We here describe a patient who survived SHS with recurrent Escherichia coli (E. coli) urosepsis and CMV infection. PMID:27703835

  11. [Morphological fibroblastic changes in cytomegalovirus infection].

    PubMed

    Parkhomenko, Iu V; Solnyshkova, T G; Tishkivich, O A; Shakhgil'dian, V I; Nikonova, E A

    2006-01-01

    Cytomegalovirus (CMV) infection is widely spread among population. While immunocompetent patients suffer rarely from this virus, it can lead to a lethal outcome in immunocompromised patients. An electron microscopic study has detected fibroblastic morphological changes of a definite cytodestructive character. The nuclei of some fibroblasts have chromatine condensation. A clear zone arising due to vacuolization near this inclusion may reflect nuclear rearrangement leading to further CMV metamorphosis of the cell. This metamorphosis is characteristic of the changes developing in the cells of different parenchymatous organs.

  12. [Ulcerative colitis and cytomegalovirus infection].

    PubMed

    Tárraga Rodríguez, I; Ferreras Fernández, P; Vicente Gutiérrez, M; de Arriba, J J; García Mouriño, M L

    2003-02-01

    Colitis ulcerous and citomegalovirus infection association have been reported in medical literature in sometimes, althougth this prevalence have lately increased. We report a case record of this association and do a review of this subject. It is not clear what factors are involved in this association, being necessary hore studies to know them.

  13. Cytomegalovirus infection: the state of the art.

    PubMed

    Mosca, F; Pugni, L

    2007-10-01

    Cytomegalovirus (CMV) is the leading cause of congenital infection in humans and constitutes a major public health problem. Congenitally infected infants, both symptomatic and asymptomatic at birth, may develop sequelae, particularly sensorineural hearing loss (SNHL) and brain damage. Transmission of the virus from mother to fetus can occur during either primary or recurrent maternal infection; however it is much higher in primary infected mothers than in mothers with preconceptional immunity. Routine CMV screening for primary infection during pregnancy constitutes a controversial issue, because of the lack of prenatal recommended therapy for congenital CMV infection. Ganciclovir may be used to treat neonates with symptoms at birth. Despite advances in antiviral therapy, congenitally infected infants, both symptomatic and asymptomatic at birth, need a follow up evaluation to detect sequelae. Congenital CMV infection cna be diagnosed at birth by using a test based on detection of viral DNA by PCR in dried blood spots (Guthrie card) collected on filter paper in the first days of life. Therefore, universal newborn screening for CMV by using DBS test should be recommended to detect sequelae as early as possible, so that infants can receive intervention promptly.

  14. PCR detection of cytomegalovirus DNA in serum as a diagnostic test for congenital cytomegalovirus infection.

    PubMed Central

    Nelson, C T; Istas, A S; Wilkerson, M K; Demmler, G J

    1995-01-01

    PCR detected cytomegalovirus (CMV) DNA in the serum of 18 of 18 infants with symptomatic congenital CMV infection, 1 of 2 infants with asymptomatic congenital CMV infection, and 0 of 32 controls. Serum CMV PCR provided a rapid, sensitive, and specific method for diagnosis of congenital CMV infection in infants who were symptomatic at birth. PMID:8586726

  15. Cytomegalovirus infection improves immune responses to influenza

    PubMed Central

    Furman, David; Jojic, Vladimir; Sharma, Shalini; Shen-Orr, Shai; Angel, Cesar J Lopez; Onengut-Gumuscu, Suna; Kidd, Brian; Maecker, Holden T; Concannon, Patrick; Dekker, Cornelia L; Thomas, Paul G; Davis, Mark M

    2015-01-01

    Cytomegalovirus (CMV) is a beta-herpes virus present in a latent form in most people worldwide. In immunosuppressed individuals, CMV can reactivate and cause serious clinical complications, but the effect of the latent state on healthy people remains elusive. We undertook a systems approach to understand the differences between seropositive and negative subjects and measured hundreds of immune system components from blood samples including cytokines and chemokines, immune cell phenotyping, gene expression, ex vivo cell responses to cytokine stimuli and the antibody response to seasonal influenza vaccination. As expected, we found decreased responses to vaccination and an overall down-regulation of immune components in aged individuals regardless of CMV serostatus. In contrast, CMV-infected young adults exhibited an overall up-regulation of immune components including enhanced antibody responses to influenza vaccination, increased CD8+ T cell sensitivity, and elevated levels of circulating IFN-γ compared to uninfected individuals. Experiments with young mice infected with murine CMV also showed significant protection from an influenza virus challenge compared with uninfected animals, although this effect declined with time. These data show that CMV and its murine equivalent can have a beneficial effect on the immune response of young, healthy individuals, which may explain the continued coexistence of CMV and mammals throughout their evolution. PMID:25834109

  16. Bone-marrow-derived mesenchymal stem cells as a target for cytomegalovirus infection: Implications for hematopoiesis, self-renewal and differentiation potential

    SciTech Connect

    Smirnov, Sergey V.; Harbacheuski, Ryhor; Lewis-Antes, Anita; Zhu Hua; Rameshwar, Pranela; Kotenko, Sergei V. . E-mail: kotenkse@umdnj.edu

    2007-03-30

    Mesenchymal stem cells (MSCs) in bone marrow (BM) regulate the differentiation and proliferation of adjacent hematopoietic precursor cells and contribute to the regeneration of mesenchymal tissues, including bone, cartilage, fat and connective tissue. BM is an important site for the pathogenesis of human cytomegalovirus (HCMV) where the virus establishes latency in hematopoietic progenitors and can transmit after reactivation to neighboring cells. Here we demonstrate that BM-MSCs are permissive to productive HCMV infection, and that HCMV alters the function of MSCs: (i) by changing the repertoire of cell surface molecules in BM-MSCs, HCMV modifies the pattern of interaction between BM-MSCs and hematopoietic cells; (ii) HCMV infection of BM-MSCs undergoing adipogenic or osteogenic differentiation impaired the process of differentiation. Our results suggest that by altering BM-MSC biology, HCMV may contribute to the development of various diseases.

  17. Transient antiphospholipid syndrome associated with primary cytomegalovirus infection: a case report and literature review.

    PubMed

    Nakayama, Tsuyoshi; Akahoshi, Mitsuteru; Irino, Kensuke; Kimoto, Yasutaka; Arinobu, Yojiro; Niiro, Hiroaki; Tsukamoto, Hiroshi; Horiuchi, Takahiko; Akashi, Koichi

    2014-01-01

    Viral infection is known to induce transient autoimmunity in humans. Acute cytomegalovirus (CMV) infection is implicated in occasional thrombosis formation. We here, for the first time, report a 19-year-old female who had an acute CMV infection, leading to a deep venous thrombosis and a pulmonary embolism along with transient appearance of lupus anticoagulant. The pathological role of antiphospholipid antibodies in CMV-mediated thrombosis is discussed.

  18. Brief Report: Autistic Disorder in Three Children with Cytomegalovirus Infection

    ERIC Educational Resources Information Center

    Sweeten, Thayne L.; Posey, David J.; McDougle, Christopher J.

    2004-01-01

    Previous research has identified a relationship between autistic disorder (autism) and specific congenital infections. Three cases of congenital or perinatal cytomegalovirus (CMV) infection occurring in association with autism are described. Hypothetical mechanisms relating congenital infection, such as CMV, to the development of autism are…

  19. Prognostic markers of symptomatic congenital cytomegalovirus infection.

    PubMed

    Romanelli, Roberta Maia de Castro; Magny, Jean François; Jacquemard, François

    2008-02-01

    The objective of this research was to identify maternal and fetal characteristics as prognostic markers of congenital cytomegalovirus (CMV) infection. This is a descriptive study of 13 cases of congenital CMV infection referred to Institute de Puericulture et Perinatologie de Paris (IPP) from January 2005 to October 2006. Amniotic fluid puncture was performed to research CMV polimerase chain reaction (PCR). Cordocentesis and cord blood samples at delivery were also analyzed to determinate fetal platelets count, GGT, ASAT, ALAT, CMV-DNA and IgM antibody. Variables of symptomatic and asymptomatic infants were then compared. Data were analyzed by SPSS--15.0. Mean gestational age of amniocentesis was 24.6 weeks and there was no difference of mean viral load in amniotic fluid considering infant features. Mean gestational age of cordocentesis was 26.1 weeks. There were no statistical differences of fetal viral load, IgM, platelets, GGT, ASAT and ALAT analyzed at cordocentesis samples, but at delivery, mean values of IgM and ASAT of fetal blood were increased in symptomatic ones (p= 0.03 for both parameters). When considering groups with normal and abnormal parameters, ASAT of cordon samples was also increased in symptomatic infants (p= 0.02). Sensibility, specificity, positive and negative predictive value of fetal ultrasound anomalies to detect symptomatic infants were, respectively, 80%, 62.5%, 57.1% and 83.3%. Thus, identification of markers of CMV symptomatic infants should be aimed. Prenatal diagnosis, identification and follow up of congenital CMV infected infants are important to consider treatment for symptomatic infants, trying to avoid or reducing some possible sequels.

  20. Prevention of Primary Cytomegalovirus Infection in Pregnancy☆

    PubMed Central

    Revello, Maria Grazia; Tibaldi, Cecilia; Masuelli, Giulia; Frisina, Valentina; Sacchi, Alessandra; Furione, Milena; Arossa, Alessia; Spinillo, Arsenio; Klersy, Catherine; Ceccarelli, Manuela; Gerna, Giuseppe; Todros, Tullia

    2015-01-01

    Background Cytomegalovirus (CMV) is the leading infectious agent causing congenital sensorineural hearing loss and psychomotor retardation. CMV vaccine is currently unavailable and treatment options in pregnancy are limited. Susceptible pregnant women caring for children are at high risk for primary infection. CMV educational and hygienic measures have the potential to prevent primary maternal infection. Methods A mixed interventional and observational controlled study was conducted to investigate the effectiveness of hygiene information among pregnant women at risk for primary CMV infection for personal/occupational reasons. In the intervention arm, CMV-seronegative women, identified at the time of maternal serum screening for fetal aneuploidy at 11–12 weeks of gestation, were given hygiene information and prospectively tested for CMV until delivery. The comparison arm consisted of women enrolled at delivery who were neither tested for nor informed about CMV during pregnancy, and who had a serum sample stored at the screening for fetal aneuploidy. By design, groups were homogeneous for age, parity, education, and exposure to at least one risk factor. The primary outcome was CMV seroconversion. Acceptance of hygiene recommendations was a secondary objective and was measured by a self-report. Findings Four out of 331 (1.2%) women seroconverted in the intervention group compared to 24/315 (7.6%) in the comparison group (delta = 6.4%; 95% CI 3.2–9.6; P < 0.001). There were 3 newborns with congenital infection in the intervention group and 8 in the comparison group (1 with cerebral ultrasound abnormalities at birth). Ninety-three percent of women felt hygiene recommendations were worth suggesting to all pregnant women at risk for infection. Interpretation This controlled study provides evidence that an intervention based on the identification and hygiene counseling of CMV-seronegative pregnant women significantly prevents maternal infection. While waiting for

  1. Autism in a Child with Congenital Cytomegalovirus Infection.

    ERIC Educational Resources Information Center

    Markowitz, Phillip I.

    1983-01-01

    A case study is described in which early infantile autism was diagnosed in a child with congenital cytomegalovirus (CMU) infection. It is suggested that congenital infection should be considered as an etiological agent in autism. The case's synergistic effect of CMU-induced brain damage, deafness, and maternal deprivation in noted. (CL)

  2. Severe acquired cytomegalovirus infection in a full-term, formula-fed infant: Case Report

    PubMed Central

    2011-01-01

    Background Cases of cytomegalovirus colitis are exceptionally reported in immuno-competent infant. The pathogenesis is uncertain but breast-feeding is considered as a main source of postnatal infection. Case Presentation Here we report a full-term, formula-fed infant who developed a severe cytomegalovirus anaemia and colitis when aged 2 months. Conclusion Even if the molecular identity between the cytomegalovirus-isolate of the infant and the maternal virus could not be demonstrated, we confirmed through laboratory investigation that cytomegalovirus infection was acquired postnatally. However, the source of cytomegalovirus infection remained unclear. Alternative modes of cytomegalovirus transmission are discussed. PMID:21645352

  3. Absence of human cytomegalovirus infection in childhood brain tumors

    PubMed Central

    Sardi, Iacopo; Lucchesi, Maurizio; Becciani, Sabrina; Facchini, Ludovica; Guidi, Milena; Buccoliero, Anna Maria; Moriondo, Maria; Baroni, Gianna; Stival, Alessia; Farina, Silvia; Genitori, Lorenzo; de Martino, Maurizio

    2015-01-01

    Human cytomegalovirus (HCMV) is a common human pathogen which induces different clinical manifestations related to the age and the immune conditions of the host. HCMV infection seems to be involved in the pathogenesis of adult glioblastomas. The aim of our study was to detect the presence of HCMV in high grade gliomas and other pediatric brain tumors. This hypothesis might have important therapeutic implications, offering a new target for adjuvant therapies. Among 106 pediatric patients affected by CNS tumors we selected 27 patients with a positive HCMV serology. The serological analysis revealed 7 patients with positive HCMV IGG (≥14 U/mL), whom had also a high HCMV IgG avidity, suggesting a more than 6 months-dated infection. Furthermore, HCMV IGM were positive (≥22 U/mL) in 20 patients. Molecular and immunohistochemical analyses were performed in all the 27 samples. Despite a positive HCMV serology, confirmed by ELISA, no viral DNA was shown at the PCR analysis in the patients’ neoplastic cells. At immunohistochemistry, no expression of HCMV antigens was observed in tumoral cells. Our results are in agreement with recent results in adults which did not evidence the presence of HCMV genome in glioblastoma lesions. We did not find any correlation between HCMV infection and pediatric CNS tumors. PMID:26396923

  4. Cytomegalovirus (CMV) Infection: A Guide for Patients and Families After Stem Cell Transplant

    MedlinePlus

    ... Infection: A Guide for Patients and Families after Stem Cell Transplant What is cytomegalovirus (CMV)? Cytomegalovirus (CMV), a ... weakened by medicines that you must take after stem cell transplant and by the transplant itself. Your body ...

  5. Infantile Spasms and Cytomegalovirus Infection: Antiviral and Antiepileptic Treatment

    ERIC Educational Resources Information Center

    Dunin-Wasowicz, Dorota; Kasprzyk-Obara, Jolanta; Jurkiewicz, Elzbieta; Kapusta, Monika; Milewska-Bobula, Bogumila

    2007-01-01

    From 1 January 1995 to 31 December 2004, 22 patients (13 males, nine females; age range 2-12mo) with infantile spasms and cytomegalovirus (CMV) infection were treated with intravenous ganciclovir (GCV) and antiepileptic drugs. GCV was given for 3 to 12 weeks with a 1-month interval (one, two, or three courses). Epileptic spasms occurred before…

  6. Cross-Species Rhesus Cytomegalovirus Infection of Cynomolgus Macaques

    PubMed Central

    Bimber, Benjamin N.; Reed, Jason S.; Uebelhoer, Luke S.; Bhusari, Amruta; Hammond, Katherine B.; Klug, Alex; Legasse, Alfred W.; Axthelm, Michael K.; Nelson, Jay A.; Streblow, Daniel N.; Picker, Louis J.; Früh, Klaus; Sacha, Jonah B.

    2016-01-01

    Cytomegaloviruses (CMV) are highly species-specific due to millennia of co-evolution and adaptation to their host, with no successful experimental cross-species infection in primates reported to date. Accordingly, full genome phylogenetic analysis of multiple new CMV field isolates derived from two closely related nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM), revealed distinct and tight lineage clustering according to the species of origin, with MCM CMV isolates mirroring the limited genetic diversity of their primate host that underwent a population bottleneck 400 years ago. Despite the ability of Rhesus CMV (RhCMV) laboratory strain 68–1 to replicate efficiently in MCM fibroblasts and potently inhibit antigen presentation to MCM T cells in vitro, RhCMV 68–1 failed to productively infect MCM in vivo, even in the absence of host CD8+ T and NK cells. In contrast, RhCMV clone 68–1.2, genetically repaired to express the homologues of the HCMV anti-apoptosis gene UL36 and epithelial cell tropism genes UL128 and UL130 absent in 68–1, efficiently infected MCM as evidenced by the induction of transgene-specific T cells and virus shedding. Recombinant variants of RhCMV 68–1 and 68–1.2 revealed that expression of either UL36 or UL128 together with UL130 enabled productive MCM infection, indicating that multiple layers of cross-species restriction operate even between closely related hosts. Cumulatively, these results implicate cell tropism and evasion of apoptosis as critical determinants of CMV transmission across primate species barriers, and extend the macaque model of human CMV infection and immunology to MCM, a nonhuman primate species with uniquely simplified host immunogenetics. PMID:27829026

  7. Guillain-Barré syndrome and cytomegalovirus infection during pregnancy.

    PubMed

    Lupo, Julien; Germi, Raphaële; Jean, Dominique; Baccard-Longère, Monique; Casez, Olivier; Besson, Gérard; Rougé, Alain; Boutonnat, Jean; Schwebel, Carole; Hoffmann, Pascale; Morand, Patrice

    2016-06-01

    Guillain-Barré syndrome (GBS) is an immune-mediated disorder which can be triggered by cytomegalovirus (CMV) infection. GBS following CMV primary infection is a rare event during pregnancy, which raises the question of maternal and fetal management. We describe an unusual case of GBS after CMV primary infection in a pregnant woman. The mother was successfully treated with standard immunoglobulins but in utero fetal death caused by CMV congenital infection unfortunately occurred. Similar cases have rarely been reported in the literature.

  8. Cytomegalovirus Infection After Intestinal Transplantation in Children

    PubMed Central

    Bueno, Javier; Green, Michael; Kocoshis, Samuel; Furukawa, Hiroyuki; Ahu-Elmagd, Kareem; Yunis, Eduardo; Irish, William; Todo, Satoru; Reyes, Jorge; Starzl, Thomas E.

    2010-01-01

    Sixteen episodes of cytomegalovirus (CMV) disease occurred in 10 of 41 children undergoing intestinal transplantation from 1990 to 1995. Stratification of CMV disease by donor (D)/recipient (R) serological status was as follows: 3 of 8, D+/R−; 3 of 9, D+/R+; 4 of 9, D−/R+; and 0 of 15, D−/R−. Treatment resulted in resolution of CMV disease in 93.3% of episodes. No deaths attributable to CMV disease occurred in this series. CMV in D+/R− children resulted in more extensive and persistent disease. However, patient and graft survival rates were similar in the different D/R subgroups and between children with and without CMV disease. Cumulative dose of steroid boluses (relative risk [RR]. 1.59; 95% confidence interval [CI]. 1.14–2.21) and history of steroid recycles (RR, 2.72; 95% CI, 1.21–6.13) were associated with CMV disease. These results suggest that although CMV-associated morbidity in pediatric intestinal transplant recipients was substantial, it was not associated with an increased rate of mortality or graft loss, even among high-risk D+/R− patients. PMID:9402361

  9. [Ménétrieŕs disease associated with cytomegalovirus infection].

    PubMed

    Fernández Caamaño, B; Ramos Boluda, E; Martínez-Ojinaga Nodal, E; Molina Arias, M; Sarría Osés, J; Prieto Bozano, G

    2015-01-01

    Menetrier's disease is a rare entity in children, characterized by a protein-losing gastroenteropathy with thickening of the gastric mucosa and generalized edema. The most common etiology is viral, and cytomegalovirus is the agent most frequently implicated. Unlike in the adult, it is a self-limited disorder with a good prognosis in children. Four patients (three boys and one girl) diagnosed with Ménétrier disease in the past five years were reviewed. The mean age at presentation was 28.7 months (range: 10-48 months). The most common clinical symptoms were fever, vomiting, and edema. Endoscopy showed thickened gastric folds and erosions in several stages. All patients had an associated gastric cytomegalovirus infection, and a favorable outcome, with resolution of the disorder,was observed within a few weeks.

  10. Development of subunit preparations of cytomegalovirus antigen by aqueous extraction for immunization against cytomegalovirus infection.

    PubMed

    Billstrom, M A; Davies, J A; Buchan, A; Skinner, G R

    1993-01-01

    This study has examined different methods of preparation of a subunit vaccine from cytomegalovirus (CMV)-infected MRC cells in terms of protein and DNA content, antigenicity and immunogenicity. Two preparations have been developed where CMV proteins were obtained by extraction of infected cells with water. Virus particles were removed from the preparations by ultracentrifugation and residual virus was inactivated by formaldehyde in the WUF preparations or by chloroform in the WUCh preparations. The preparations contained CMV proteins which may play a role in protective immune responses, and the preparations were antigenic as determined by immunodiffusion, ELISA and immunoblotting. Immunogenicity as evaluated in rabbits indicated that the preparations stimulated neutralizing and immunoprecipitating antibody. These results suggest that the gentle method of water extraction of viral antigens may be a useful protocol for vaccine preparation.

  11. Cutaneous involvement by cytomegalovirus in a renal transplant recipient as an indicator of severe systemic infection*

    PubMed Central

    Neumann, Antonielle Borges Faria; Daxbacher, Egon Luiz Rodrigues; Chiaratti, Francielle Chiavelli; Jeunon, Thiago

    2016-01-01

    Cytomegalovirus is an opportunistic virus that commonly affects immunosuppressed patients. Cutaneous involvement by this virus is rare and occurs in significantly immunocompromised hosts, with a poor prognosis. Skin ulcers may represent the first sign of systemic infection by cytomegalovirus in these patients. Herein, a case of a systemic infection by Cytomegalovirus presenting as genital and oral ulcers in a kidney-transplant recipient is reported. PMID:26982783

  12. Acquired chemotactic inhibitors during infection with guinea pig cytomegalovirus.

    PubMed Central

    Tannous, R; Myers, M G

    1983-01-01

    Factors involved in neutrophil and monocyte migrations were serially studied in strain 2 guinea pigs undergoing initial cytomegalovirus infection and sham-inoculated controls. All studies remained unchanged in uninfected animals. Monocyte migrations and neutrophil spontaneous migration remained unchanged in infected animals. However, transient abnormalities occurred early in infection, comprising a decrease in neutrophil-directed migration towards C5-derived chemotactic fractions (C5-fr) and a decrease in the chemotactic activity of zymosan-activated plasma. Consequently, the presence of neutrophil- and chemotaxin-directed inhibitors in plasma was investigated. Normal neutrophils, C5-fr, Escherichia coli-derived bacterial factor, and the synthetic peptide F-met-leu-phe were first incubated with control or infected plasmas and then assayed for directed migration and lysosomal enzyme release. Results indicated the de novo appearance of both neutrophil- and chemotaxin-directed inhibitory activities in plasma during early infection. The neutrophil-directed inhibition was heat stable (56 degrees C for 120 min) and nonspecific (responses to all chemotaxins were inhibited). The chemotaxin-directed inhibition was heat stable and C5-fr specific. The cytomegalovirus-induced inhibitors may be important in the enhanced susceptibility to concurrent opportunistic infections. PMID:6305847

  13. Alopecia in mice infected with murine cytomegalovirus (MCMV).

    PubMed Central

    Mims, C. A.

    1985-01-01

    When mouse cytomegalovirus was injected subcutaneously into 4-12 day old CDI mice there was infection of dermal cells and the dermal papillae of hair follicles. Infected cells were never seen in the epidermis nor in the epithelium of hair follicles. When larger doses of virus (5 X 10(4) pfu) were given, dermal infection led to gross necrosis of the skin, ulceration, scabbing and healing with alopecia. Smaller doses (10(4) pfu) did not cause gross necrosis but damage to follicles resulted in alopecia or sparse hair growth. Skin lesions were not seen after infection of 4-8 week old mice, even when the inoculated skin area had been epilated, or when hyaluronidase was mixed with the virus inoculum. These experiments show that cytomegalovirus, in contrast to herpes simplex and varicella-zoster viruses, infects dermal but not epidermal cells, and that dermal tropism is age-restricted. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:3002414

  14. Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries

    PubMed Central

    Weekes, M. P.; Antrobus, R.; Rorbach, J.; van Haute, L.; Umrania, Y.; Smith, D. L.; Minczuk, M.; Lehner, P. J.; Sinclair, J. H.

    2016-01-01

    ABSTRACT Infection with human cytomegalovirus (HCMV) profoundly affects cellular metabolism. Like in tumor cells, HCMV infection increases glycolysis, and glucose carbon is shifted from the mitochondrial tricarboxylic acid cycle to the biosynthesis of fatty acids. However, unlike in many tumor cells, where aerobic glycolysis is accompanied by suppression of mitochondrial oxidative phosphorylation, HCMV induces mitochondrial biogenesis and respiration. Here, we affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We found that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth under bioenergetically restricting conditions. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication. PMID:27025248

  15. Growth in Agarose of Human Cells Infected with Cytomegalovirus

    PubMed Central

    Lang, David J.; Montagnier, Luc; Latarjet, Raymond

    1974-01-01

    After infection by human cytomegalovirus (CMV), human diploid fibroblasts could grow in agarose medium for several generations. Clones of infected cells grew for weeks, although in every case they ultimately underwent lysis owing to the cytopathic effect of the virus. Virus was inoculated at high dilution and after UV irradiation in an effort to derive cells infected with noninfectious defective particles still capable of inducing cell stimulation. Dilute or irradiated virus occasionally yielded large colonies of replicating cells, although permanent transformation was not observed. One clone derived from UV-CMV-infected cells was passaged four times before undergoing lysis. During these passages the cells exhibited alterations in morphology and orientation. Images PMID:4367907

  16. Active cytomegalovirus infection in patients with atopic dermatitis.

    PubMed

    Hafez, Shereen F; Shehata, Iman H; Abdel Aziz, Ghada A; Kamal, Mahmoud M

    2005-01-01

    Atopic dermatitis (AD) is a complex immunologic skin disorder that is expressed when genetically predisposed individuals are exposed to certain environmental stimuli. Inspite of the high prevalence of cytomegalovirus (CMV) infection and its potent immunomodulatory activities, the relation of CMV to AD is still poorly understood and is still to be clarified. The aim of the present study was to evaluate the frequency of active CMV infection in patients with AD and its possible etiologic role in the pathogenesis of the disease. Also, we tried to find if a relation between active CMV infection and disease severity exists. The present study was carried on 31 patients with AD with various degrees of disease severity. Ten apparently healthy subjects were enrolled in the study as a control group. Anti CMV IgG antibodies were estimated by quantitative enzyme immunoassay to discriminate between recent CMV infection and CMV reactivation. Active CMV infection was diagnosed by using nested PCR to detect CMV DNA in the sera of the studied subjects. The detection rate of CMV genome was higher in patients with AD in comparison to the control group. Cytomegalovirus genome was detected in the sera of 52% (16/31) of patients with AD (87.5% of them were seropositive for anti-CMV IgG antibodies). On the other hand no CMV DNA was detected in any of the serum samples of the control subjects. The difference was statistically significant. No significant relation was found between active CMV infection and disease severity. Also, no significant statistical difference was found between the two studied groups as regards the prevalence of latent CMV infection. In addition, no significant difference was detected between anti-CMV IgG antibody levels in all seropositive subjects. Our results denote that active subclinical CMV infection is more frequent in patients with AD and may have possible immunomodulatory role in the etiopathogenesis of AD but it is not related to disease severity.

  17. Human Cytomegalovirus: detection of congenital and perinatal infection in Argentina

    PubMed Central

    Distéfano, Angélica Lidia; Alonso, Alicia; Martin, Fabián; Pardon, Fabián

    2004-01-01

    Background Human cytomegalovirus (CMV) is one of the most commonly found agents of congenital infections. Primary maternal infection is associated with risk of symptomatic congenital diseases, and high morbidity is frequently associated with very low birth weight. Neonates with asymptomatic infection develop various sequelae during infancy. This is the first Argentine study performed in neonates with congenital and postnatal HCMV infection. The purpose of this study was to evaluate the performance of the polymerase chain reaction (PCR) technique with different pairs of primers, to detect cytomegalovirus isolated in tissue cultures and directly in urine and dried blood spot (DBS) specimens. Results were compared with IgM detection. Methods The study was performed between 1999 and 2001 on routine samples in the Laboratory. A total of 61 urine and 56 serum samples were selected from 61 newborns/infants, 33 patients whose samples were analyzed during the first two to three weeks of life were considered congenital infections; the remaining 28 patients whose samples were taken later than the third week were grouped as perinatal infections, although only in 4 the perinatal transmission of infection was determined unequivocally Cytomegalovirus diagnosis was made by isolating the virus from urine samples in human foreskin fibroblast cells. Three different primer pairs directed to IE, LA and gB genes were used for the HCMV PCR assay in viral isolates. Subsequently, PCR and nested PCR (nPCR) assays with gB primers were performed directly in urine and in 11 samples of dried blood spot (DBS) on Guthrie Card, these results were then compared with serology. Results The main clinical manifestations of the 33 patients with congenital infection were purpura, jaundice, hepatomegaly and anaemia. Three patients presented low birth weight as single symptom, 10, intracranial calcifications, and 2, kidney failure. In the 28 patients grouped as with perinatal infection, anaemia

  18. Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection

    PubMed Central

    Tu, Wenjuan; Rao, Sudha

    2016-01-01

    The ability of the human immune system to protect against infectious disease declines with age and efficacy of vaccination reduces significantly in the elderly. Aging of the immune system, also termed as immunosenescence, involves many changes in human T cell immunity that is characterized by a loss in naïve T cell population and an increase in highly differentiated CD28- memory T cell subset. There is extensive data showing that latent persistent human cytomegalovirus (HCMV) infection is also associated with age-related immune dysfunction in the T cells, which might enhance immunosenescence. Understanding the molecular mechanisms underlying age-related and HCMV-related immunosenescence is critical for the development of effective age-targeted vaccines and immunotherapies. In this review, we will address the role of both aging and HCMV infection that contribute to the T cell senescence and discuss the potential molecular mechanisms in aged T cells. PMID:28082969

  19. Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection.

    PubMed

    Fodil-Cornu, N; Kozij, N; Wu, Q; Rozen, R; Vidal, S M

    2009-10-01

    Folates provide one-carbon units for nucleotide synthesis and methylation reactions. A common polymorphism in the MTHFR gene (677C --> T) results in reduced enzymatic activity, and is associated with an increased risk for neural tube defects and cardiovascular disease. The high prevalence of this polymorphism suggests that it may have experienced a selective advantage under environmental pressure, possibly an infectious agent. To test the hypothesis that methylenetetrahydrofolate reductase (MTHFR) genotype influences the outcome of infectious disease, we examined the response of Mthfr-deficient mice against mouse cytomegalovirus (MCMV) infection. Acute MCMV infection of Mthfr(-/-) mice resulted in early control of cytokine secretion, decreased viral titer and preservation of spleen immune cells, in contrast to Mthfr wild-type littermates. The phenotype was abolished in MTHFR transgenic mice carrying an extra copy of the gene. Infection of primary fibroblasts with MCMV showed a decrease in viral replication and in the number of productively infected cells in Mthfr(+/-) fibroblasts compared with wild-type cells. These results indicate that Mthfr deficiency protects against MCMV infection in vivo and in vitro, suggesting that human genetic variants may provide an advantage in the host response against certain pathogens.

  20. Hepatic involvement in congenital cytomegalovirus infection - infrequent yet significant.

    PubMed

    Bilavsky, E; Schwarz, M; Bar-Sever, Z; Pardo, J; Amir, J

    2015-09-01

    Congenital cytomegalovirus (cCMV) infection can reside in many organ systems; however, the virus has a particular predilection towards inhabiting the reticuloendothelial system, especially the liver. Specific studies focusing only on hepatic involvement in infants with cCMV are lacking. We report our experience with a large cohort of infants treated in our hospital clinic due to cCMV and hepatic involvement. Hepatic involvement was defined either as hepatitis (elevated alanine transaminases (ALT) >80 units/L without cholestatic disease) or cholestatic disease (elevated ALT >80 units/L combined with direct bilirubin >2 mg/dL). During the study period, 198 infants were diagnosed with symptomatic cCMV in our clinic. Hepatic involvement was observed in 13 infants (6.6%); 7 (3.5%) with hepatitis and 6 (3%) with cholestatic disease. Maternal primary infection with cytomegalovirus during pregnancy was diagnosed in 7 (53.8%) of the 13 infants, nonprimary in 3 (23.1%) and unknown in 3 (23.1%). Among these 13 infants, central nervous system (CNS) involvement was observed in 11 (84.6%) and hearing impairment in 7 (53.8%). Treatment with an antiviral agent was initiated in all cases. Gradual improvement of hepatic enzymes and cholestasis was observed over a prolonged period. We found that the incidence of hepatic involvement in infants with cCMV is much less frequent than previously reported. The hepatic involvement in these infants may manifest in two different ways, and thus, a high index of suspicion and a stepwise approach will help in correctly diagnosing these infants. Antiviral treatment due to CNS involvement is warranted and prognosis is excellent.

  1. Human fetal inner ear involvement in congenital cytomegalovirus infection

    PubMed Central

    2013-01-01

    Background Congenital cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL). The mechanisms of pathogenesis of CMV-related SNHL are still unclear. The aim is to study congenital CMV-related damage in the fetal inner ear, in order to better understand the underlying pathophysiology behind CMV-SNHL. Results We studied inner ears and brains of 20 human fetuses, all at 21 week gestational age, with a high viral load in the amniotic fluid, with and without ultrasound (US) brain abnormalities. We evaluated histological brain damage, inner ear infection, local inflammatory response and tissue viral load. Immunohistochemistry revealed that CMV was positive in 14/20 brains (70%) and in the inner ears of 9/20 fetuses (45%). In the cases with inner ear infection, the marginal cell layer of the stria vascularis was always infected, followed by infection in the Reissner’s membrane. The highest tissue viral load was observed in the inner ear with infected Organ of Corti. Vestibular labyrinth showed CMV infection of sensory cells in the utricle and in the crista ampullaris. US cerebral anomalies were detected in 6 cases, and in all those cases, the inner ear was always involved. In the other 14 cases with normal brain scan, histological brain damage was present in 8 fetuses and 3 of them presented inner ear infection. Conclusions CMV-infection of the marginal cell layer of the stria vascularis may alter potassium and ion circulation, dissipating the endocochlear potential with consequent SNHL. Although abnormal cerebral US is highly predictive of brain and inner ear damage, normal US findings cannot exclude them either. PMID:24252374

  2. Coexisting cytomegalovirus infection in immunocompetent patients with Clostridium difficile colitis.

    PubMed

    Chan, Khee-Siang; Lee, Wen-Ying; Yu, Wen-Liang

    2016-12-01

    Cytomegalovirus (CMV) colitis usually occurs in immunocompromised patients with human immunodeficiency virus infection, organ transplantation, and malignancy receiving chemotherapy or ulcerative colitis receiving immunosuppressive agents. However, CMV colitis is increasingly recognized in immunocompetent hosts. Notably, CMV colitis coexisting with Clostridium difficile infection (CDI) in apparently healthy individuals has been published in recent years, which could result in high morbidity and mortality. CMV colitis is a rare but possible differential diagnosis in immunocompetent patients with abdominal pain, watery, or especially bloody diarrhea, which could be refractory to standard treatment for CDI. As a characteristic of CDI, however, pseudomembranous colitis may be only caused by CMV infection. Real-time CMV-polymerase chain reaction (PCR) for blood and stool samples may be a useful and noninvasive diagnostic strategy to identify CMV infection when treatment of CDI eventually fails to show significant benefits. Quantitative CMV-PCR in mucosal biopsies may increase the diagnostic yield of traditional histopathology. CMV colitis is potentially life-threatening if severe complications occur, such as sepsis secondary to colitis, massive colorectal bleeding, toxic megacolon, and colonic perforation, so that may necessitate pre-emptive antiviral treatment for those who are positive for CMV-PCR in blood and/or stool samples while pending histological diagnosis.

  3. Disseminated Cytomegalovirus Infection and Protein Losing Enteropathy as Presenting Feature of Pediatric Patient with Crohn's Disease

    PubMed Central

    Ersoz, Safak; Akbulut, Ulas Emre

    2015-01-01

    We report a pediatric patient admitted with abdominal pain, diffuse lower extremity edema and watery diarrhea for two months. Laboratory findings including complete blood count, serum albumin, lipid and immunoglobulin levels were compatible with protein losing enteropathy. Colonoscopic examination revealed diffuse ulcers with smooth raised edge (like "punched out holes") in the colon and terminal ileum. Histopathological examination showed active colitis, ulcerations and inclusion bodies. Immunostaining for cytomegalovirus was positive. Despite supportive management, antiviral therapy, the clinical condition of the patient worsened and developed disseminated cytomegalovirus infection and the patient died. Protein losing enteropathy and disseminated cytomegalovirus infection a presenting of feature in steroid-naive patient with inflammatory bowel disease is very rare. Hypogammaglobulinemia associated with protein losing enteropathy in Crohn's disease may predispose the cytomegalovirus infection in previously healthy children. PMID:25866735

  4. Non-cytomegalovirus ocular opportunistic infections in patients with AIDS

    PubMed Central

    Gangaputra, Sapna; Drye, Lea; Vaidya, Vijay; Thorne, Jennifer E.; Jabs, Douglas A; Lyon, Alice T.

    2014-01-01

    Purpose To report the incidence and clinical outcomes of non-cytomegalovirus (non-CMV) ocular opportunistic infections in patients with AIDS in the era of highly active antiretroviral therapy (HAART). Design Multicenter, prospective, observational study of patients with AIDS Methods Medical history, ophthalmologic examination, and laboratory tests were performed at enrollment and every 6 months subsequently. Once an ocular opportunistic infection was diagnosed, patients were seen every 3 months for outcomes. Results At enrollment, 37 non-CMV ocular opportunistic infections were diagnosed: 16 patients, herpetic retinitis; 11 patients, toxoplasmic retinitis; and 10 patients, choroiditis. During the follow-up period, the estimated incidences (and 95% confidence intervals [CI]) of these were: herpetic retinitis, 0.007/100 person-years (PY) (95% CI 0.0004, 0.039); toxoplasmic retinitis, 0.007/100 PY (95% CI 0.004, 0.039); and choroiditis 0.014/100 PY (95% CI 0.0025, 0.050). The mortality rates appeared higher among those patients with newly diagnosed or incident herpetic retinitis and choroiditis (rates=21.7 deaths/100 PY [P=0.02] and 12.8 deaths/100 PY [P=0.04]) respectively, than that for patients with AIDS without an ocular opportunistic infection (4.1 deaths/100 PY); Toxoplasmic retinitis did not appear to be associated with greater mortality (6.4/100 PY, P=0.47). Eyes with newly-diagnosed herpetic retinitis appeared to have a poor visual prognosis with high rates of visual impairment (37.9/100 PY) and blindness (17.5/100 PY), whereas those outcomes in eyes with choroiditis appeared to be lower (2.3/100 PY and 0/100 PY, respectively). Conclusions Although uncommon, non-CMV ocular opportunistic infections may be associated with high rates of visual loss and/or mortality. PMID:23068916

  5. [Giant gastric ulcer by cytomegalovirus in infection VIH/SIDA].

    PubMed

    Pérez-Pereyra, Julia; Morales, Domingo; Díaz, Ramiro; Yoza, Max; Frisancho, Oscar

    2008-01-01

    Cytomegalovirus infection is an important cause of morbidity in immunosupressed patients with Human Immunodeficiency Virus (HIV). In this paper we present a 43 years old man with renal failure under hemodialysis, several blood transfusions because of anemia and three months of disease characterized by epigastric pain, specially at nights, ameliorated with antacid drugs. Other symptoms were early satisfy, vomits and weigh loss (18Kg). At clinical exam, the patient was pallid, presented adenopathies at cervical and inguinal regions and had a pain at epigastric region in profound touch palpation. The most important exams were HB: 10mg/dl, CMV: 83.5, leukocytes 7000, lymphocytes: 1715, erythrocyte sedimentation rate 49mm/h, the venon test (-), and Giardia lamblia trophozoites in stools. The studies demonstrated the patient was seropositive for HIV and the tests for IgG CMV and IgG Herpes virus resulted seropositives too. At endoscopy the esophagus mucosa was covered by a white plaque which suggests candida infection. In the stomach, over the body gastric, we found a big and deep ulcerated lesion (45 x 41mm), with defined rims and white fund. Biopsy from the edges of the gastric ulcer had the characteristic CMV intranuclear and intracytoplasmic inclusions; we confirmed the diagnosis by immunohystochemistry. The patient receives ganciclovir an then HAART and is getting well.

  6. Viral loads in dual infection with HIV-1 and cytomegalovirus

    PubMed Central

    Boriskin, Y.; Sharland, M.; Dalton, R.; duMont, G.; Booth, J.

    1999-01-01

    OBJECTIVE—A one year study of the relation between cytomegalovirus (CMV) and human immunodeficiency virus (HIV) viral loads in a cohort of children with vertically acquired HIV-1 infection.
DESIGN—Comparative analysis of viral load measurements for CMV and HIV-1 in peripheral blood leucocytes (PBLs) of individual children in relation to age and clinical staging.
METHODS—Nested polymerase chain reaction (PCR) was used to measure HIV-1 proviral DNA and CMV genomic DNA in PBLs of 56children.
RESULTS—The CMV load was highest in 0-2 year old HIV positive children with stage C disease (range, 1-7143 copies/100 ng DNA; median, 125) and was significantly lower in older children. Although higher in young children, HIV-1 viral load did not show the same marked reduction with age that is seen with CMV. Over a one year period, testing of serial samples for both viruses in a subgroup of children revealed a discordant relation between viral loads for CMV and HIV-1.
CONCLUSIONS—CMV viral load falls much faster than HIV viral load in dually infected children. Screening for clinical CMV disease is most likely to be of benefit in children under 2 years of age with stage C disease. In the few children studied, levels of CMV and HIV replication appear to be independent.

 PMID:10325727

  7. Cytomegalovirus infection enhances the immune response to influenza.

    PubMed

    Furman, David; Jojic, Vladimir; Sharma, Shalini; Shen-Orr, Shai S; Angel, Cesar J L; Onengut-Gumuscu, Suna; Kidd, Brian A; Maecker, Holden T; Concannon, Patrick; Dekker, Cornelia L; Thomas, Paul G; Davis, Mark M

    2015-04-01

    Cytomegalovirus (CMV) is a β-herpesvirus present in a latent form in most people worldwide. In immunosuppressed individuals, CMV can reactivate and cause serious clinical complications, but the effect of the latent state on healthy people remains elusive. We undertook a systems approach to understand the differences between seropositive and negative subjects and measured hundreds of immune system components from blood samples including cytokines and chemokines, immune cell phenotyping, gene expression, ex vivo cell responses to cytokine stimuli, and the antibody response to seasonal influenza vaccination. As expected, we found decreased responses to vaccination and an overall down-regulation of immune components in aged individuals regardless of CMV status. In contrast, CMV-seropositive young adults exhibited enhanced antibody responses to influenza vaccination, increased CD8(+) T cell sensitivity, and elevated levels of circulating interferon-γ compared to seronegative individuals. Experiments with young mice infected with murine CMV also showed significant protection from an influenza virus challenge compared with uninfected animals, although this effect declined with time. These data show that CMV and its murine equivalent can have a beneficial effect on the immune response of young, healthy individuals, which may explain the ubiquity of CMV infection in humans and many other species.

  8. The 2001 Garrod lecture. The treatment of cytomegalovirus infection.

    PubMed

    Griffiths, Paul D

    2002-02-01

    This named lecture provides an opportunity to take an historical perspective on cytomegalovirus (CMV) infection. A major theme will be that modern molecular biological research has questioned the conventional wisdom that CMV is a slow-growing virus, which only damages a few individuals. I will first review details of the genetic constitution of the virus, emphasizing that wild strains contain many genes which are missing from their laboratory-adapted cousins. I will then review the diseases associated with CMV, not just the end-organ diseases of pneumonitis/retinitis, etc., but the so-called indirect effects, including graft rejection, secondary microbial infections and accelerated atherosclerosis. The urgent need for safe and potent antiviral drugs to prevent these diseases will be considered in two ways: first, the failure of the conventional drug discovery approach; and secondly, the opportunities offered by targeting novel gene functions. The controlled clinical trials performed to date will be summarized, together with suggestions about pharmacodynamic evaluations in the future.

  9. Bioactive Molecules Released From Cells Infected with the Human Cytomegalovirus

    PubMed Central

    Luganini, Anna; Terlizzi, Maria E.; Gribaudo, Giorgio

    2016-01-01

    Following primary infection in humans, the human cytomegalovirus (HCMV) persists in a latent state throughout the host’s lifetime despite a strong and efficient immune response. If the host experiences some form of immune dysregulation, such as immunosuppression or immunodeficiency, HCMV reactivates, thereby emerging from latency. Thus, in the absence of effective functional immune responses, as occurs in immunocompromised or immunoimmature individuals, both HCMV primary infections and reactivations from latency can cause significant morbidity and mortality. However, even in immunocompetent hosts, HCMV represents a relevant risk factor for the development of several chronic inflammatory diseases and certain forms of neoplasia. HCMV infection may shift between the lytic and latent state, regulated by a delicate and intricate balance between virus-mediated immunomodulation and host immune defenses. Indeed, HCMV is a master in manipulating innate and adaptive host defense pathways, and a large portion of its genome is devoted to encoding immunomodulatory proteins; such proteins may thus represent important virulence determinants. However, the pathogenesis of HCMV-related diseases is strengthened by the activities of bioactive molecules, of both viral and cellular origin, that are secreted from infected cells and collectively named as the secretome. Here, we review the state of knowledge on the composition and functions of HCMV-derived secretomes. In lytic infections of fibroblasts and different types of endothelial cells, the majority of HCMV-induced secreted proteins act in a paracrine fashion to stimulate the generation of an inflammatory microenvironment around infected cells; this may lead to vascular inflammation and angiogenesis that, in turn, foster HCMV replication and its dissemination through host tissues. Conversely, the HCMV secretome derived from latently infected hematopoietic progenitor cells induces an immunosuppressive extracellular environment that

  10. Horizontal In Utero Acquisition of Cytomegalovirus Infection in a Twin Pregnancy

    PubMed Central

    Gabrielli, Liliana; Lazzarotto, Tiziana; Foschini, Maria Pia; Lanari, Marcello; Guerra, Brunella; Eusebi, Vincenzo; Landini, Maria Paola

    2003-01-01

    It is generally accepted that viral infections can be transmitted horizontally by direct or indirect contact with virus-excreting persons, and some viral infections can be transmitted vertically, either prenatally or perinatally, from mother to child. This report presents data strongly supporting a prenatal horizontal acquisition of human cytomegalovirus infection in a twin pregnancy. PMID:12624079

  11. Human Cytomegalovirus Infection Enhances NK Cell Activity In Vitro

    PubMed Central

    Tschan-Plessl, Astrid; Stern, Martin; Schmied, Laurent; Retière, Christelle; Hirsch, Hans H.; Garzoni, Christian; van Delden, Christian; Boggian, Katia; Mueller, Nicolas J.; Berger, Christoph; Villard, Jean; Manuel, Oriol; Meylan, Pascal; Terszowski, Grzegorz

    2016-01-01

    Background Occurring frequently after solid organ and hematopoietic stem cell transplantation, cytomegalovirus (CMV) replication remains a relevant cause of mortality and morbidity in affected patients. Despite these adverse effects, an increased alloreactivity of natural killer (NK) cells after CMV infection has been assumed, but the underlying physiopathological mechanisms have remained elusive. Methods We used serial analyses of NK cells before and after CMV infection in kidney transplant recipients as an in vivo model for CMV primary infection to explore the imprint of CMV infection using every patient as their own control: We analyzed NK cell phenotype and function in 47 CMV seronegative recipients of CMV seropositive kidney grafts, who developed CMV primary infection posttransplant. Seronegative recipients of seronegative kidney grafts served as controls. Results We observed a significant increase of NKG2C expressing NK cells after CMV infection (mean increase, 17.5%; 95% confidence interval [95% CI], 10.2-24.9, P < 0.001), whereas cluster of differentiation (CD)57 expressing cells decreased (mean decrease, 14.1%; 95% CI, 8.0-20.2; P < 0.001). Analysis of killer immunoglobulin-like receptor (KIR) expression showed an increase of cells expressing KIR2DL1 as their only inhibitory KIR in patients carrying the cognate ligand HLA-C2 (mean increase, 10.0%; 95% CI, 1.7-18.3; P = 0.018). In C2-negative individuals, KIR2DL1 expression decreased (mean decrease, 3.9%; 95% CI, 1.6-6.2; P = 0.001). As for activating KIR, there was no conclusive change pattern. Most importantly, we observed a significantly higher NK cell degranulation and IFNγ production in response to different target cells (target K562, CD107a: mean increase, 9.9%; 95% CI, 4.8-15.0; P < 0.001; IFNγ: mean increase, 6.6%; 95% CI, 1.6-11.1; P < 0.001; target MRC-5, CD107a: mean increase, 6.9%; 95% CI, 0.7-13.1; P = 0.03; IFNγ: mean increase, 4.8%; 95% CI, 1.7-7.8; P = 0.002). Conclusions We report

  12. Cytomegalovirus infection in renal transplantation: clinical aspects, management and the perspectives

    PubMed Central

    Requião-Moura, Lúcio Roberto; de Matos, Ana Cristina Carvalho; Pacheco-Silva, Alvaro

    2015-01-01

    Cytomegalovirus infection is one of most frequent infectious complications after renal transplantation, and can be classified as primo-infection, when the transmission occurs through the graft, or reactivation, when the recipient is cytomegalovirus seropositive. After transplantation, cytomegalovirus can appear as an infection, when the patient presents with evidence of viral replication without symptoms or disease, which has two clinical spectra: typical viral syndrome or invasive disease, which is a less common form. Their effects can be classified as direct, while the disease is developed, or indirect, with an increase of acute rejection and chronic allograft dysfunction risks. Diagnosis must be made based on viremia by one of the standardized methods: antigenemia or PCR, which is more sensitive. The risk factors related to infection after transplantation are the serologic matching (positive donor and negative recipient) and anti-lymphocyte antibody drugs. One of the strategies to reduce risk of disease should be chosen for patients at high risk: preemptive treatment or universal prophylaxis. Recent clinical research has described ganciclovir resistance as an emergent problem in management of cytomegalovirus infection. Two types of mutation that cause resistance were described: UL97 (most frequent) and UL54. Today, sophisticated methods of immunologic monitoring to detect specific T-cell clones against cytomegalovirus are used in clinical practice to improve the management of high-risk patients after renal transplantation. PMID:25993081

  13. Human cytomegalovirus infection downregulates vitamin-D receptor in mammalian cells.

    PubMed

    Rieder, Franz J J; Gröschel, Charlotte; Kastner, Marie-Theres; Kosulin, Karin; Laengle, Johannes; Zadnikar, Rene; Marculescu, Rodrig; Schneider, Martina; Lion, Thomas; Bergmann, Michael; Kallay, Enikö; Steininger, Christoph

    2017-01-01

    Vitamin D (VD) is essential for the human body and involved in a wide variety of critical physiological processes including bone, muscle, and cardiovascular health, as well as innate immunity and antimicrobial responses. Here, we elucidated the significance of the VD system in cytomegalovirus (CMV) infection, which is one of the most common opportunistic infections in immunocompromised or -suppressed patients. We found that expression of vitamin D receptor (VDR) was downregulated in CMV-infected cells within 12h [hrs] post infection [p.i.] to 12% relative to VDR expression in mock-infected fibroblasts and did not recover during the CMV replication cycle of 96h. None of the biologically active metabolites of VD, cholecalciferol, calcidiol, or calcitriol, inhibit CMV replication significantly in human fibroblasts. In a feedback loop, expression of CYP24A1 dropped to 3% by 12h p.i. and expression of CYP27B1 increased gradually during the replication cycle of CMV to 970% probably as a consequence of VDR inhibition. VDR expression was not downregulated during influenza virus or adenovirus replication. The potent synthetic vitamin D analog EB-1089 was not able to inhibit CMV replication or antagonize its effect on VDR expression. Only CMV replication, and none of the other viral pathogens evaluated, inhibited the vitamin D system in vitro. In view of the pleiotropism of VDR, CMV-mediated downregulation may have far-reaching virological, immunological, and clinical implications and thus warrant further evaluations in vitro and in vivo.

  14. Activity of histidine in peripheral blood erythrocytes of pregnant women during exacerbation of cytomegalovirus infection.

    PubMed

    Lutsenko, M T; Andrievskaya, I A

    2014-10-01

    We studied the effect of active cytomegalovirus infection on histidine content in peripheral blood erythrocytes of pregnant women at gestation weeks 20-22 and its involvement into hemoglobin oxygenation. Using the histochemical technique developed by us, we studied the distribution of products of specific reaction for histidine in peripheral blood erythrocytes of pregnant women. The percentage of histidine-positive erythrocytes and their area were evaluated. The relationship between the distribution of the products of the reaction for histidine in peripheral blood erythrocytes of pregnant women and the titer of anti-cytomegalovirus IgG was revealed. The histidine content in peripheral blood erythrocytes of pregnant women with active cytomegalovirus infection was reduced, which impaired heme binding to globin and decreased the formation of oxyhemoglobin.

  15. Electrophoretic analysis of polypeptides immune precipitated from cytomegalovirus-infected cell extracts by human sera.

    PubMed Central

    Pereira, L; Hoffman, M; Cremer, N

    1982-01-01

    Serodiagnosis of cytomegalovirus (CMV) infection by complement fixation tests depends on showing a fourfold rise in antibody titer from acute- to convalescent-phase sera. Freeze-thaw and glycine-extracted, infected cell culture antigens used for these tests give markedly different titers in reactions with the same sera. In this study, we characterized the CMV-infected cell polypeptides contained in freeze-thaw and glycine-extracted antigens and identified the proteins precipitated by 23 pairs of human acute and convalescent sera. Our results were as follows. First, freeze-thaw and glycine-extracted antigens prepared from infected cells radiolabeled with [35S]methionine and subjected to electrophoresis in sodium dodecyl sulfate-polyacrylamide gels yielded similar patterns, and the bulk of the label was contained in late structural proteins and glycoproteins. Glycine-extracted preparations contained a greater proportion of soluble 66,000- and 50,000-molecular-weight proteins than did freeze-thaw antigens. Second, convalescent sera precipitated proteins migrating with apparent molecular weights of 150,000, 130,000, 110,000, 96,000, 74,000, 66,000, 50,000, 34,000, 32,000, and 25,000. Of these the 130,000-, 110,000-, 96,000-, 66,000-, 50,000-, and 25,000-molecular-weight proteins comigrated with glucosamine-labeled polypeptides. Both immunoglobulin G and M antibodies in human sera precipitated these proteins from CMV-infected cell preparations. Implications of the results for serodiagnosis of CMV infections are discussed. Images FIG. 1 FIG. 2 FIG. 3 FIG. 4 FIG. 5 FIG. 6 FIG. 7 FIG. 8 FIG. 9 FIG. 10 PMID:6284646

  16. [Visual and auditory impairment in children with congenital cytomegalovirus and Toxoplasma gondii infection].

    PubMed

    Lipka, Bozena; Milewska-Bobula, Bogumiła; Idzik, Mirosława; Marciński, Paweł; Dunin-Wasowicz, Dorota; Kassur-Siemieńska, Barbara; Bauer, Anna; Sebiguli Marishekome, Augustin; Hautz, Wojciech; Radziszewska, Marzanna

    2002-01-01

    Intrauterine infections are an important cause of hearing and visual impairment in children. The aim of this paper was to evaluate the character and frequency of hearing and visual disturbances in children with congenital toxoplasmosis and cytomegalovirus infection. 38 out of 54 children with congenital toxoplasmosis as well as 34 out of 403 children with congenital human cytomegalovirus disease, with visual/auditory impairment, hospitalized in Infant Department in Children's Memorial Health Institute between 1995-2001 were enrolled in this study. Visual impairment was observed in all children with toxoplasmosis (with visual dysfunction rate of 74%), but there was no deafness found. Vision impairment had been observed in 18% of children with congenital cytomegalovirus infection compared to 35% of children with auditory impairment (bilateral deafness had been found in half of them). Neurological deficits' rate was much higher in children with toxoplasmosis (52% vs. 4%). Because of common hearing impairment in children with congenital cytomegalovirus infection and vision impairment in children with congenital toxoplasmosis, it is essential to start the prophylaxis to decrease the percentage of handicapped children.

  17. Cytomegalovirus implicated in a case of progressive outer retinal necrosis (PORN).

    PubMed

    Sfeir, Maroun

    2015-08-01

    Progressive outer retinal necrosis, also known as PORN, has been described as a variant of necrotizing herpetic retinopathy, occurring particularly in patients with acquired immune deficiency syndrome (AIDS). Although the etiologic organism has been reported to be Varicella-zoster virus, cytomegalovirus (CMV) can be an etiologic agent. Our case illustrates the occurrence of two opportunistic infections: PORN associated with CMV and Mycobacterium avium intracellulare duodenitis in a patient with uncontrolled HIV infection.

  18. Control of murine cytomegalovirus infection by γδ T cells.

    PubMed

    Sell, Sabrina; Dietz, Monika; Schneider, Andrea; Holtappels, Rafaela; Mach, Michael; Winkler, Thomas H

    2015-02-01

    Infections with cytomegalovirus (CMV) can cause severe disease in immunosuppressed patients and infected newborns. Innate as well as cellular and humoral adaptive immune effector functions contribute to the control of CMV in immunocompetent individuals. None of the innate or adaptive immune functions are essential for virus control, however. Expansion of γδ T cells has been observed during human CMV (HCMV) infection in the fetus and in transplant patients with HCMV reactivation but the protective function of γδ T cells under these conditions remains unclear. Here we show for murine CMV (MCMV) infections that mice that lack CD8 and CD4 αβ-T cells as well as B lymphocytes can control a MCMV infection that is lethal in RAG-1(-/-) mice lacking any T- and B-cells. γδ T cells, isolated from infected mice can kill MCMV infected target cells in vitro and, importantly, provide long-term protection in infected RAG-1(-/-) mice after adoptive transfer. γδ T cells in MCMV infected hosts undergo a prominent and long-lasting phenotypic change most compatible with the view that the majority of the γδ T cell population persists in an effector/memory state even after resolution of the acute phase of the infection. A clonotypically focused Vγ1 and Vγ2 repertoire was observed at later stages of the infection in the organs where MCMV persists. These findings add γδ T cells as yet another protective component to the anti-CMV immune response. Our data provide clear evidence that γδ T cells can provide an effective control mechanism of acute CMV infections, particularly when conventional adaptive immune mechanisms are insufficient or absent, like in transplant patient or in the developing immune system in utero. The findings have implications in the stem cell transplant setting, as antigen recognition by γδ T cells is not MHC-restricted and dual reactivity against CMV and tumors has been described.

  19. A Supraglottic Pseudotumor in an Immunocompromised Patient with Nephrotic Syndrome, Herpes Zoster, and a Cytomegalovirus Infection

    PubMed Central

    Akimoto, Tetsu; Yamazaki, Tomoyuki; Saito, Osamu; Muto, Shigeaki; Kusano, Eiji; Nagata, Daisuke

    2016-01-01

    Several viral infections may occasionally induce supraglottic mass lesions, resulting in an obstructive airway emergency. We herein report one such case in a 63-year-old male immunocompromised patient with nephrotic syndrome due to membranous nephropathy who also had ophthalmic herpes zoster with a laryngeal mass, which required urgent intubation and mechanical ventilation. The patient was initially treated with acyclovir; however, because a serological analysis revealed a concurrent cytomegalovirus infection, we discontinued the administration of acyclovir and gave priority to the simultaneous treatment of the cytomegalovirus and varicella-zoster virus infections with ganciclovir. The clinical course was favorable, and he was weaned from the ventilator 10 days later when a serial imaging analysis revealed no signs of the supraglottic mass, leading us to conclude that these two viral infections could have additively or synergistically contributed to the development of the local pseudotumor. The diagnostic and therapeutic concerns arising in the current case are also discussed. PMID:27547043

  20. An atypical case of acute disseminated encephalomyelitis associated with cytomegalovirus infection.

    PubMed

    De Fino, Chiara; Nociti, Viviana; Modoni, Anna; Bizzarro, Alessandra; Mirabella, Massimiliano

    2016-01-01

    We present the case of a young man admitted to our hospital for persistent headache associated with fever, retrorbitary pain and vomiting, who rapidly developed encephalopathy with drowsiness, paraplegia, hypoesthesia with a D6 sensory level and urinary retention. Brain and spinal cord MRI revealed findings compatible with acute disseminated encephalomyelitis (ADEM) and microbiological tests documented a cytomegalovirus (CMV) infection. CMV infection is extraordinarily associated with ADEM, but must be included in microbiological tests, because early diagnosis and treatment ameliorate the neurological outcome.

  1. Murine cytomegalovirus infection of mouse macrophages stimulates early expression of suppressor of cytokine signaling (SOCS)1 and SOCS3

    PubMed Central

    Alston, Christine I.; Dix, Richard D.

    2017-01-01

    Human cytomegalovirus (HCMV) is a species-specific β-herpesvirus that infects for life up to 80% of the world’s population and causes severe morbidity in at-risk immunocompromised populations. Suppressors of cytokine signaling (SOCS)1 and SOCS3 are host proteins that act as inducible negative feedback regulators of cytokine signaling and have been implicated in several ocular diseases and viral infections. We recently found in our mouse model of experimental cytomegalovirus retinitis that subretinally-injected murine cytomegalovirus (MCMV) stimulates ocular SOCS1 and SOCS3 during retrovirus-induced immune suppression of murine AIDS (MAIDS), and that infiltrating macrophages are prominent cellular sources of retinal SOCS1 and SOCS3 expression. Herein we investigate possible virologic mechanisms whereby MCMV infection may stimulate SOCS1 and/or SOCS3 expression in cell culture. We report that infection of IC-21 mouse macrophages with MCMV propagated through the salivary glands of BALB/c mice, but not from tissue culture in C57BL/6 fibroblasts, transiently stimulates SOCS1 and SOCS3 mRNA transcripts, but not SOCS5 mRNA. Viral tegument proteins are insufficient for this stimulation, as replication-deficient UV-inactivated MCMV fails to stimulate SOCS1 or SOCS3 in IC-21 macrophages. By contrast, infection of murine embryonic fibroblasts (MEFs) with either productive MCMV or UV-inactivated MCMV significantly stimulates SOCS1 and SOCS3 mRNA expression early after infection. Treatment of MCMV-infected IC-21 mouse macrophages with the antiviral drug ganciclovir significantly decreases MCMV-stimulated SOCS3 expression at 3 days post-infection. These data suggest cell type-specific, different roles for viral immediate early or early gene expression and/or viral tegument proteins in the early stimulation of SOCS1 and SOCS3 during MCMV infection. Furthermore, putative biphasic stimulation of SOCS3 during late MCMV infection of IC-21 mouse macrophages may occur by divergent

  2. Genotypic Diversity and Mixed Infection in Newborn Disease and Hearing Loss in Congenital Cytomegalovirus Infection

    PubMed Central

    Pati, Sunil; Pinninti, Swetha; Novak, Zdenek; Chowdhury, Nazma; Patro, Raj; Fowler, Karen; Ross, Shannon; Boppana, Suresh

    2013-01-01

    Background Congenital cytomegalovirus (cCMV) is a common congenital infection and a leading non-genetic cause of sensorineural hearing loss (SNHL). CMV exhibits extensive genetic variability and infection with multiple CMV strains (mixed infection) was shown to be common in cCMV. The role of mixed infections in disease and outcome remains to be defined. Methods Genotyping of envelope glycoproteins, UL55 (gB), UL73 (gN) and UL75 (gH) was performed on saliva specimens from 79 infants from the ongoing CMV and Hearing Multicenter Screening Study (CHIMES) and on blood and urine specimens from 52 infants who participated in natural history studies at the University of Alabama at Birmingham. Genotyping of UL144 and US28 was also performed in the CHIMES cohort. The association of individual genotypes and mixed infection with clinical findings at birth and SNHL was examined. Results Thirty seven of 131 infants (28%) were symptomatic at birth and 26 (20%) had SNHL at birth. All known genotypes of UL55, UL75, UL73, and US28 were represented and no particular genotype was associated with symptomatic infection or SNHL. UL144 subtype C was more common in symptomatic babies but not associated with SNHL. Mixed infection was observed in 59 infants (45%) and not associated with symptoms (p = 0.43) or SNHL at birth (p = 0.82). In the cohort of 52 infants with long-term hearing outcome, mixed infection at birth was not predictive of SNHL. Conclusions Mixed infection is common in infants with cCMV but is neither associated with symptomatic infection nor with SNHL. PMID:23694837

  3. Inhibition of cytomegalovirus infection and photothermolysis of infected cells using bioconjugated gold nanoparticles

    PubMed Central

    DeRussy, Bernadette M.; Aylward, Madeline A.; Fan, Zhen; Ray, Paresh C.; Tandon, Ritesh

    2014-01-01

    Human cytomegalovirus (CMV) is a herpesvirus that causes major health problems in neonates as well as in immunocompromised individuals1. At present, a vaccine is not available for CMV infection and the available antiviral drugs suffer from toxicity, poor efficacy and resistance12. Here, we chemically conjugated a monoclonal antibody raised against CMV surface glycoprotein (gB) with gold nanoparticles (GNP) and characterized the potential of this gB-GNP conjugate for antiviral activity against CMV. The gB-GNP blocks viral replication, virus-induced cytopathogenic effects and virus spread in cell culture without inducing cytotoxicity. High concentrations of gB-GNP that coat the surface of virus particles block virus entry, whereas lower concentrations block a later stage of virus life cycle. Also, cells treated with gB-GNP gain resistance to CMV infection. In addition, infected cells when bound to gB-GNP can be selectively lysed after exposing them to specific wavelength of laser (nanophotothermolysis). Thus, we have not only designed a potential antiviral strategy that specifically blocks CMV infection at multiple stages of virus life cycle, but we have also characterized a technique that can potentially be useful in eliminating CMV infected cells from donor tissue during transplant or transfusion. PMID:24989498

  4. [Diagnosis of congenital cytomegalovirus infection in newborn dried blood spots on Guthrie cards. A promissory technique].

    PubMed

    Distéfano, Angélica L; González, Cecilia A; Pardón, Fabián; Sarubi, María A; Canero Velazco, Cristina

    2008-04-01

    Laboratories play a crucial role in the diagnosis of congenital and perinatal cytomegalovirus infection, considering that other viral infections in newborn infants have similar clinical characteristics. The objectives of this work are to compare the results of the polymerase reaction in blood spots and urine as well as point out the relevance of the result in the Guthrie cards to differentiate congenital from perinatal infection. A total of 148 patients suspicious of CMVH infections were studied in the Congenital Perinatal Infections and Sexual Transmission Laboratory, at the National Institute "Carlos G. Malbrán". The dry blood samples (Guthrie cards) and urine of all patients were studied through the polymerase chain reaction. From the 148 patients, 3 presented other infections, 95 tested negative and 50 positive for cytomegalovirus: 35 had congenital infection and 15 perinatal. In the congenital cases, the polymerase reaction in dry blood was positive (sensitivity 100%, specificity 98.9%, VPP 98% and VPN 100%). Four of them with tardive symptoms were studied retrospectively. The urine specimens from the remaining 15 patients that were taken 15 days after birth were analyzed through the same methods, showing a sensitivity of 100%, the retrospective analysis of this dry blood group yielded negative results, so the infection was considered perinatal. Thus, the dry blood polymerase reaction of the newborn infants makes it a reliable assay for diagnosing congenital cytomegalovirus infection and could be used as an alternative method to urine polymerase reaction. In addition, this test is able to reveal whether the infection is congenital or perinatal in those cases of late symptom or other cases of controversial origin.

  5. Human cytomegalovirus infection and colorectal cancer risk: a meta-analysis

    PubMed Central

    Bai, Bingjun; Wang, Xingxing; Chen, Engeng; Zhu, Hongbo

    2016-01-01

    Human cytomegalovirus infection (HCMV) has been recently considered as a factor for tumorigenesis. The current study used meta-analytical techniques to explore the prevalence of HCMV in tumor tissues and the relationship between human cytomegalovirus and colorectal cancer (CRC) risk. 11 studies detecting HCMV DNA in tumor tissues were included in meta-analysis. The prevalence rate and odds ratio (OR) were two main parameters. The overall prevalence of human cytomegalovirus DNA in tumor tissues were 27.5% (95% CI = 17.2%−37.8%). Binary logistic regression showed that the studies reported before 2010 involving formalin-fixed specimens from patients in developed region represented a lower proportion of HCMV. The tumor tissues had a significantly higher rate of virus infection compared with normal tissues (OR = 6.59, 95% CI = 4.48−9.69, I2 = 0%, P = 0.71). Subgroup analysis revealed the prevalence of the virus didn't differ in patients with different tumor stages, in tumor cells with different histologic grades, also in different kinds of specimen (polyp and adenocarcinoma). The results of current study suggested a statistically association between the virus infection and an increased risk of colorectal cancer. PMID:27732934

  6. Severe steroid-resistant thrombocytopenia secondary to cytomegalovirus infection in an immunocompetent adult.

    PubMed

    Sugioka, Takashi; Kubota, Yasushi; Wakayama, Kazuo; Kimura, Shinya

    2012-01-01

    Severe thrombocytopenia secondary to cytomegalovirus (CMV) infection is rare in immunocompetent hosts. We describe a case of severe thrombocytopenia secondary to CMV infection in an immunocompetent 30-year-old man who presented with pyrexia and bleeding tendency. A diagnosis of immune thrombocytopenia (ITP) was made following hematological and serological testing, and bone marrow aspiration. Acute CMV infection was confirmed by serological testing, antigenemia, and detection of CMV-DNA. Corticosteroid therapy was ineffective and intravenous immunoglobulin (IVIG) was therefore administered. This resulted in immediate recovery of the platelet count and cessation of nasal bleeding. Early IVIG administration should be considered in steroid-resistant cases.

  7. Management of cytomegalovirus infection in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations.

    PubMed

    Torre-Cisneros, J; Aguado, J M; Caston, J J; Almenar, L; Alonso, A; Cantisán, S; Carratalá, J; Cervera, C; Cordero, E; Fariñas, M C; Fernández-Ruiz, M; Fortún, J; Frauca, E; Gavaldá, J; Hernández, D; Herrero, I; Len, O; Lopez-Medrano, F; Manito, N; Marcos, M A; Martín-Dávila, P; Monforte, V; Montejo, M; Moreno, A; Muñoz, P; Navarro, D; Pérez-Romero, P; Rodriguez-Bernot, A; Rumbao, J; San Juan, R; Vaquero, J M; Vidal, E

    2016-07-01

    Cytomegalovirus (CMV) infection remains a major complication of solid organ transplantation. Because of management of CMV is variable among transplant centers, in 2011 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, new publications have clarified or questioned the aspects covered in the previous document. For that reason, a panel of experts revised the evidence on CMV management, including immunological monitoring, diagnostics, prevention, vaccines, indirect effects, treatment, drug resistance, immunotherapy, investigational drugs, and pediatric issues. This document summarizes the recommendations.

  8. Design of cocktail peptide vaccine against Cytomegalovirus infection

    PubMed Central

    Tabaei, Samira; Mashkani, Baratali; Esmaili, Arezoo; Karimi, Reza; Jamehdar, Saeid Amel

    2016-01-01

    Objective(s): Human Cytomegalovirus (HCMV) remains a major morbidity and mortality cause in immuno suppressed patients. Therefore, significant effort has been made towards the development of a vaccine. In this study, the expression of the pp65 and gB fusion peptides and Fc domain of mouse IgG2a as a novel delivery system for selective uptake of antigens by antigen-presenting cells (APCs) in Pichia pastoris yeast system were studied. Materials and Method: In this study, four immune dominant sequences in pp65 protein and 3 immuno dominant sequences in gB protein were selected according to literature review. Peptide linker -GGGGS- was used for construction of fusion peptide. This fusion peptide was cloned in the pPICZαA expression vector and transfected into P. pastoris host cells. Results: Dot blot and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) techniques showed that a high level of pp65-gB-Fc fusion peptide was expressed. Conclusion: This CMV pp65-gB-Fc fusion peptide could be a promising candidate for the development of a novel peptide vaccine. PMID:27279990

  9. Mother-to-Child Transmission of Cytomegalovirus and Prevention of Congenital Infection.

    PubMed

    Pass, Robert F; Anderson, Brenna

    2014-09-01

    Mother-to-child transmission (MTCT) of cytomegalovirus (CMV) occurs transplacentally (congenital infection), during birth and through breast milk, although the latter 2 modes of transmission are not associated with the central nervous system sequelae that occur with congenital infection. CMV persists indefinitely in its human host, and MTCT can occur if the mother was infected in the past or during the current pregnancy. The goal of efforts to prevent MTCT of CMV is to prevent congenital infection, an important cause of disability due to hearing loss, impaired vision, cognitive impairment, and neuromotor deficits. Vaccines for prevention of maternal and congenital CMV infection are being developed but will not likely be available for at least a decade. Rather than waiting for an effective vaccine to solve the problem, more effort must be devoted to defining the potential for public health measures to prevent congenital CMV infection by reducing rates of maternal infection during pregnancy.

  10. Cytomegalovirus Infection of the Rat Developing Brain In Utero Prominently Targets Immune Cells and Promotes Early Microglial Activation

    PubMed Central

    Cloarec, Robin; Bauer, Sylvian; Luche, Hervé; Buhler, Emmanuelle; Pallesi-Pocachard, Emilie; Salmi, Manal; Courtens, Sandra; Massacrier, Annick; Grenot, Pierre; Teissier, Natacha; Watrin, Françoise; Schaller, Fabienne; Adle-Biassette, Homa; Gressens, Pierre; Malissen, Marie; Stamminger, Thomas; Streblow, Daniel N.; Bruneau, Nadine; Szepetowski, Pierre

    2016-01-01

    Background Congenital cytomegalovirus infections are a leading cause of neurodevelopmental disorders in human and represent a major health care and socio-economical burden. In contrast with this medical importance, the pathophysiological events remain poorly known. Murine models of brain cytomegalovirus infection, mostly neonatal, have brought recent insights into the possible pathogenesis, with convergent evidence for the alteration and possible involvement of brain immune cells. Objectives and Methods In order to confirm and expand those findings, particularly concerning the early developmental stages following infection of the fetal brain, we have created a model of in utero cytomegalovirus infection in the developing rat brain. Rat cytomegalovirus was injected intraventricularly at embryonic day 15 (E15) and the brains analyzed at various stages until the first postnatal day, using a combination of gene expression analysis, immunohistochemistry and multicolor flow cytometry experiments. Results Rat cytomegalovirus infection was increasingly seen in various brain areas including the choroid plexi and the ventricular and subventricular areas and was prominently detected in CD45low/int, CD11b+ microglial cells, in CD45high, CD11b+ cells of the myeloid lineage including macrophages, and in CD45+, CD11b– lymphocytes and non-B non-T cells. In parallel, rat cytomegalovirus infection of the developing rat brain rapidly triggered a cascade of pathophysiological events comprising: chemokines upregulation, including CCL2-4, 7 and 12; infiltration by peripheral cells including B-cells and monocytes at E17 and P1, and T-cells at P1; and microglia activation at E17 and P1. Conclusion In line with previous findings in neonatal murine models and in human specimen, our study further suggests that neuroimmune alterations might play critical roles in the early stages following cytomegalovirus infection of the brain in utero. Further studies are now needed to determine which

  11. Transmission of murine cytomegalovirus in breast milk: a model of natural infection in neonates.

    PubMed

    Wu, Carol A; Paveglio, Sara A; Lingenheld, Elizabeth G; Zhu, Li; Lefrançois, Leo; Puddington, Lynn

    2011-05-01

    Vertical transmission of viruses in breast milk can expose neonates to infectious pathogens at a time when the capacity of their immune system to control infections is limited. We developed a mouse model to study the outcomes of acquisition of murine cytomegalovirus (MCMV) when neonates are breastfed by mothers with acute or latent infection. Breast milk leukocytes collected from lactating mice were examined for the presence of MCMV IE-1 mRNA by reverse transcription-PCR (RT-PCR) with Southern analysis. As determined by this criterion, breast milk leukocytes from both acute and latent mothers were positive for MCMV. This mimics the outcome seen in humans with latent cytomegalovirus infection, where reactivation of virus occurs specifically in the lactating mammary gland. Interestingly, intraperitoneal injection of breast milk collected from mothers with latent infection was sufficient to transfer MCMV to neonatal mice, demonstrating that breast milk was a source of virus. Furthermore, we found that MCMV was transmitted from infected mothers to breastfed neonates, with MCMV IE-1 mRNA or infectious virus present in multiple organs, including the brain. In fact, 1 day of nursing was sufficient to transmit MCMV from latent mothers to breastfed neonatal mice. Together, these data validate this mouse model of vertical transmission of MCMV from mothers with acute or latent MCMV infection to breastfed neonates. Its relevance to human disease should prove useful in future studies designed to elucidate the immunological and pathological ramifications of neonatal infection acquired via this natural route.

  12. [Ureterostomy cytomegalovirus infection presenting as stoma ulceration in a kidney allograft receptor: a case report].

    PubMed

    Rico, J E; Cardona, X; Rodelo, J; Reino, A; Arias, L F; Arbeláez, M

    2008-06-01

    Cytomegalovirus (CMV) is the most common viral infection affecting transplant patients, but urinary tract involvement has been rare. Only a few cases of symptomatic ureteritis have been reported in renal transplant recipients. In previous reports the presentation of CMV ureteritis is obstructive nephropathy, often in the absence of systemic illness, or rarely it may also mimic allograft rejection with minimal obstructive symptoms. We describe an additional case of CMV ureteritis in a patient with cutaneous ureterostomy. The unusual clinical presentation with urinary infection symptoms and ureterostomy stoma ulceration constitute a very particular presentation. The increasing report cases with CMV ureteritis suggest an increase of this post-transplant complication.

  13. Management strategies for cytomegalovirus infection and disease in solid organ transplant recipients.

    PubMed

    Razonable, Raymund R

    2013-06-01

    Cytomegalovirus is the most common viral pathogen that affects solid organ transplant recipients. It directly causes fever, myelosuppression, and tissue-invasive disease, and indirectly, it negatively impacts allograft and patient survival. Nucleic acid amplification testing is the preferred method to confirm the diagnosis of CMV infection. Prevention of CMV disease using antiviral prophylaxis or preemptive therapy is critical in the management of transplant patients. Intravenous ganciclovir and oral valganciclovir are the first line drugs for antiviral treatment. This article provides a comprehensive review of the current epidemiology, diagnosis, prevention and treatment of CMV infection in solid organ transplant recipients.

  14. Natural Killer Cell Evasion Is Essential for Infection by Rhesus Cytomegalovirus

    PubMed Central

    Sturgill, Elizabeth R.; Malouli, Daniel; Hansen, Scott G.; Burwitz, Benjamin J.; Schneider, Christine L.; Womack, Jennie L.; Verweij, Marieke C.; Ventura, Abigail B.; Bhusari, Amruta; Jeffries, Krystal M.; Legasse, Alfred W.; Axthelm, Michael K.; Hudson, Amy W.; Sacha, Jonah B.; Picker, Louis J.; Früh, Klaus

    2016-01-01

    The natural killer cell receptor NKG2D activates NK cells by engaging one of several ligands (NKG2DLs) belonging to either the MIC or ULBP families. Human cytomegalovirus (HCMV) UL16 and UL142 counteract this activation by retaining NKG2DLs and US18 and US20 act via lysomal degradation but the importance of NK cell evasion for infection is unknown. Since NKG2DLs are highly conserved in rhesus macaques, we characterized how NKG2DL interception by rhesus cytomegalovirus (RhCMV) impacts infection in vivo. Interestingly, RhCMV lacks homologs of UL16 and UL142 but instead employs Rh159, the homolog of UL148, to prevent NKG2DL surface expression. Rh159 resides in the endoplasmic reticulum and retains several NKG2DLs whereas UL148 does not interfere with NKG2DL expression. Deletion of Rh159 releases human and rhesus MIC proteins, but not ULBPs, from retention while increasing NK cell stimulation by infected cells. Importantly, RhCMV lacking Rh159 cannot infect CMV-naïve animals unless CD8+ cells, including NK cells, are depleted. However, infection can be rescued by replacing Rh159 with HCMV UL16 suggesting that Rh159 and UL16 perform similar functions in vivo. We therefore conclude that cytomegaloviral interference with NK cell activation is essential to establish but not to maintain chronic infection. PMID:27580123

  15. Rapid diagnosis of cytomegalovirus infection by in-situ hybridisation in liver grafts.

    PubMed

    Naoumov, N V; Alexander, G J; O'Grady, J G; Sutherland, S; Aldis, P; Portmann, B C; Williams, R

    1988-06-18

    Cytomegalovirus (CMV) is a major cause of hepatic dysfunction after liver transplantation, but proof of infection and distinguishing CMV hepatitis from other causes of impaired liver function can be difficult. In-situ hybridisation for CMV-DNA in liver biopsy specimens was assessed in 25 liver graft recipients in whom CMV was suspected on clinical grounds. CMV-DNA was detected in all 10 patients with primary CMV infection, in whom a close correlation was found between the number of CMV-DNA-positive cells and both the number of cells containing viral inclusions identified by light microscopy and the clinical severity of disease. In contrast, CMV-DNA was not detected in patients with secondary CMV infection, or in those without evidence of CMV infection. In-situ hybridisation for CMV-DNA provides an accurate and rapid diagnosis of CMV infection, and allows specific antiviral therapy to be used earlier.

  16. Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs

    PubMed Central

    Farrell, Helen E.; Lawler, Clara; Oliveira, Martha T.; Davis-Poynter, Nick

    2015-01-01

    ABSTRACT Cytomegaloviruses (CMVs) infect the lungs and cause pathological damage there in immunocompromised hosts. How lung infection starts is unknown. Inhaled murine CMV (MCMV) directly infected alveolar macrophages (AMs) and type 2 alveolar epithelial cells (AEC2s) but not type 1 alveolar epithelial cells (AEC1s). In contrast, herpes simplex virus 1 infected AEC1s and murid herpesvirus 4 (MuHV-4) infected AEC1s via AMs. MCMV-infected AMs prominently expressed viral reporter genes from a human CMV IE1 promoter; but most IE1-positive cells were AEC2s, and CD11c-cre mice, which express cre in AMs, switched the fluorochrome expression of <5% of floxed MCMV in the lungs. In contrast, CD11C-cre mice exhibited fluorochrome switching in >90% of floxed MuHV-4 in the lungs and 50% of floxed MCMV in the blood. AM depletion increased MCMV titers in the lung during the acute phase of infection. Thus, the influence of AMs was more restrictive than permissive. Circulating monocytes entered infected lungs in large numbers and became infected, but not directly; infection occurred mainly via AEC2s. Mice infected with an MCMV mutant lacking its m131/m129 chemokine homolog, which promotes macrophage infection, showed levels of lung infection equivalent to those of wild-type MCMV-infected mice. The level of lung infiltration by Gr-1-positive cells infected with the MCMV m131/m129-null mutant was modestly different from that for wild-type MCMV-infected lungs. These results are consistent with myeloid cells mainly disseminating MCMV from the lungs, whereas AEC2s provide local amplification. IMPORTANCE Cytomegaloviruses (CMVs) chronically and systemically infect most mammals. Human CMV infection is usually asymptomatic but causes lung disease in people with poor immune function. As human infection is hard to analyze, studies with related animal viruses provide important insights. We show that murine CMV has two targets in the lungs: macrophages and surfactant-secreting epithelial cells

  17. Neuropathogenesis of Congenital Cytomegalovirus Infection: Disease Mechanisms and Prospects for Intervention

    PubMed Central

    Cheeran, Maxim C.-J.; Lokensgard, James R.; Schleiss, Mark R.

    2009-01-01

    Congenital cytomegalovirus (CMV) infection is the leading infectious cause of mental retardation and hearing loss in the developed world. In recent years, there has been an improved understanding of the epidemiology, pathogenesis, and long-term disabilities associated with CMV infection. In this review, current concepts regarding the pathogenesis of neurological injury caused by CMV infections acquired by the developing fetus are summarized. The pathogenesis of CMV-induced disabilities is considered in the context of the epidemiology of CMV infection in pregnant women and newborn infants, and the clinical manifestations of brain injury are reviewed. The prospects for intervention, including antiviral therapies and vaccines, are summarized. Priorities for future research are suggested to improve the understanding of this common and disabling illness of infancy. PMID:19136436

  18. The DNA damage response induced by infection with human cytomegalovirus and other viruses.

    PubMed

    Xiaofei, E; Kowalik, Timothy F

    2014-05-23

    Viruses use different strategies to overcome the host defense system. Recent studies have shown that viruses can induce DNA damage response (DDR). Many of these viruses use DDR signaling to benefit their replication, while other viruses block or inactivate DDR signaling. This review focuses on the effects of DDR and DNA repair on human cytomegalovirus (HCMV) replication. Here, we review the DDR induced by HCMV infection and its similarities and differences to DDR induced by other viruses. As DDR signaling pathways are critical for the replication of many viruses, blocking these pathways may represent novel therapeutic opportunities for the treatment of certain infectious diseases. Lastly, future perspectives in the field are discussed.

  19. Spontaneous Bladder Rupture and Cytomegalovirus Infection Complicating Renal Transplantation: Cause or Coincidence?

    PubMed Central

    Davis, Jackson L.; Callender, Clive O.

    1982-01-01

    The high incidence of surgical complications following renal transplantation is well known. Urologic complications, however, present some of the most challenging problems to the transplant surgeon. The authors present here a detailed case report of spontaneous (delayed) bladder rupture (SDBR) which occurred 90 days after kidney transplantation in a recipient with cytomegalovirus infection (CMV). Urinary catheter drainage is recommended in preference to surgical intervention for the successful correction of SDBR. It is postulated further that, despite a negative bladder biopsy, CMV may have infiltrated the bladder and contributed to this “spontaneous” bladder wall rupture. ImagesFigure 1Figure 2Figure 3 PMID:6294313

  20. Severe Thrombocytopenia and Acute Cytomegalovirus Colitis during Primary Human Immunodeficiency Virus Infection

    PubMed Central

    Furuhata, Masanori; Yanagisawa, Naoki; Nishiki, Shingo; Sasaki, Shugo; Suganuma, Akihiko; Imamura, Akifumi; Ajisawa, Atsushi

    2016-01-01

    We herein report the case of a 25-year-old man who was referred to our hospital due to acute cytomegalovirus (CMV) colitis. The initial blood tests showed that the patient had concurrent primary human immunodeficiency virus (HIV) infection and severe thrombocytopenia. Raltegravir-based antiretroviral therapy (ART) was initiated without the use of ganciclovir or corticosteroids and resulted in a rapid clinical improvement. Platelet transfusions were only necessary for a short period, and subsequent colonoscopy revealed a completely healed ulcer. This case implies that ART alone could be effective for treating severe thrombocytopenia during primary HIV and CMV coinfection. PMID:27980271

  1. Pathology of Murine Cytomegalovirus Infection in Newborn Mice. Muscle, Heart and Brown Fat Lesions

    PubMed Central

    Lussier, G.

    1974-01-01

    Newborn mice were inoculated intracerebrally with murine cytomegalovirus and studies were made of the pathological changes in the striate and cardiac muscle and brown fat. Widespread necrosis was seen in muscle and brown fat in the early stages of the infection. Necrotic lesions became calcified. By 56 days lesions were not resolved in the heart and brown fat but were completely resolved in skeletal muscle. ImagesFig. 1.Fig. 2.Fig. 3.Fig. 4.Fig. 5.Fig. 6.Fig. 7.Fig. 8.Fig. 9. PMID:4363374

  2. Distribution of Cytomegalovirus Genotypes among Neonates Born to Infected Mothers in Islamabad, Pakistan

    PubMed Central

    Mujtaba, Ghulam; Khurshid, Adnan; Sharif, Salmaan; Alam, Muhammad Masroor; Aamir, Uzma Bashir; Shaukat, Shahzad; Angez, Mehar; Rana, Muhammad Suleman; Umair, Massab; Shah, Aamer Ali; Zaidi, Syed Sohail Zahoor

    2016-01-01

    Background Congenital cytomegalovirus (cCMV) infection contributes to considerable long-term sequelae in neonates and children all over the world. The association between viral genotypes and severity of clinical cytomegalovirus (CMV) infection is yet to be defined. The objective of this study was to find the impact of active CMV infection during pregnancy and the clinical significance of genotypes in neonates with congenital cytomegalovirus infections in Pakistan. Methods A total of 409 blood samples from pregnant women seeking health care services at the two antenatal hospitals of Islamabad during January to December 2012 were tested by ELISA and nested-PCR. Pregnant women with active infection (detected as IgM positive, PCR positive or positive on both assays) were followed until delivery, to detect the outcome of overt cCMV infection in neonates. Genetic characterization of CMV strains was performed by sequence analysis of envelope glycoproteins: gB, gN and gH to detect the contributing CMV genotypes. Results The seroprevalence of anti-CMV IgG and IgM was 97.5% (399 out of 409) and 12.7% (52 out of 409), respectively, while 20% (82/409) pregnant women were found positive for CMV DNA by PCR. Logistic regression analysis showed a significant association of active infection with parity [OR = 2.56, 95% CI = 1.82–2.62, p = 0.04], febrile illness [OR = 1.84, 95% CI = 1.76–3.65, p = 0.01] and jaundice [OR = 22.5, 95% CI = 4.53–85.02, p = 0.002]. We were able to isolate virus in 41 out of 70 neonates; 36.6% (15 out of 41) of them were symptomatic at birth while 63.4% (26 out of 41) were asymptomatic. The most prominent clinical feature observed in symptomatic neonates was hepatosplenomegaly (26.6%; 4 out of 15). All three genotypes gB, gN and gH were found with the highest frequency of gB1 genotype, found in 75% infants with hepatic damage. Phylogenetic analysis of Pakistani strains showed 96%-100% homology to their prototype strains. Conclusions Active CMV

  3. Potential Contribution of Cytomegalovirus Infection to Prenatal and Early Neonatal Mortality of Monkeys in the Adler Breeding Center.

    PubMed

    Shamsutdinova, O A; Agumava, A A; Chikobava, M G; Vyshemirsky, O I

    2015-11-01

    Scrapings from the cervical canals and uterine cavities of females with a history of miscarriages, pathological deliveries, and stillbirths were tested for the cytomegalovirus DNA. The incidence of the agent in the females with a history of gestosis and abnormal deliveries was significantly higher than in females without anamnesis of this kind. Parenchymatous organs of stillborn neonates and animals dead during the first month of life were studied. This analysis and studies of the umbilical cords and placentas showed generalized cytomegalovirus infection in 22% dead animals, which objectively proved intrauterine infection.

  4. Modeling the Potential Impact of Vaccination on the Epidemiology of Congenital Cytomegalovirus Infection

    PubMed Central

    Lanzieri, Tatiana M.; Bialek, Stephanie R.; Ortega-Sanchez, Ismael R.; Gambhir, Manoj

    2016-01-01

    Background Understanding the potential for vaccination to change cytomegalovirus (CMV) epidemiology is important for developing CMV vaccines and designing clinical trials. Methods We constructed a deterministic, age-specific and time-dependent mathematical model of pathogen transmission, parameterized using CMV seroprevalence from the United States and Brazil, to predict the impact of vaccination on congenital CMV infection. Findings Concurrent vaccination of young children and adolescents would result in the greatest reductions in congenital CMV infections in populations with moderate and high baseline maternal seroprevalence. Such a vaccination strategy, assuming 70% vaccine efficacy, 90% coverage and 5-year duration of protection, could ultimately prevent 30%-50% of congenital CMV infections. At equilibrium, this strategy could result in a 30% reduction in congenital CMV infections due to primary maternal infection in the United States but a 3% increase in Brazil. The potential for an increase in congenital CMV infections due to primary maternal infections in Brazil was not predicted with use of a vaccine that confers protection for greater than 5 years. Interpretation Modeling suggests that vaccination strategies that include young children will result in greater declines in congenital CMV infection than those restricted to adolescents or women of reproductive age. Our study highlights the critical need for better understanding of the relative contribution of type of maternal infection to congenital CMV infection and disease, the main focus of vaccine prevention. PMID:24837782

  5. [Possible role of cytomegalovirus infection in the pathogenesis of human vascular diseases].

    PubMed

    Yonemitsu, Y; Komori, K; Sueishi, K; Sugimachi, K

    1998-01-01

    In order to evaluate the pathogenic role of human cytomegalovirus(CMV) infection in human vascular disease, we first examined the role of CMV immediate early gene (CMV-IE) expression in vascular smooth muscle cell (VSMC) proliferation. The in vitro IE gene transfer stimulated VSMC proliferation. The in vivo IE gene transfer showed neointimal thickening while the control arteries did not. In the wall of "so-called" inflammatory abdominal aortic aneurysm (IAAA), CMV infected cells were more frequently encountered than in that of AA and control cases. CMV infected cells were largely identified as macrophages or fibroblasts, and these cells frequently expressed CMV-IE gene. These findings thus suggest that the persistent expression of CMV-IE gene in the vessel wall may play a role in the vascular cellular responses, including progression of atherosclerosis or vasculitis, in vivo.

  6. The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

    PubMed

    Wills, Mark R; Poole, Emma; Lau, Betty; Krishna, Ben; Sinclair, John H

    2015-03-01

    While the host immune response following primary human cytomegalovirus (HCMV) infection is generally effective at stopping virus replication and dissemination, virus is never cleared by the host and like all herpesviruses, persists for life. At least in part, this persistence is known to be facilitated by the ability of HCMV to establish latency in myeloid cells in which infection is essentially silent with, importantly, a total lack of new virus production. However, although the viral transcription programme during latency is much suppressed, a number of viral genes are expressed during latent infection at the protein level and many of these have been shown to have profound effects on the latent cell and its environment. Intriguingly, many of these latency-associated genes are also expressed during lytic infection. Therefore, why the same potent host immune responses generated during lytic infection to these viral gene products are not recognized during latency, thereby allowing clearance of latently infected cells, is far from clear. Reactivation from latency is also a major cause of HCMV-mediated disease, particularly in the immune compromised and immune naive, and is also likely to be a major source of virus in chronic subclinical HCMV infection which has been suggested to be associated with long-term diseases such as atherosclerosis and some neoplasias. Consequently, understanding latency and why latently infected cells appear to be immunoprivileged is crucial for an understanding of the pathogenesis of HCMV and may help to design strategies to eliminate latent virus reservoirs, at least in certain clinical settings.

  7. Cytomegalovirus infection after allogeneic transplantation: comparison of cord blood with peripheral blood and marrow graft sources.

    PubMed

    Walker, Christopher M; van Burik, Jo-Anne H; De For, Todd E; Weisdorf, Daniel J

    2007-09-01

    Cytomegalovirus (CMV) infection is an important complication following allogeneic hematopoietic stem cell transplant (HSCT), but the natural history in the cord blood setting has not been well studied. We assessed CMV infection episodes in 753 consecutive allogeneic HSCT recipients at the University of Minnesota between January 1, 1998 and December 31, 2003. The 6-month cumulative incidence of viremia/antigenemia was 22% by day +182: 21% (95% confidence interval 16%-26%) in cord blood recipients (UCB), 24% (20%-28%) in marrow (BM), and 22% (16%-28%) using peripheral blood grafts (PBSC). CMV disease incidence was 6% (2%-10%) in UCB, 8% (5%-11%) in BM, and 9% (6%-12%) in PBSC. In multivariate analysis, CMV infection (viremia/antigenemia and disease) was significantly more likely in patients who were seropositive to CMV, in those with acute graft versus host disease, and in those receiving T cell-depleted grafts. Graft source did not independently contribute to the risk of CMV infection and did not impact survival after CMV infection. These data confirm that recipient CMV serostatus remains the dominant risk factor for CMV infection. Recipients of UCB have similar risks of CMV infection, responses to antiviral therapy, and survival following CMV infection as recipients of either marrow or PBSC.

  8. The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients

    PubMed Central

    Hasanzamani, Boshra; Hami, Maryam; Zolfaghari, Vajihe; Torkamani, Mahtab; Ghorban Sabagh, Mahin; Ahmadi Simab, Saiideh

    2016-01-01

    Introduction: It is known that cytomegalovirus (CMV) infection is a common problem among kidney transplant patients. This infection can be increased morbidity and decreased graft survival. This problem has been associated with acute rejection too. Patients and Methods: One hundred and thirty renal transplant patients were included in a prospective, case-control study. The renal transplant patients were divided into two groups; patients group with CMV infection and control group without CMV infection. Serum CMV-IgG in all patients was positive (donor and recipients). None of patients had received anti-thymocyte-globulin and thymoglobulin. CMV infection was diagnosed by quantitative CMV-PCR (polymerase chain reaction) test (more than 500 copies/μg). Rejection episode was defined by kidney isotope scan or biopsy. Results: In the group of 66 CMV infection patients (41 male [62.1%] and 25 female [37.9%]) the incidence of graft rejection was 36%, however in the group of 64 control patients the incidence of graft rejection was 9.4 % (P < 0.005). Conclusion: CMV infection is important predisposing factor for acute allograft rejection after kidney transplantation. The results of this study suggests that the control of CMV infection could decrease episodes of acute kidney rejection. PMID:27471740

  9. [Review and guidelines on the prevention, diagnosis and treatment of post-natal cytomegalovirus infection].

    PubMed

    Alarcón Allen, A; Baquero-Artigao, F

    2011-01-01

    Postnatal cytomegalovirus (CMV) infection in the newborn can occur from exposure to maternal cervical secretions during birth, ingestion of breast milk, transfusion of blood products or transmission by body fluids of infected people. Breast milk is the main source of infection, given the high rate of CMV-positive mothers excreting CMV in milk. Freezing reduces the risk of CMV transmission by breastfeeding, although it does not eliminate it completely. Pasteurisation prevents such transmission, but it can alter the immunological properties of breast milk. Postnatal CMV infection is usually asymptomatic, as it normally results from viral reactivation in the mother, and the neonate is born with protective antibodies. However, in the very low birth weight premature infant the amount of transferred antibodies is smaller and a symptomatic infection can occur. Symptomatic post-natal CMV infection in the newborn typically causes hepatitis, neutropenia, thrombocytopenia or sepsis-like syndrome. Pneumonitis and enteritis are less common, but very characteristic. Diagnosis is based on urine virus detection at the time of onset of symptoms. Postnatal CMV infection in the newborn generally resolves spontaneously without antiviral treatment. Ganciclovir should be reserved for severe cases. Unlike congenital CMV disease, post-natal CMV infection in the preterm infant does not seem to be associated with hearing loss or abnormal neuro-development in long term follow-up.

  10. Cervical shedding of cytomegalovirus in human immunodeficiency virus type 1-infected women.

    PubMed

    Mostad, S B; Kreiss, J K; Ryncarz, A J; Overbaugh, J; Mandaliya, K; Chohan, B; Ndinya-Achola, J; Bwayo, J J; Corey, L

    1999-12-01

    Cervical shedding of cytomegalovirus (CMV) is important in transmission of CMV to exposed sexual partners and neonates. We evaluated prevalence and correlates of CMV DNA shedding in cervical secretions from a large cohort of HIV-1-seropositive women. Using polymerase chain reaction (PCR) assays, CMV DNA was detected in 183 (59%) cervical swab samples from 311 women. Cervical shedding of CMV DNA was significantly associated with shedding of HIV-1 DNA (odds ratio 1.8; 95% confidence interval 1.1-2.8). CMV shedding was also more frequent in women with Neisseria gonorrhoeae and Trichomonas vaginalis infections, but these associations were not statistically significant. Cervical shedding of CMV in HIV-1-infected women is very frequent and may reflect higher risk of transmission to sexual partners and neonates than previously appreciated.

  11. Combination antiviral therapy for ganciclovir-resistant cytomegalovirus infection in solid-organ transplant recipients.

    PubMed

    Mylonakis, Eleftherios; Kallas, Wendy M; Fishman, Jay A

    2002-05-15

    The resistance of cytomegalovirus (CMV) to ganciclovir is a factor in therapeutic failure and disease progression. The clinical significance of such resistance in solid-organ transplantation has not been completely established. Six patients who developed persistent infection due to ganciclovir-resistant CMV were treated with a combination of ganciclovir (50% of the therapeutic dose) and a daily dose of intravenous foscarnet that gradually increased to a maximum of 125 mg/kg. All patients responded clinically within 72-96 hours. Magnesium depletion occurred in all patients. No clinical or laboratory relapses have been observed in 6-30 months of follow-up. Gradually increasing doses of foscarnet combined with half-dose regimens of ganciclovir are safe and can be beneficial in organ transplant recipients with ganciclovir-resistant CMV infection. Larger studies are needed to identify the patients who are most likely to benefit from this regimen.

  12. Management of cytomegalovirus infection in a patient with malignant glioma treated with temozolomide and steroids.

    PubMed

    Okita, Yoshiko; Narita, Yoshitaka; Miyakita, Yasuji; Ohno, Makoto; Nagai, Shoichi; Shibui, Soichiro

    2012-01-01

    Temozolomide (TMZ) is the standard chemotherapy treatment for glioblastoma. Lymphocytopenia is reported to be the most frequent and severe adverse effect of TMZ and leads to opportunistic infections. Few cases of TMZ-induced cytomegalovirus (CMV) reactivation have so far been reported, and there are no guidelines regarding the use of chemotherapy after recovery from CMV reactivation. We herein report the case of a 45-year-old man with glioblastoma who developed CMV hepatitis following surgery and chemoradiotherapy with concomitant TMZ and steroids. After successful treatment of the CMV infection with an antiviral agent and recovery from the lymphocytopenia were achieved, the patient resumed maintenance therapy with TMZ under careful monitoring of his lymphocyte count and CMV pp65 antigenemia level.

  13. Diagnosis and Management of Human Cytomegalovirus Infection in the Mother, Fetus, and Newborn Infant

    PubMed Central

    Revello, Maria Grazia; Gerna, Giuseppe

    2002-01-01

    Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection and mental retardation. HCMV infection, while causing asymptomatic infections in most immunocompetent subjects, can be transmitted during pregnancy from the mother with primary (and also recurrent) infection to the fetus. Hence, careful diagnosis of primary infection is required in the pregnant woman based on the most sensitive serologic assays (immunoglobulin M [IgM] and IgG avidity assays) and conventional virologic and molecular procedures for virus detection in blood. Maternal prognostic markers of fetal infection are still under investigation. If primary infection is diagnosed in a timely manner, prenatal diagnosis can be offered, including the search for virus and virus components in fetal blood and amniotic fluid, with fetal prognostic markers of HCMV disease still to be defined. However, the final step for definite diagnosis of congenital HCMV infection is detection of virus in the blood or urine in the first 1 to 2 weeks of life. To date, treatment of congenital infection with antiviral drugs is only palliative both prior to and after birth, whereas the only efficacious preventive measure seems to be the development of a safe and immunogenic vaccine, including recombinant, subunit, DNA, and peptide-based vaccines now under investigation. The following controversial issues are discussed in the light of the most recent advances in the field: the actual perception of the problem; universal serologic screening before pregnancy; the impact of correct counseling on decision making by the couple involved; the role of prenatal diagnosis in ascertaining transmission of virus to the fetus; the impact of preconceptional and periconceptional infections on the prevalence of congenital infection; and the prevalence of congenitally infected babies born to mothers who were immune prior to pregnancy compared to the number born to mothers undergoing primary infection during pregnancy. PMID

  14. In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia.

    PubMed

    Francis, Stephen Starko; Wallace, Amelia D; Wendt, George A; Li, Linlin; Liu, Fenyong; Riley, Lee W; Kogan, Scott; Walsh, Kyle M; de Smith, Adam J; Dahl, Gary V; Ma, Xiaomei; Delwart, Eric; Metayer, Catherine; Wiemels, Joseph L

    2017-03-23

    It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pretreatment bone marrow specimens (n = 127 ALL in comparison with 38 acute myeloid leukemia cases in a comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n = 268) than healthy controls (n = 270) (odds ratio [OR], 3.71, confidence interval [CI], 1.56-7.92, P = .0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) than in non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted.

  15. The clinical impact of cytomegalovirus infection following allogeneic hematopoietic cell transplantation: Why the quest for meaningful prophylaxis still matters.

    PubMed

    Chan, Shawna T; Logan, Aaron C

    2017-02-02

    Latent infection with human cytomegalovirus (CMV) is common. Functional immunity effectively contains such latent infections; however, CMV reactivation may cause significant complications in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). In spite of the universal implementation of post-transplant screening for CMV viremia and the institution of pre-emptive antiviral management, CMV disease still occurs in a small portion of patients. Moreover, interactions between CMV and the immune system have significant implications for the incidence of graft-versus-host disease, the recurrence of malignancy, and non-relapse mortality following alloHCT, even in the era of pre-emptive antiviral management. CMV serostatus thus remains an important consideration for patients undergoing alloHCT. We review the clinical impact of CMV in the setting of alloHCT, interactions between CMV serostatus, viral reactivation, and transplant outcomes, as well as current and evolving strategies for prevention and treatment of CMV-related complications that may have significant impact for alloHCT recipients.

  16. Cytomegalovirus-Infected Cells Resist T Cell Mediated Killing in an HLA-Recognition Independent Manner.

    PubMed

    Proff, Julia; Walterskirchen, Christian; Brey, Charlotte; Geyeregger, Rene; Full, Florian; Ensser, Armin; Lehner, Manfred; Holter, Wolfgang

    2016-01-01

    In order to explore the potential of HLA-independent T cell therapy for human cytomegalovirus (HCMV) infections, we developed a chimeric antigen receptor (CAR) directed against the HCMV encoded glycoprotein B (gB), which is expressed at high levels on the surface of infected cells. T cells engineered with this anti-gB CAR recognized HCMV-infected cells and released cytokines and cytotoxic granules. Unexpectedly, and in contrast to analogous approaches for HIV, Hepatitis B or Hepatitis C virus, we found that HCMV-infected cells were resistant to killing by the CAR-modified T cells. In order to elucidate whether this phenomenon was restricted to the use of CARs, we extended our experiments to T cell receptor (TCR)-mediated recognition of infected cells. To this end we infected fibroblasts with HCMV-strains deficient in viral inhibitors of antigenic peptide presentation and targeted these HLA-class I expressing peptide-loaded infected cells with peptide-specific cytotoxic T cells (CTLs). Despite strong degranulation and cytokine production by the T cells, we again found significant inhibition of lysis of HCMV-infected cells. Impairment of cell lysis became detectable 1 day after HCMV infection and gradually increased during the following 3 days. We thus postulate that viral anti-apoptotic factors, known to inhibit suicide of infected host cells, have evolved additional functions to directly abrogate T cell cytotoxicity. In line with this hypothesis, CAR-T cell cytotoxicity was strongly inhibited in non-infected fibroblasts by expression of the HCMV-protein UL37x1, and even more so by additional expression of UL36. Our data extend the current knowledge on Betaherpesviral evasion from T cell immunity and show for the first time that, beyond impaired antigen presentation, infected cells are efficiently protected by direct blockade of cytotoxic effector functions through viral proteins.

  17. Sequence of protein synthesis in cells infected by human cytomegalovirus: early and late virus-induced polypeptides.

    PubMed Central

    Stinski, M F

    1978-01-01

    At least 10 distinct early virus-induced polypeptides were synthesized within 0 to 6 h after infection of permissive cells with cytomegalovirus. These virus-induced polypeptides were synthesized before and independently of viral DNA replication. A majority of these early virus-induced polypeptides were also synthesized in nonpermissive cells, which do not permit viral DNA replication. The virus-induced polypeptides synthesized before viral DNA replication were hypothesized to be nonstructural proteins coded for by the cytomegalovirus genome. Their synthesis was found to be a sequential process, since three proteins preceded the synthesis of the others. Synthesis of all early cytomegalovirus-induced proteins was a transient process; the proteins reached their highest molar ratios before the onset of viral DNA replication. Late viral proteins were synthesized at the time of the onset of viral DNA replication, which was approximately 15 h after infection. Their synthesis was continuous and increased in molar ratios with the accumulation of newly synthesized viral DNA in the cells. The presence of the amino acid analog canavanine or azetadine during the early stage of infection suppressed viral DNA replication. The amount of viral DNA synthesis was directly correlated to the relative amount of late viral protein synthesis. Because synthesis of late viral proteins depended upon viral DNA replication, the proteins were not detected in permissive cells treated with an inhibitor of viral DNA synthesis or in nonpermissive cells that are restrictive for cytomegalovirus DNA replication. Images PMID:209215

  18. Interstitial pneumonia and subclinical infection after intranasal inoculation of murine cytomegalovirus.

    PubMed Central

    Jordan, M C

    1978-01-01

    Although cytomegalovirus (CMV) infections are common throughout the world, little is known about the means of person-to-person transmission. To determine whether infection could be established by a respiratory route, studies were conducted in a murine CMV (MCMV) model by using intranasal inoculation. The infectious dose which resulted in pulmonary and systemic infection of half the mice was 100 plaque-forming units of MCMV. Here, infection was subclinical, but virus replicated in the lungs and subsequently disseminated via the blood to other organs within 7 days. The serum immunofluorescence antibody titer peaked by day 21. None of these mice died, although focal peribronchial interstitial pneumonitis was found in infected animals. In mice given greater than or equal to 10(4) plaque-forming units of MCMV intranasally, severe diffuse interstitial pneumonitis resulted uniformly, closely resembling that seen in immunocompromised patients and in newborn infants, and 20% of the animals died. Normal pulmonary architecture was obliterated by sheets of histiocytes, many containing MCMV intranuclear inclusions, and by accumulation of proteinaceous fluid in the interstitial and alveolar spaces. Of relevance to human disease, these experiments show that MCMV as a sole pathogen can cause severe interstitial pneumonitis in normal mice and that subclinical systemic infection results from respiratory inoculation of small amounts of virus. Images PMID:213384

  19. Sustained CD8+ T cell memory inflation after infection with a single-cycle cytomegalovirus.

    PubMed

    Snyder, Christopher M; Cho, Kathy S; Bonnett, Elizabeth L; Allan, Jane E; Hill, Ann B

    2011-10-01

    Cytomegalovirus (CMV) is a β-herpesvirus that establishes a lifelong latent or persistent infection. A hallmark of chronic CMV infection is the lifelong persistence of large numbers of virus-specific CD8+ effector/effector memory T cells, a phenomenon called "memory inflation". How the virus continuously stimulates these T cells without being eradicated remains an enigma. The prevailing view is that CMV establishes a low grade "smoldering" infection characterized by tiny bursts of productive infection which are rapidly extinguished, leaving no detectable virus but replenishing the latent pool and leaving the immune system in a highly charged state. However, since abortive reactivation with limited viral gene expression is known to occur commonly, we investigated the necessity for virus reproduction in maintaining the inflationary T cell pool. We inhibited viral replication or spread in vivo using two different mutants of murine CMV (MCMV). First, famcyclovir blocked the replication of MCMV encoding the HSV Thymidine Kinase gene, but had no impact on the CD8+ T cell memory inflation once the infection was established. Second, MCMV that lacks the essential glycoprotein L, and thus is completely unable to spread from cell to cell, also drove memory inflation if the virus was administered systemically. Our data suggest that CMV which cannot spread from the cells it initially infects can repeatedly generate viral antigens to drive memory inflation without suffering eradication of the latent genome pool.

  20. The Transcription and Translation Landscapes during Human Cytomegalovirus Infection Reveal Novel Host-Pathogen Interactions

    PubMed Central

    Shitrit, Alina; Shani, Odem; Le-Trilling, Vu Thuy Khanh; Trilling, Mirko; Friedlander, Gilgi; Tanenbaum, Marvin; Stern-Ginossar, Noam

    2015-01-01

    Viruses are by definition fully dependent on the cellular translation machinery, and develop diverse mechanisms to co-opt this machinery for their own benefit. Unlike many viruses, human cytomegalovirus (HCMV) does suppress the host translation machinery, and the extent to which translation machinery contributes to the overall pattern of viral replication and pathogenesis remains elusive. Here, we combine RNA sequencing and ribosomal profiling analyses to systematically address this question. By simultaneously examining the changes in transcription and translation along HCMV infection, we uncover extensive transcriptional control that dominates the response to infection, but also diverse and dynamic translational regulation for subsets of host genes. We were also able to show that, at late time points in infection, translation of viral mRNAs is higher than that of cellular mRNAs. Lastly, integration of our translation measurements with recent measurements of protein abundance enabled comprehensive identification of dozens of host proteins that are targeted for degradation during HCMV infection. Since targeted degradation indicates a strong biological importance, this approach should be applicable for discovering central host functions during viral infection. Our work provides a framework for studying the contribution of transcription, translation and degradation during infection with any virus. PMID:26599541

  1. Thrombosis associated with cytomegalovirus infection in patients with ANCA-positive vasculitis.

    PubMed

    Wolf, G; Porth, J; Stahl, R A

    2001-11-01

    Three cases of venous thrombosis with pulmonary embolism in two patients associated with underlying antineutrophil cytoplasmic autoantibody (ANCA)-positive vasculitis and reactivated cytomegalovirus (CMV) infection are described. In vitro studies previously have shown that infection of endothelium with CMV increases the release of procoagulant factors and stimulates the expression of adhesion molecules. Because the endothelial cell plays a pivotal role in maintaining the equilibrium between procoagulant and anticoagulant states, injury by ANCA-positive vasculitis and additional infection with CMV may ignite a local thrombosis easily. Although venous thrombosis is uncommon in CMV infection (eg, in the immunosuppressed state after organ transplantation), the combination of vasculitis and reactivated CMV infection may have contributed to injury of the vessel wall with subsequent development of thrombosis. A better awareness of this association could improve morbidity and may lead to prevention of potentially life-threatening pulmonary embolism. Patients with ANCA-positive vasculitis and CMV infection may profit from prophylactic anticoagulant therapy with heparin or low-molecular-weight heparin.

  2. Impaired cellular immune response to tetanus toxoid but not to cytomegalovirus in effectively HAART-treated HIV-infected children.

    PubMed

    Alsina, Laia; Noguera-Julian, Antoni; Fortuny, Clàudia

    2013-05-07

    Despite of highly active antiretroviral therapy, the response to vaccines in HIV-infected children is poor and short-lived, probably due to a defect in cellular immune responses. We compared the cellular immune response (assessed in terms of IFN-γ production) to tetanus toxoid and to cytomegalovirus in a series of 13 HIV-perinatally-infected children and adolescents with optimal immunovirological response to first line antiretroviral therapy, implemented during chronic infection. A stronger cellular response to cytomegalovirus (11 out of 13 patients) was observed, as compared to tetanus toxoid (1 out of 13; p=0.003). These results suggest that the repeated exposition to CMV, as opposed to the past exposition to TT, is able to maintain an effective antigen-specific immune response in stable HIV-infected pediatric patients and strengthen current recommendations on immunization practices in these children.

  3. Hepatic angiosarcoma mimicking congenital cytomegalovirus infection in an infant with thrombocytopenia.

    PubMed

    Yoon, Hoi Soo; Choi, Yong-Sung; Im, Ho Joon

    2015-04-01

    Hepatic angiosarcomas are uncommon, highly aggressive tumors, rarely seen in children. A 3-month-old female infant was admitted to hospital for evaluation of multiple petechiae on her body. She had hepatosplenomegaly and scattered petechiae over her entire body. Laboratory tests indicated thrombocytopenia and positive cytomegalovirus (CMV) polymerase chain reaction. Ganciclovir was started, and the platelet count increased. After 4 months the patient was readmitted to hospital for drowsy mental status and eventually died from severe bleeding. Needle biopsy of the liver was performed after receiving written consent from the parents. Pathological findings of the liver lesion included features consistent with hepatic angiosarcoma. There have been no previous reports of hepatic angiosarcoma in Korean infants. Here, we report an infant with hepatosplenomegaly and thrombocytopenia who was diagnosed with hepatic angiosarcoma mimicking congenital CMV infection.

  4. Serological markers of hepatitis B virus and cytomegalovirus infections in Norwegians with coagulation factor defects.

    PubMed

    Rollag, H; Evensen, S A; Frøland, S S; Glomstein, A

    1990-02-01

    The prevalence of serological markers for present and past hepatitis B virus (HBV) infection and antibodies against cytomegalovirus (CMV) among Norwegians with coagulation factor defects was examined in serum samples collected before virus-inactivated coagulation concentrates came into use. Sera collected in 1985/86 from 324 of 377 (86%) registered persons with such defects were available. Three persons were chronic carriers of HBsAg. The prevalence of HBV antibodies was 28% compared with about 5% in the general population. The highest prevalence rate was found among patients with severe haemophilia A (44%) and in patients with haemophilia B (39%). The prevalence of anti-CMV antibodies was 75% which is similar to that found in the general Norwegian population.

  5. cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection

    PubMed Central

    McDonald, Bryan; Takahashi, Mariko; Dhanwani, Rekha; Sharma, Nikita; Huang, Jenny; Pham, Elise; Benedict, Chris A.

    2016-01-01

    ABSTRACT Several innate sensing pathways contribute to the control of early cytomegalovirus (CMV) infection, leading to a multiphasic type I interferon (IFN-I) response that limits viral replication and promotes host defenses. Toll-like receptor (TLR)-dependent pathways induce IFN-I production in CMV-infected plasmacytoid dendritic cells; however, the initial burst of IFN-I that occurs within the first few hours in vivo is TLR independent and emanates from stromal cells. Here we show that primary human endothelial cells mount robust IFN-I responses to human CMV that are dependent upon cyclic GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3) signaling. Disruption of STING expression in endothelial cells by clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 revealed that it is essential for the induction of IFN-I and restriction of CMV replication. Consistently, STING was necessary to mount the first phase of IFN-I production and curb CMV replication in infected mice. Thus, DNA sensing through STING is critical for primary detection of both human and mouse CMV in nonhematopoietic cells and drives the initial wave of IFN-I that is key for controlling early viral replication in vivo. IMPORTANCE Cytomegalovirus (CMV) is one of the most common viral pathogens, with the majority of people contracting the virus in their lifetime. Although acute infection is mostly asymptomatic in healthy persons, significant pathology is observed in immunocompromised individuals, and chronic CMV infection may exacerbate a myriad of inflammatory conditions. Here we show that primary human endothelial cells mount robust IFN-I responses against CMV via a cGAS/STING/IRF3 pathway. Disruption of STING expression by CRISPRs revealed an essential role in eliciting IFN-I responses and restricting CMV replication. Consistently, in mice, STING is necessary for the first phase of IFN-I production that limits early CMV replication. Our results demonstrate a

  6. The epidemiology and prevention of congenital cytomegalovirus infection and disease: activities of the Centers for Disease Control and Prevention Workgroup.

    PubMed

    Ross, Danielle S; Dollard, Sheila C; Victor, Marcia; Sumartojo, Esther; Cannon, Michael J

    2006-04-01

    Perhaps no single cause of birth defects and developmental disabilities in the United States currently provides greater opportunity for improved outcomes in more children than congenital cytomegalovirus (CMV). --Cannon and Davis. BMC Public Health 2005;5:70 Each year in the United States, thousands of children and their families are affected by congenital cytomegalovirus (CMV) infection. More children may be affected by congenital CMV than by other, better known childhood conditions, such as Down syndrome, fetal alcohol syndrome, and spina bifida. The Centers for Disease Control and Prevention (CDC) has formed a Workgroup on Congenital CMV, led by the National Center on Birth Defects and Developmental Disabilities and the National Center on Infectious Diseases. This report provides background on congenital CMV infection and describes the goals and activities of the workgroup for reducing the burden of sequelae of congenital CMV infection.

  7. Clinical significance of cytomegalovirus infection in patients with inflammatory bowel disease.

    PubMed

    Garrido, Elena; Carrera, Elisa; Manzano, Rebeca; Lopez-Sanroman, Antonio

    2013-01-07

    Cytomegalovirus (CMV) infection is common in humans. The virus then enters a "latency phase" and can reactivate to different stimuli such as immunosuppression. The clinical significance of CMV infection in inflammatory bowel disease is different in Crohn's disease (CD) and ulcerative colitis (UC). CMV does not interfere in the clinical course of CD. However, CMV reactivation is frequent in severe or steroid-resistant UC. It is not known whether the virus exacerbates the disease or simply appears as a bystander of a severe disease. Different methods are used to diagnose CMV colitis. Diagnosis is classically based on histopathological identification of viral-infected cells or CMV antigens in biopsied tissues using haematoxylin-eosin or immunohistochemistry, other tests on blood or tissue samples are currently being investigated. Polymerase chain reaction performed in colonic mucosa has a high sensitivity and a positive result could be associated with a worse prognosis disease; further studies are needed to determine the most appropriate strategy with positive CMV-DNA in colonic mucosa. Specific endoscopic features have not been described in active UC and CMV infection. CMV colitis is usually treated with ganciclovir for several weeks, there are different opinions about whether or not to stop immunosuppressive therapy. Other antiviral drugs may be used. Multicenter controlled studies would needed to determine which subgroup of UC patients would benefit from early antiviral treatment.

  8. Murine Cytomegalovirus Abortively Infects Human Dendritic Cells, Leading to Expression and Presentation of Virally Vectored Genes

    PubMed Central

    Wang, Xiuqing; Messerle, Martin; Sapinoro, Ramil; Santos, Kathlyn; Hocknell, Peter K.; Jin, Xia; Dewhurst, Stephen

    2003-01-01

    Dendritic cells (DC) are potent antigen-presenting cells that play a crucial role in antigen-specific immune responses. Thus, the targeting of exogenous antigens to DC has become a popular approach for cancer immunotherapy and vaccine development. In this report, we studied the interplay between murine cytomegalovirus (MCMV) and human monocyte-derived DC. The results showed that an enhanced green fluorescent protein (EGFP)-encoding, replication-competent MCMV vector underwent abortive infection in human DC; this was accompanied by the efficient expression of EGFP. Infection of human DC by this vector resulted in a modest increase in the expression of cell surface proteins associated with DC maturation and has no significant effect on the immunostimulatory function of the cells, as reflected by their ability to support T-cell proliferation in a mixed-lymphocyte reaction. Finally, an MCMV vector encoding the human immunodeficiency virus type 1 (HIV-1) gp120 envelope glycoprotein was constructed and used to infect cultured human DC. The infected DC were shown to be capable of stimulating the expansion of autologous, gp120-specific, class I-restricted T lymphocytes from an HIV-1-negative donor, as determined by tetramer staining and enzyme-linked immunospot analysis. Taken together, these results suggest that MCMV may have potential utility as a vector for human vaccine development. PMID:12805417

  9. Enhanced capacity of DNA repair in human cytomegalovirus-infected cells

    SciTech Connect

    Nishiyama, Y.; Rapp, F.

    1981-04-01

    Plaque formation in Vero cells by UV-irradiated herpes simplex virus was enhanced by infection with human cytomegalovirus (HCMV), UV irradiation, or treatment with methylmethanesulfonate. Preinfection of Vero cells with HCMV enhanced reactivation of UV-irradiated herpes simplex virus more significantly than did treatment with UV or methylmethanesulfonate alone. A similar enhancement by HCMV was observed in human embryonic fibroblasts, but not in xeroderma pigmentosum (XP12BE) cells. It was also found that HCMV infection enhanced hydroxyurea-resistant DNA synthesis induced by UV light or methylmethanesulfonate. Alkaline sucrose gradient sedimentation analysis revealed an enhanced rate of synthesis of all size classes of DNA in UV-irradiated HCMV-infected Vero cells. However, HCMV infection did not induce repairable lesions in cellular DNA and did not significantly inhibit host cell DNA synthesis, unlike UV or methylmethanesulfonate. These results indicate that HCMV enhanced DNA repair capacity in the host cells without producing detectable lesions in cellular DNA and without inhibiting DNA synthesis. This repair appeared to be error proof for UV-damaged herpes simplex virus DNA when tested with herpes simplex virus thymidine kinase-negative mutants.

  10. Congenital cytomegalovirus infection in pregnancy: a review of prevalence, clinical features, diagnosis and prevention.

    PubMed

    Naing, Zin W; Scott, Gillian M; Shand, Antonia; Hamilton, Stuart T; van Zuylen, Wendy J; Basha, James; Hall, Beverly; Craig, Maria E; Rawlinson, William D

    2016-02-01

    Human cytomegalovirus (CMV) is under-recognised, despite being the leading infectious cause of congenital malformation, affecting ~0.3% of Australian live births. Approximately 11% of infants born with congenital CMV infection are symptomatic, resulting in clinical manifestations, including jaundice, hepatosplenomegaly, petechiae, microcephaly, intrauterine growth restriction and death. Congenital CMV infection may cause severe long-term sequelae, including progressive sensorineural hearing loss and developmental delay in 40-58% of symptomatic neonates, and ~14% of initially asymptomatic infected neonates. Up to 50% of maternal CMV infections have nonspecific clinical manifestations, and most remain undetected unless specific serological testing is undertaken. The combination of serology tests for CMV-specific IgM, IgG and IgG avidity provide improved distinction between primary and secondary maternal infections. In pregnancies with confirmed primary maternal CMV infection, amniocentesis with CMV-PCR performed on amniotic fluid, undertaken after 21-22 weeks gestation, may determine whether maternofetal virus transmission has occurred. Ultrasound and, to a lesser extent, magnetic resonance imaging are valuable tools to assess fetal structural and growth abnormalities, although the absence of fetal abnormalities does not exclude fetal damage. Diagnosis of congenital CMV infection at birth or in the first 3 weeks of an infant's life is crucial, as this should prompt interventions for prevention of delayed-onset hearing loss and neurodevelopmental delay in affected infants. Prevention strategies should also target mothers because increased awareness and hygiene measures may reduce maternal infection. Recognition of the importance of CMV in pregnancy and in neonates is increasingly needed, particularly as therapeutic and preventive interventions expand for this serious problem.

  11. Macrophage activation associated with chronic murine cytomegalovirus infection results in more severe experimental choroidal neovascularization.

    PubMed

    Cousins, Scott W; Espinosa-Heidmann, Diego G; Miller, Daniel M; Pereira-Simon, Simone; Hernandez, Eleut P; Chien, Hsin; Meier-Jewett, Courtney; Dix, Richard D

    2012-01-01

    The neovascular (wet) form of age-related macular degeneration (AMD) leads to vision loss due to choroidal neovascularization (CNV). Since macrophages are important in CNV development, and cytomegalovirus (CMV)-specific IgG serum titers in patients with wet AMD are elevated, we hypothesized that chronic CMV infection contributes to wet AMD, possibly by pro-angiogenic macrophage activation. This hypothesis was tested using an established mouse model of experimental CNV. At 6 days, 6 weeks, or 12 weeks after infection with murine CMV (MCMV), laser-induced CNV was performed, and CNV severity was determined 4 weeks later by analysis of choroidal flatmounts. Although all MCMV-infected mice exhibited more severe CNV when compared with control mice, the most severe CNV developed in mice with chronic infection, a time when MCMV-specific gene sequences could not be detected within choroidal tissues. Splenic macrophages collected from mice with chronic MCMV infection, however, expressed significantly greater levels of TNF-α, COX-2, MMP-9, and, most significantly, VEGF transcripts by quantitative RT-PCR assay when compared to splenic macrophages from control mice. Direct MCMV infection of monolayers of IC-21 mouse macrophages confirmed significant stimulation of VEGF mRNA and VEGF protein as determined by quantitative RT-PCR assay, ELISA, and immunostaining. Stimulation of VEGF production in vivo and in vitro was sensitive to the antiviral ganciclovir. These studies suggest that chronic CMV infection may serve as a heretofore unrecognized risk factor in the pathogenesis of wet AMD. One mechanism by which chronic CMV infection might promote increased CNV severity is via stimulation of macrophages to make pro-angiogenic factors (VEGF), an outcome that requires active virus replication.

  12. Genetic mechanism associated with congenital cytomegalovirus infection and analysis of effects of the infection on pregnancy outcome.

    PubMed

    Li, J M; Zhang, H F; Zhang, X Q; Huang, G L; Huang, H Z; Yu, W W

    2015-10-27

    We aimed to compare the diagnostic value of various detection methods for cytomegalovirus (CMV) infection, to investigate the genetic mechanism associated with CMV infection in pregnant women, and to analyze the risk of sequelae development in fetuses with CMV infection. A total of 300 participants who had the same immunosuppressive regimen and received preemptive therapy for CMV infection were prospectively enrolled in this study; they included 289 vaccine trial participants. The gB-absorbed CMV IgG assay was performed for each vaccine trial participant. The healthy women were divided into 2 groups, and amniotic fluids were collected from them at 15-18 weeks of gestation to test for CMV seropositivity before conception by using IgM specific antibodies, CMV-DNA, and IgG analysis. In 104 cases, cord blood sera and urine specimens were also collected from the infants and examined. The sensitivity and specificity of immediate-early messenger RNA and pp67 (late) messenger RNA detection by the nucleic acid sequence-based amplification technique was comparable to those of virus isolation and PCR. Furthermore, an association between single nucleotide polymorphisms in the TLR-2 gene and congenital CMV infection was observed and confirmed. Moreover, CMV infection during early pregnancy has been shown to have a much more severe effect on the pregnancy outcome compared to infection during later stages of pregnancy.

  13. Effects of cytomegalovirus infection on the prognosis of inflammatory bowel disease patients

    PubMed Central

    Zhang, Wei-Xia; Ma, Cheng-Yan; Zhang, Jian-Guo; He, Feng; Liu, Qing-Min; Cheng, Aibin; Liu, Tiejun; Zhang, Junwei; Wang, Jianjun; Bu, Xuan; Xie, Yuxi; Diao, Zengli; Bai, Jing

    2016-01-01

    The aim of the present study was to investigate the effects of cytomegalovirus (CMV) infection on the prognosis of inflammatory bowel disease (IBD). Various databases were searched using a combination of keywords associated with CMV infection and IBD. Subsequent to the selection of relevant studies in line with strict inclusion and exclusion criteria, a meta-analysis was conducted using the Stata 12.0 software. A total of 195 studies were initially retrieved, including 28 studies in Chinese and 167 in English. Following the exclusion of unsuitable studies, 7 cohort studies with 374 IBD patients were included in the meta-analysis. The results of the present study identified significant differences between patients with and without CMV infection regarding the disease duration of IBD [standardized mean difference, −0.81; 95% confidence interval (CI), −1.19 to −0.43; P<0.001], the efficacy of corticosteroid therapy [relative risk (RR), 1.24; 95% CI, 1.02–1.49; P=0.029], the colectomy rate (RR, 2.13; 95% CI, 1.03–4.40; P=0.042) and the incidence of severe IBD (RR, 1.32; 95% CI, 1.04–1.67; P=0.022). Considering the IBD onset area, patients with CMV infection may have higher susceptibility to pancolitis (RR, 1.31; 95% CI; 1.01–1.72; P=0.045); however, no difference in susceptibility to left-sided IBD was observed between patients with or without CMV infection (RR, 0.97; 95% CI, 0.72–1.30; P=0.828). In conclusion, CMV infection may be associated with the disease duration, efficacy of corticosteroid therapy, colectomy rate, severe IBD incidence and disease location of IBD; thus, the presence of CMV infection may be considered as an important biomarker for determining the prognosis of IBD. PMID:27882151

  14. Intrinsic Contribution of Perforin to NK-Cell Homeostasis during Mouse Cytomegalovirus Infection.

    PubMed

    Arapović, Maja; Brizić, Ilija; Popović, Branka; Jurković, Slaven; Jordan, Stefan; Krmpotić, Astrid; Arapović, Jurica; Jonjić, Stipan

    2016-01-01

    In addition to their role as effector cells in virus control, natural killer (NK) cells have an immunoregulatory function in shaping the antiviral T-cell response. This function is further pronounced in perforin-deficient mice that show the enhanced NK-cell proliferation and cytokine secretion upon mouse cytomegalovirus (MCMV) infection. Here, we confirmed that stronger activation and maturation of NK cells in perforin-deficient mice correlates with higher MCMV load. To further characterize the immunoregulatory potential of perforin, we compared the response of NK cells that express or do not express perforin using bone-marrow chimeras. Our results demonstrated that the enhanced proliferation and maturation of NK cells in MCMV-infected bone-marrow chimeras is an intrinsic property of perforin-deficient NK cells. Thus, in addition to confirming that NK-cell proliferation is virus load dependent, our data extend this notion demonstrating that perforin plays an intrinsic role as a feedback mechanism in the regulation of NK-cell proliferation during viral infections.

  15. Murine Cytomegalovirus Infection Induces Susceptibility to EAE in Resistant BALB/c Mice

    PubMed Central

    Milovanovic, Jelena; Popovic, Branka; Milovanovic, Marija; Kvestak, Daria; Arsenijevic, Aleksandar; Stojanovic, Bojana; Tanaskovic, Irena; Krmpotic, Astrid; Arsenijevic, Nebojsa; Jonjic, Stipan; Lukic, Miodrag L.

    2017-01-01

    In contrast to C57BL/6 mice, BALB/c mice are relatively resistant to the induction of experimental autoimmune encephalomyelitis (EAE) after challenge with MOG35–55 peptide. Here, we provide the first evidence that infection with murine cytomegalovirus (MCMV) in adulthood abrogates this resistance. Infected BALB/c mice developed clinical and histological signs similar to those seen in susceptible C57BL/6 mice. In addition to CD4+ cells, large proportion of cells in the infiltrate of diseased BALB/c mice was CD8+, similar with findings in multiple sclerosis. CD8+ cells that responded to ex vivo restimulation with MOG35–55 were not specific for viral epitopes pp89 and m164. MCMV infection favors proinflammatory type of dendritic cells (CD86+CD40+CD11c+) in the peripheral lymph organs, M1 type of microglia in central nervous system, and increases development of Th1/Th17 encephalitogenic cells. This study indicates that MCMV may enhance autoimmune neuropathology and abrogate inherent resistance to EAE in mouse strain by enhancing proinflammatory phenotype of antigen-presenting cells, Th1/Th17, and CD8 response to MOG35–55. PMID:28289417

  16. Impact of Persistent Cytomegalovirus Infection on Dynamic Changes in Human Immune System Profile

    PubMed Central

    Vescovini, Rosanna; Telera, Anna Rita; Pedrazzoni, Mario; Abbate, Barbara; Rossetti, Pietro; Verzicco, Ignazio; Arcangeletti, Maria Cristina; Medici, Maria Cristina; Calderaro, Adriana; Volpi, Riccardo; Sansoni, Paolo; Fagnoni, Francesco Fausto

    2016-01-01

    Human cytomegalovirus (HCMV) imprints the immune system after primary infection, however its effect during chronic infection still needs to be deciphered. In this study we report the variation of blood cell count along with anti-HCMV IgG and T cell responses to pp-65 and IE-1 antigens, that occurred after an interval of five years in a cohort of 25 seropositive healthy adults. We found increased anti-viral IgG antibody responses and intracellular interferon-gamma secreting CD8+ T cell responses to pp-65: a result consistent with memory inflation. With the only exception of shortage in naive CD8+ T cells most memory T cell subsets as well as total CD8+ T cells, T cells, lymphocytes, monocytes and leukocytes had increased. By contrast, none of the cell types tested were found to have increased in 14 subjects stably seronegative. Rather, in addition to a shortage in naive CD8+ T cells, also memory T cell subsets and most other cell types decreased, either in a statistically significant or non-significant manner. The trend of T cell pool representation with regard to CD4/CD8 ratio was in the opposing directions depending on HCMV serology. Globally, this study demonstrates different dynamic changes of most blood cell types depending on presence or absence of HCMV infection. Therefore, HCMV plays a continual role in modulating homeostasis of blood T cells and a broader expanding effect on other cell populations of lymphoid and myeloid origin. PMID:26990192

  17. Awareness of Cytomegalovirus Infection among Pregnant Women in Geneva, Switzerland: A Cross-sectional Study

    PubMed Central

    Willame, Alexia; Blanchard-Rohner, Geraldine; Combescure, Christophe; Irion, Olivier; Posfay-Barbe, Klara; Martinez de Tejada, Begoña

    2015-01-01

    Background: Cytomegalovirus (CMV) is the most frequent cause of congenital infection and commonly associated with sensorineural deficit. At present, there is neither prophylaxis nor treatment during pregnancy. The objective of this study was to evaluate the level of awareness regarding CMV infection and its consequences in women delivering at the University of Geneva Hospitals (Geneva, Switzerland). Methods: The study consisted of a validated questionnaire completed by women in the immediate postpartum period. Results: The questionnaire was completed by 59% (314/528) of delivering women. Only 39% (123/314) knew about CMV and 19.7% (62/314) had received information about preventive measures. Women were more aware about other congenital diseases, such as toxoplasmosis (87%); human immunodeficiency virus (99%); syphilis (85.5%); rubella (92.3%); and group B Streptococcus (63%). Factors associated with CMV awareness were Swiss nationality, high education level, employment in health care or with children, and being followed by an obstetrician. Regarding quality of information, few were aware of the main CMV complications (deafness, 25.2%; mental retardation, 34.5%). Among those informed about CMV, most (74.6%) knew about preventive measures. Among these, 82.5% thought that these were easily applicable. Conclusions: Most women are unaware of CMV infection and its potential risks during pregnancy. It is crucial to improve CMV information given to pregnant women to prevent the risks for the fetus/newborn. PMID:26633451

  18. Treatment of Cytomegalovirus Infection with Cidofovir and CMV Immune Globulin in a Lung Transplant Recipient.

    PubMed

    Wilkens, Heinrike; Sester, Martina

    2016-01-01

    Cytomegalovirus (CMV) infection after lung transplantation is associated with increased risk for pneumonitis and bronchiolitis obliterans as well as allograft rejection and opportunistic infections. Ganciclovir is the mainstay of prophylaxis and treatment but CMV infections can be unresponsive. Apart from direct antiviral drugs, CMV immunoglobulin (CMVIG) preparations may be considered but are only licensed for prophylaxis. A CMV-seronegative 42-year-old man with cystic fibrosis received a lung from a CMV-seropositive donor. Intravenous ganciclovir prophylaxis was delayed until day 12 due to acute postoperative renal failure and was accompanied by five doses of CMVIG (10 g). By day 16, CMV-DNA was detectable and rising; CMV-specific T-cells were undetectable. Switch from ganciclovir to foscarnet prompted a transient decrease in CMV viral load, but after increasing again to reach 3600 copies/mL foscarnet was changed to intravenous cidofovir and CMVIG was restarted. CMV load continued to fluctuate and declined slowly, whereas CMV-specific T-cells were detected five months later and increased thereafter. At last follow-up, the patient was in very good clinical condition with no evidence of bronchiolitis obliterans. No side effects of this treatment were observed. In this hard-to-treat case, the combination of cidofovir with off-label use of CMVIG contributed to a successful outcome.

  19. Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease.

    PubMed

    Lurain, Nell S; Hanson, Barbara A; Martinson, Jeffrey; Leurgans, Sue E; Landay, Alan L; Bennett, David A; Schneider, Julie A

    2013-08-15

    Serum, cerebrospinal fluid (CSF), and cryopreserved lymphocytes from subjects in the Rush Alzheimer's Disease Center Religious Orders Study were analyzed for associations between cytomegalovirus (CMV) infection and clinical and pathological markers of Alzheimer disease. CMV antibody levels were associated with neurofibrillary tangles (NFTs). CSF interferon γ was only detected in seropositive subjects and was significantly associated with NFTs. The percentage of senescent T cells (CD4+ or CD8+CD28-CD57+) was significantly higher for CMV-seropositive as compared to CMV-seronegative subjects and was marginally associated with the pathologic diagnosis of Alzheimer disease (CD4+) or amyloid-β (CD8+). Immunocytochemical analysis showed induction of amyloid-β in human foreskin fibroblasts (HFFs) infected with each of 3 clinical CMV strains. In the same subjects, there was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid-β. These data support an association between CMV and the development of Alzheimer disease.

  20. ACSS2-mediated acetyl-CoA synthesis from acetate is necessary for human cytomegalovirus infection.

    PubMed

    Vysochan, Anna; Sengupta, Arjun; Weljie, Aalim M; Alwine, James C; Yu, Yongjun

    2017-02-21

    Recent studies have shown that human cytomegalovirus (HCMV) can induce a robust increase in lipid synthesis which is critical for the success of infection. In mammalian cells the central precursor for lipid biosynthesis, cytosolic acetyl CoA (Ac-CoA), is produced by ATP-citrate lyase (ACLY) from mitochondria-derived citrate or by acetyl-CoA synthetase short-chain family member 2 (ACSS2) from acetate. It has been reported that ACLY is the primary enzyme involved in making cytosolic Ac-CoA in cells with abundant nutrients. However, using CRISPR/Cas9 technology, we have shown that ACLY is not essential for HCMV growth and virally induced lipogenesis. Instead, we found that in HCMV-infected cells glucose carbon can be used for lipid synthesis by both ACLY and ACSS2 reactions. Further, the ACSS2 reaction can compensate for the loss of ACLY. However, in ACSS2-KO human fibroblasts both HCMV-induced lipogenesis from glucose and viral growth were sharply reduced. This reduction suggests that glucose-derived acetate is being used to synthesize cytosolic Ac-CoA by ACSS2. Previous studies have not established a mechanism for the production of acetate directly from glucose metabolism. Here we show that HCMV-infected cells produce more glucose-derived pyruvate, which can be converted to acetate through a nonenzymatic mechanism.

  1. Comparative analysis of NK cell receptor repertoire in adults and very elderly subjects with cytomegalovirus infection.

    PubMed

    Juárez-Vega, Guillermo; Rangel-Ramírez, Velia; Monsiváis-Urenda, Adriana; Niño-Moreno, Perla; Garcia-Sepúlveda, Christian; Noyola, Daniel E; González-Amaro, Roberto

    2017-01-16

    Human cytomegalovirus (HCMV) infection in children and young adults has been associated with changes in the innate immune system. We herein analyzed the possible effect of very long term HCMV infection on the expression of several NK cell receptors. Ninety HCMV-seropositive individuals were included and classified as young adults (n=30), elderly (n=30) and very elderly subjects (n=30). A peripheral blood sample was obtained and the expression of NK cell receptors (NKG2A, NKG2C, ILT2, CD161, KIR2DL1, KIR3DL1, and KIR3DL2) by NK and other lymphocyte subsets was assessed by flow cytometry. In addition, the frequency of the sixteen KIR genes was analyzed by polymerase chain reaction. We found a significant increase in the number of NKG2C+ NK and T cells in elderly individuals compared to young adults accompanied by an opposite trend in the number of NKG2A+ lymphocytes, and ILT2+ cells were also increased in elderly individuals. A significant increase in the levels of CD3-CD56+NKG2C+CD57+ cells was also detected in the elderly groups. Finally, KIR gene analysis revealed that the KIR genotype 2 was significantly less frequent in the elderly individuals. Our results support that long-term infection by HCMV exerts a significant progressive effect on the innate immune system.

  2. High-Resolution Profiling and Analysis of Viral and Host Small RNAs during Human Cytomegalovirus Infection

    PubMed Central

    Stark, Thomas J.; Arnold, Justin D.; Spector, Deborah H.

    2012-01-01

    Human cytomegalovirus (HCMV) contributes its own set of microRNAs (miRNAs) during lytic infection of cells, likely fine-tuning conditions important for viral replication. To enhance our understanding of this component of the HCMV-host transcriptome, we have conducted deep-sequencing analysis of small RNAs (smRNA-seq) from infected human fibroblast cells. We found that HCMV-encoded miRNAs accumulate to ∼20% of the total smRNA population at late stages of infection, and our analysis led to improvements in viral miRNA annotations and identification of two novel HCMV miRNAs, miR-US22 and miR-US33as. Both of these miRNAs were capable of functionally repressing synthetic targets in transient transfection experiments. Additionally, through cross-linking and immunoprecipitation (CLIP) of Argonaute (Ago)-bound RNAs from infected cells, followed by high-throughput sequencing, we have obtained direct evidence for incorporation of all HCMV miRNAs into the endogenous host silencing machinery. Surprisingly, three HCMV miRNA precursors exhibited differential incorporation of their mature miRNA arms between Ago2 and Ago1 complexes. Host miRNA abundances were also affected by HCMV infection, with significant upregulation observed for an miRNA cluster containing miR-96, miR-182, and miR-183. In addition to miRNAs, we also identified novel forms of virus-derived smRNAs, revealing greater complexity within the smRNA population during HCMV infection. PMID:22013051

  3. Human cytomegalovirus tropism for endothelial/epithelial cells: scientific background and clinical implications.

    PubMed

    Revello, M Grazia; Gerna, Giuseppe

    2010-05-01

    Human cytomegalovirus (HCMV) has been routinely isolated from and propagated in vitro in human embryonic lung fibroblast (HELF) cell cultures, while in vivo it is known to infect predominantly endothelial and epithelial cells. In recent years, genetic determinants of the HCMV tropism for endothelial/epithelial cells were identified in the UL131A/UL130/UL128 locus of HCMV genome of wild-type strains. UL131A-UL128 gene products form a complex with glycoprotein H (gH) and L (gL) resulting in a gH/gL/UL131A-UL128 complex that is required for HCMV entry into endothelial/epithelial cells. In contrast, virus entry into fibroblasts has its genetic determinants in the complex gH/gL/gO (or gH/gL). During primary HCMV infection, the neutralising antibody response measured in endothelial cells (EC) is potent, occurs very early and is directed mostly against combinations of two or three gene products of the UL131A-128 locus. On the contrary, neutralising antibodies measured in fibroblasts appear late, are relatively weak in potency and are directed against gH and gB. The T-cell immune response to UL131A-UL128 gene products remains to be investigated. Recently, a role has been proposed for neutralising antibody in conferring prevention/protection against HCMV infection/disease in pregnant women with primary HCMV infection. However, the level of cooperation between humoral immunity and the well-established T-cell protection remains to be defined.

  4. Genital Cytomegalovirus Replication Predicts Syphilis Acquisition among HIV-1 Infected Men Who Have Sex with Men

    PubMed Central

    Gianella, Sara; Smith, Davey M.; Daar, Eric S.; Dube, Michael P.; Lisco, Andrea; Vanpouille, Christophe; Margolis, Leonid; Haubrich, Richard H.; Morris, Sheldon R.

    2015-01-01

    Objective Sexually transmitted infections (STI) are common among HIV-infected men who have sex with men (MSM). While behavioral factors are important in STI acquisition, other biological factors such as immune modulation due to chronic viral infection may further predispose to STI acquisition. Design Post Hoc analysis including data collected over 12 months of follow-up from 131 HIV-infected MSM receiving antiretroviral therapy and screened for incident bacterial STI every 3 months. Methods Genital secretions collected at baseline were used to measure herpesvirus replication and inflammatory cytokines. Baseline predictors of STI were determined using survival analysis of time to incident STI. Results All participants were seropositive for cytomegalovirus (CMV), and 52% had detectable genital CMV at baseline. Thirty-five individuals acquired STI during follow-up, sometimes with multiple pathogen (17 syphilis, 21 gonorrhea, 14 chlamydia). Syphilis acquisition was associated with genital CMV replication at baseline (19.1% CMV-shedders versus 4.8% non-shedders, p=0.03) and younger age (p=0.02). Lower seminal MCP-1 was associated with higher seminal CMV levels and with syphilis acquisition (p<0.01). For syphilis acquisition, in multivariable Cox-Proportional Hazard model adjusted hazard rates were 3.56 (95%CI:1.00–12.73) for baseline CMV replication and 2.50 (0.92–6.77) for younger age. Conclusions This post hoc analysis suggest that CMV-associated decrease in seminal MCP-1 levels might predispose HIV-infected MSM to syphilis acquisition, but not other STI. Future studies should determine underlying mechanisms and if a causal association exists. PMID:26061824

  5. Mouse Embryonic Stem Cells Inhibit Murine Cytomegalovirus Infection through a Multi-Step Process

    PubMed Central

    Kawasaki, Hideya; Kosugi, Isao; Arai, Yoshifumi; Iwashita, Toshihide; Tsutsui, Yoshihiro

    2011-01-01

    In humans, cytomegalovirus (CMV) is the most significant infectious cause of intrauterine infections that cause congenital anomalies of the central nervous system. Currently, it is not known how this process is affected by the timing of infection and the susceptibility of early-gestational-period cells. Embryonic stem (ES) cells are more resistant to CMV than most other cell types, although the mechanism responsible for this resistance is not well understood. Using a plaque assay and evaluation of immediate-early 1 mRNA and protein expression, we found that mouse ES cells were resistant to murine CMV (MCMV) at the point of transcription. In ES cells infected with MCMV, treatment with forskolin and trichostatin A did not confer full permissiveness to MCMV. In ES cultures infected with elongation factor-1α (EF-1α) promoter-green fluorescent protein (GFP) recombinant MCMV at a multiplicity of infection of 10, less than 5% of cells were GFP-positive, despite the fact that ES cells have relatively high EF-1α promoter activity. Quantitative PCR analysis of the MCMV genome showed that ES cells allow approximately 20-fold less MCMV DNA to enter the nucleus than mouse embryonic fibroblasts (MEFs) do, and that this inhibition occurs in a multi-step manner. In situ hybridization revealed that ES cell nuclei have significantly less MCMV DNA than MEF nuclei. This appears to be facilitated by the fact that ES cells express less heparan sulfate, β1 integrin, and vimentin, and have fewer nuclear pores, than MEF. This may reduce the ability of MCMV to attach to and enter through the cellular membrane, translocate to the nucleus, and cross the nuclear membrane in pluripotent stem cells (ES/induced pluripotent stem cells). The results presented here provide perspective on the relationship between CMV susceptibility and cell differentiation. PMID:21407806

  6. Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

    PubMed Central

    Spiess, Katja; Jeppesen, Mads G.; Malmgaard-Clausen, Mikkel; Krzywkowski, Karen

    2017-01-01

    Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher selectivity in its binding to US28 versus CX3CR1, the endogenous receptor for CX3CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate for HCMV treatment. Many viruses encode internalizing receptors suggesting that not only HCMV but also, for instance, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus may be targeted by FTPs. PMID:28251165

  7. Human Cytomegalovirus Carries a Cell-Derived Phospholipase A2 Required for Infectivity

    PubMed Central

    Allal, Cuider; Buisson-Brenac, Claire; Marion, Vincent; Claudel-Renard, Clotilde; Faraut, Thomas; Dal Monte, Paola; Streblow, Daniel; Record, Michel

    2004-01-01

    Human cytomegalovirus (HCMV) is known to carry host cell-derived proteins and mRNAs whose role in cell infection is not understood. We have identified a phospholipase A2 (PLA2) activity borne by HCMV by using an assay based on the hydrolysis of fluorescent phosphatidylcholine. This activity was found in all virus strains analyzed and in purified strains. It was calcium dependent and was sensitive to inhibitors of cytosolic PLA2 (cPLA2) but not to inhibitors of soluble PLA2 or calcium-independent PLA2. No other phospholipase activity was detected in the virus. Purified virus was found to contain human cellular cPLA2α, as detected by monoclonal antibody. No homology with PLA2 was found in the genome of HCMV, indicating that HCMV does not code for a PLA2. Decreased de novo expression of immediate-early proteins 1 and 2 (IE1 and IE2), tegument phosphoprotein pp65, and virus production was observed when HCMV was treated with inhibitors of cPLA2. Cell entry of HCMV was not altered by those inhibitors, suggesting the action of cPLA2 was postentry. Together, our results indicate a selective sorting of a cell-derived cPLA2 during HCMV maturation, which is further required for infectivity. PMID:15220446

  8. US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection

    PubMed Central

    Lee, Sungjin; Chung, Yoon Hee; Lee, Choongho

    2017-01-01

    Viruses continue to evolve a new strategy to take advantage of every aspect of host cells in order to maximize their survival. Due to their central roles in transducing a variety of transmembrane signals, GPCRs seem to be a prime target for viruses to pirate for their own use. Incorporation of GPCR functionality into the genome of herpesviruses has been demonstrated to be essential for pathogenesis of many herpesviruses-induced diseases. Here, we introduce US28 of human cytomegalovirus (HCMV) as the best-studied example of virally-encoded GPCRs to manipulate host GPCR signaling. In this review, we wish to summarize a number of US28-related topics including its regulation of host signaling pathways, its constitutive internalization, its structural and functional analysis, its roles in HCMV biology and pathogenesis, its proliferative activities and role in oncogenesis, and pharmacological modulation of its biological activities. This review will aid in our understanding of how pathogenic viruses usurp the host GPCR signaling for successful viral infection. This kind of knowledge will enable us to build a better strategy to control viral infection by normalizing the virally-dysregulated host GPCR signaling. PMID:28035083

  9. A serological study of cytomegalovirus and herpes simplex virus infections in Peninsular Malaysia

    PubMed Central

    Tan, Dora S. K.; Stern, H.

    1981-01-01

    Healthy Malaysians from various parts of Peninsular Malaysia were examined for CF antibodies against cytomegalovirus (CMV) and herpes simplex virus (HSV) type 2. CMV antibodies were detected in 1114 out of 1556 persons (71.6%) and HSV antibodies were detected in 954 persons out of 1554 (61.4%). The age distribution patterns were similar for the two infections, with maximum prevalence at 5 - 14 years of age. Prevalence was higher in women than in men. There were no significant differences among the Malay, Chinese, and Indian groups of the population with respect to CMV, 72 - 78% possessing antibodies, but in the case of HSV, 76% of the Chinese had antibodies, compared with 57 - 60% of the Malays and Indians. More than 90% of newborn infants had CMV and HSV CF antibodies, confirming the highly immune status of childbearing women in Malaysia. No CMV-specific IgM was detected in the Malaysian neonates examined but this does not exclude the possibility of congenital infection. PMID:6279323

  10. [Cytomegalovirus-induced colitis in HIV infection. Considerations on its diagnosis, treatment and complications].

    PubMed

    Sousa, A E; Lucas, M; Palhano, M J; de Deus, J; Damião, J; Victorino, R M

    1995-04-01

    The diagnosis of cytomegalovirus intestinal disease in patients with HIV (human immunodeficiency virus) infection frequently raises diagnostic problems in view of the absence of definite pathological, serological or virological markers of active CMV infection. We describe the case of a 47-year-old man with a CMV colitis which illustrates several diagnostic and therapeutic problems and that was complicated by an intestinal perforation. We emphasize that in HIV+ patients with chronic diarrhea, the presence of abdominal pain should suggest the possibility of a CMV colitis and that in such cases a colonoscopy with biopsies of the right colon should be performed, in view of the higher frequency of the typical histopathological changes at this level. On the other hand, this case presented a marked thickening of the colon wall, simulating pseudotumoral images on CAT scans, as recently described in literature. The therapeutic possibilities as well as the complications of CMV colitis are discussed in the context of the occurrence of an ileal perforation, which represents the first report of this complication in Portuguese literature and which had the particularity of having a long survival after surgery in comparison with the previous cases described in international literature.

  11. How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients

    PubMed Central

    El Chaer, Firas; Shah, Dimpy P.

    2016-01-01

    Cytomegalovirus (CMV) infection is a significant complication in hematopoietic cell transplantation (HCT) recipients. Four antiviral drugs are used for preventing or treating CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. With prolonged and repeated use of these drugs, CMV can become resistant to standard therapy, resulting in increased morbidity and mortality, especially in HCT recipients. Antiviral drug resistance should be suspected when CMV viremia (DNAemia or antigenemia) fails to improve or continue to increase after 2 weeks of appropriately dosed and delivered antiviral therapy. CMV resistance is diagnosed by detecting specific genetic mutations. UL97 mutations confer resistance to ganciclovir and valganciclovir, and a UL54 mutation confers multidrug resistance. Risk factors for resistance include prolonged or previous anti-CMV drug exposure or inadequate dosing, absorption, or bioavailability. Host risk factors include type of HCT and degree of immunosuppression. Depending on the genotyping results, multiple strategies can be adopted to treat resistant CMV infections, albeit no randomized clinical trials exist so far, after reducing immunosuppression (if possible): ganciclovir dose escalation, ganciclovir and foscarnet combination, and adjunct therapy such as CMV-specific cytotoxic T-lymphocyte infusions. Novel therapies such as maribavir, brincidofovir, and letermovir should be further studied for treatment of resistant CMV. PMID:27760756

  12. Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells.

    PubMed

    Spiess, Katja; Jeppesen, Mads G; Malmgaard-Clausen, Mikkel; Krzywkowski, Karen; Kledal, Thomas N; Rosenkilde, Mette M

    2017-01-01

    Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher selectivity in its binding to US28 versus CX3CR1, the endogenous receptor for CX3CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate for HCMV treatment. Many viruses encode internalizing receptors suggesting that not only HCMV but also, for instance, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus may be targeted by FTPs.

  13. Herpetic (non-cytomegalovirus) retinal infections in patients with the acquired immunodeficiency syndrome.

    PubMed

    Stewart, Michael W

    2013-04-01

    Human herpes viruses cause significant morbidity in patients with the acquired immunodeficiency syndrome. Even after the introduction of highly active anti-retroviral therapy (HAART), herpes viruses remain the leading causes of blindness in AIDS patients. Cytomegalovirus (CMV) retinitis and the closely-related immune reconstitution uveitis syndrome are the most common causes of blindness, but progressive outer retinal necrosis and acute retinal necrosis due to varicella zoster and herpes simplex are also important causes of vision loss. Successful treatment of these conditions requires an aggressive approach with multi-drug intravenous therapy or repeated intravitreal antiviral injections. Since the rate of retinal detachment is alarmingly high despite successful antiviral therapy, internists and ophthalmologists must work closely together to recognize and treat complications as they arise. Fortunately, Epstein-Barr virus is a rare cause of retinal infection and human herpes virus (HHV)-6, HHV-7, and HHV-8 do not appear to be primary pathogens. However, increasing evidence suggests that HHV-6 and HHV-7 play important roles in modulating the immune system and potentiating infection by CMV.

  14. Intravenous immunoglobulin prophylaxis of cytomegalovirus infection in pediatric renal transplant recipients.

    PubMed

    Flynn, J T; Kaiser, B A; Long, S S; Schulman, S L; Deforest, A; Polinsky, M S; Baluarte, H J

    1997-01-01

    Cytomegalovirus (CMV), the most significant infectious cause of morbidity following renal transplantation, may be a greater problem for children than for adults due to their relative lack of experience with this virus. Therefore, we prospectively gave Gammagard as prophylaxis to CMV-negative children who received CMV-positive allografts and compared the results to our experience with similar high-risk recipients transplanted prior to our use of intravenous immunoglobulin G (IvIgG). Symptomatic CMV disease developed in 17% of the IvIgG recipients as compared with 71% of the untreated patients (p = 0.01). The CMV infections that did occur in IvIgG recipients developed significantly later than in untreated children (median time of onset after transplantation 2.60 vs. 1.35 months; p < 0.05) and generally were less severe, although 1 IvIgG recipient died despite prophylaxis. IvIgG administration did not affect the frequency of rejection or graft or patient survival. We conclude that IvIgG administration to high-risk pediatric renal transplant recipients may protect against posttransplantation CMV disease and may lessen the severity of infections that do develop in patients who receive it.

  15. Cohort study on maternal cytomegalovirus seroprevalence and prevalence and clinical manifestations of congenital infection in China

    PubMed Central

    Wang, Shiwen; Wang, Tongzhan; Zhang, Wenqiang; Liu, Xiaolin; Wang, Xiaofang; Wang, Haiyan; He, Xiaozhou; Zhang, Shunxian; Xu, Shuhui; Yu, Yang; Jia, Xingbing; Wang, Maolin; Xu, Aiqiang; Ma, Wei; Amin, Minal M.; Bialek, Stephanie R.; Dollard, Sheila C.; Wang, Chengbin

    2017-01-01

    Abstract Congenital cytomegalovirus (CMV) infection is the leading viral cause of birth defects and developmental disabilities in developed countries. However, CMV seroprevalence and burden of congenital CMV infection are not well defined in China. Cohort of newborns from 5 birthing hospitals in 2 counties of Shandong Province, China, were enrolled from March 2011 to August 2013. Dried blood spots (DBS) and saliva were collected within 4 days after birth for IgG testing for maternal seroprevalence and real-time PCR testing for congenital CMV infection, respectively. Among 5020 newborns tested for CMV IgG, 4827 were seropositive, resulting in CMV maternal seroprevalence of 96.2% (95% confidence interval [CI]:95.6%–96.7%). Of the 10,933 newborns screened for congenital CMV infection, 75 had CMV detected, resulting in an overall prevalence of 0.7% (95% CI: 0.5%–0.9%), with prevalences of 0.4% (14/3995), 0.6% (66/10,857), and 0.7% (52/7761) for DBS, wet saliva, and dried saliva specimens screened, respectively. Prevalence of congenital CMV infection decreased with increasing maternal age (0.9%, 0.6%, and 0.3% among newborns delivered from mothers aged 16–25, 26–35, and >35 years, respectively; P = 0.03), and was higher among preterm infants than full term infants (1.3% vs 0.6%, P = 0.04), infants with intrauterine growth restriction (IUGR) than those without (1.8% vs 0.7%, P = 0.03), and twins or triplets than singleton pregnancies (2.8% vs 0.7%, P = 0.04). None of the 75 newborns exhibited symptomatic congenital CMV infection, and there was no difference in clinical characteristics and newborn hearing screening results between infants with and without congenital CMV infection at birth. Congenital CMV infection prevalence was lower and the clinical manifestations were milder in this relatively developed region of China compared to populations from other countries with similarly high maternal seroprevalence. Follow-up on children with congenital

  16. Amphipathic DNA polymers exhibit antiviral activity against systemic Murine Cytomegalovirus infection

    PubMed Central

    2009-01-01

    Background Phosphorothioated oligonucleotides (PS-ONs) have a sequence-independent, broad spectrum antiviral activity as amphipathic polymers (APs) and exhibit potent in vitro antiviral activity against a broad spectrum of herpesviruses: HSV-1, HSV-2, HCMV, VZV, EBV, and HHV-6A/B, and in vivo activity in a murine microbiocide model of genital HSV-2 infection. The activity of these agents against animal cytomegalovirus (CMV) infections in vitro and in vivo was therefore investigated. Results In vitro, a 40 mer degenerate AP (REP 9) inhibited both murine CMV (MCMV) and guinea pig CMV (GPCMV) with an IC50 of 0.045 μM and 0.16 μM, respectively, and a 40 mer poly C AP (REP 9C) inhibited MCMV with an IC50 of 0.05 μM. Addition of REP 9 to plaque assays during the first two hours of infection inhibited 78% of plaque formation whereas addition of REP 9 after 10 hours of infection did not significantly reduce the number of plaques, indicating that REP 9 antiviral activity against MCMV occurs at early times after infection. In a murine model of CMV infection, systemic treatment for 5 days significantly reduced virus replication in the spleens and livers of infected mice compared to saline-treated control mice. REP 9 and REP 9C were administered intraperitoneally for 5 consecutive days at 10 mg/kg, starting 2 days prior to MCMV infection. Splenomegaly was observed in infected mice treated with REP 9 but not in control mice or in REP 9 treated, uninfected mice, consistent with mild CpG-like activity. When REP 9C (which lacks CpG motifs) was compared to REP 9, it exhibited comparable antiviral activity as REP 9 but was not associated with splenomegaly. This suggests that the direct antiviral activity of APs is the predominant therapeutic mechanism in vivo. Moreover, REP 9C, which is acid stable, was effective when administered orally in combination with known permeation enhancers. Conclusion These studies indicate that APs exhibit potent, well tolerated antiviral activity

  17. Annexin 2-mediated enhancement of cytomegalovirus infection opposes inhibition by annexin 1 or annexin 5.

    PubMed

    Derry, Mélanie C; Sutherland, Michael R; Restall, Christina M; Waisman, David M; Pryzdial, Edward L G

    2007-01-01

    Biochemical studies have suggested that annexin 2 (A2) may participate in cytomegalovirus (CMV) infection. In the current work, effects of A2 monomer (p36) and heterotetramer (A2t; p36(2)p11(2)) were investigated. Demonstrating a role for endogenous A2, the four stages of infection that were followed were each inhibited by anti-p36 or anti-p11 at 37 degrees C. Immuno-inhibition was attenuated when the virus and cells were pre-incubated at 4 degrees C to coordinate virus entry initiated afterwards at 37 degrees C, reconciling controversy in the literature. As an explanation, CMV-induced phosphorylation of p36 was prevented by the 4 degrees C treatment. Supporting these immuno-inhibition data, purified A2t or p11 increased CMV infectious-progeny generation and CMV gene expression. A specific role for A2t was indicated by purified p36 having no effect. Unlike other steps, primary plaque formation was not enhanced by purified A2t or p11, possibly because of undetectable phosphorylation. As annexins 1 (A1) and 5 (A5) interact with A2, their effect on CMV was also tested. Both purified proteins inhibited CMV infection. In each experiment, the concentration of A1 required for half-maximal inhibition was five- to 10-fold lower than that of A5. Addition of A2 opposed A1- or A5-mediated inhibition of CMV, as did certain A2-specific antibodies that had no effect in the absence of added A1 or A5. Transfection of the p36-deficient cell line HepG2 increased CMV infection and was required for inhibition by the other annexins. These data suggest that CMV exploits A2t at physiological temperature to oppose the protection of cells conferred by A1 or A5.

  18. Hearing Loss and Cytomegalovirus.

    ERIC Educational Resources Information Center

    Strauss, Melvin

    1997-01-01

    Cytomegalovirus is the most common cause of congenital virally induced hearing loss. Maternal infection is most often asymptomatic as is the infection in the newborn. Hearing loss occurs in both clinically apparent infection and in the asymptomatic infection. Current methods of detection, treatment, and prevention and research efforts are…

  19. Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant: A case report and literature review.

    PubMed

    Morita, Shinya; Shinoda, Kazunobu; Tamaki, Satoshi; Kono, Hidaka; Asanuma, Hiroshi; Nakagawa, Ken; Oya, Mototsugu

    2016-09-01

    Ganciclovir-resistant cytomegalovirus infection is sometimes life-threatening for organ transplant recipients. Foscarnet is an alternative, although it may potentially worsen the preexistent impaired renal function. Here we report the case of a successful low-dose leflunomide treatment in a kidney transplant recipient with very high viral replication, who underwent kidney transplantation 10 years before. Administering 10mg leflunomide daily for 5 months without a loading dose completely cleared the ganciclovir-resistant cytomegalovirus strains.

  20. Polymorphisms and features of cytomegalovirus UL144 and UL146 in congenitally infected neonates with hepatic involvement.

    PubMed

    Guo, Gangqiang; Zhang, Liang; Ye, Sisi; Hu, Yingying; Li, Baoqing; Sun, Xiangwei; Mao, Chenchen; Xu, Jianfeng; Chen, Yiping; Zhang, Lifang; Xue, Xiangyang

    2017-01-01

    Human cytomegalovirus is a significant agent of hepatic involvement in neonates. In this study, we investigated the polymorphisms and features of the viral genes UL144 and UL146 as well as their significance to congenital hepatic involvement. In 79 neonates with congenital cytomegalovirus infection and hepatic involvement, full length UL144 and UL146 were successfully amplified in 73.42% and 60.76% of cases, respectively. Sequencing indicated that both genes were hypervariable. Notably, UL144 genotype B was highly associated with aspartate aminotransferase (P = 0.028) and lactate dehydrogenase (P = 0.046). Similarly, UL146 genotype G1 and G13 were significantly associated with CMV IgM (P = 0.026), CMV IgG (P = 0.034), alanine aminotransferase (P = 0.019), and aspartate aminotransferase (P = 0.032). In conclusion, dominant UL144 (genotype B) and UL146 (genotype G1 and G13) genotypes are associated with elevated levels of enzymes and CMV IgM and IgG of cytomegalovirus infection.

  1. Polymorphisms and features of cytomegalovirus UL144 and UL146 in congenitally infected neonates with hepatic involvement

    PubMed Central

    Ye, Sisi; Hu, Yingying; Li, Baoqing; Sun, Xiangwei; Mao, Chenchen; Xu, Jianfeng; Chen, Yiping; Zhang, Lifang; Xue, Xiangyang

    2017-01-01

    Human cytomegalovirus is a significant agent of hepatic involvement in neonates. In this study, we investigated the polymorphisms and features of the viral genes UL144 and UL146 as well as their significance to congenital hepatic involvement. In 79 neonates with congenital cytomegalovirus infection and hepatic involvement, full length UL144 and UL146 were successfully amplified in 73.42% and 60.76% of cases, respectively. Sequencing indicated that both genes were hypervariable. Notably, UL144 genotype B was highly associated with aspartate aminotransferase (P = 0.028) and lactate dehydrogenase (P = 0.046). Similarly, UL146 genotype G1 and G13 were significantly associated with CMV IgM (P = 0.026), CMV IgG (P = 0.034), alanine aminotransferase (P = 0.019), and aspartate aminotransferase (P = 0.032). In conclusion, dominant UL144 (genotype B) and UL146 (genotype G1 and G13) genotypes are associated with elevated levels of enzymes and CMV IgM and IgG of cytomegalovirus infection. PMID:28222150

  2. Brincidofovir Use after Foscarnet Crystal Nephropathy in a Kidney Transplant Recipient with Multiresistant Cytomegalovirus Infection

    PubMed Central

    Vial, Romain; Zandotti, Christine; Alain, Sophie; Decourt, Alexandre; Purgus, Raj; Bornet, Charleric; Daniel, Laurent; Moal, Valérie

    2017-01-01

    Background. Cytomegalovirus (CMV) antiviral drug resistance constitutes an increasing challenge in transplantation. Foscarnet is usually proposed when resistance for ganciclovir is suspected, but its use is limited by its nephrotoxicity. Case Presentation. We report a case of multiresistant CMV disease in a kidney transplant recipient. Foscarnet was prescribed after ganciclovir treatment failure in a patient with two mutations in the UL97 viral gene. Foscarnet induced biopsy-proven kidney crystal precipitation that resulted in severe acute transplant failure and nephrotic syndrome. Despite a large decrease in immunosuppression, CMV disease was not controlled and a salvage therapy with Brincidofovir (BCV), which is an oral lipid conjugate of cidofovir with limited nephrotoxicity, was attempted. Clinical and virological remission was observed after a 21-day course of BCV, despite mild and reversible liver toxicity. However, a new relapse could not be effectively cured by BCV due to a new mutation in the UL54 gene, which is known to confer resistance to cidofovir. A new course of foscarnet finally resulted in prolonged CMV remission. Herein, we present a review of foscarnet nephropathy cases in solid-organ transplanted patients. Conclusions. This unique case highlights the potential benefit of BCV use during resistant CMV infection, although mutations in the UL54 gene may limit its therapeutic efficacy. These findings need to be confirmed in clinical trials. PMID:28348914

  3. Cytomegalovirus infections following umbilical cord blood transplantation using reduced intensity conditioning regimens for adult patients.

    PubMed

    Matsumura, Tomoko; Narimatsu, Hiroto; Kami, Masahiro; Yuji, Koichiro; Kusumi, Eiji; Hori, Akiko; Murashige, Naoko; Tanaka, Yuji; Masuoka, Kazuhiro; Wake, Atsushi; Miyakoshi, Shigesaburo; Kanda, Yoshinobu; Taniguchi, Shuichi

    2007-05-01

    Cytomegalovirus (CMV) infection is a major complication after allogeneic hematopoietic stem cell transplantation (Allo-HSCT); however, we have little information on the clinical features of CMV reactivation after cord blood transplantation using reduced-intensity regimens (RI-CBT) for adults. We reviewed medical records of 140 patients who underwent RI-CBT at Toranomon Hospital between January 2002 and March 2005. All the patients were monitored for CMV-antigenemia weekly, and, if turned positive, received preemptive foscarnet or ganciclovir. Seventy-seven patients developed positive antigenemia at a median onset of day 35 (range, 4-92) after transplant. Median of the maximal number of CMV pp65-positive cells per 50,000 cells was 22 (range, 1-1806). CMV disease developed in 22 patients on a median of day 35 (range, 15-106); 21 had enterocolitis and 1 had adrenalitis. CMV antigenemia had not been detected in 2 patients, when CMV disease was diagnosed. CMV disease was successfully treated using ganciclovir or foscarnet in 14 patients. The other 8 patients died without improvement of CMV disease. In multivariate analysis, grade II-IV acute graft-versus-host disease was a risk factor of CMV disease (relative risk 3.48, 95% confidential interval 1.47-8.23). CMV reactivation and disease develop early after RI-CBT. CMV enterocolitis may be a common complication after RI-CBT.

  4. [Protein losing gastroenteropathy and possible relationship to cytomegalovirus infection: Ménétrier disease in a child].

    PubMed

    Hillman, María M; Meinarde, Leonardo L; Furnes, Raquel A; Daruich, María L; Riva, Verónica; Cuestas, Eduardo

    2013-10-01

    Ménétrier's disease is a childhood protein-losing gastroenteropathy characterized by hypertrophy of the gastric mucosa, of unknown etiology, although most of reported cases have been associated with viral infections. Clinical manifestation is edema and biochemically there are hypoproteinemia and hypoalbuminemia. This disease is very rare in children and they have a benign and self-limiting course in contrast to adults where tend to be chronic and occasionally to become malignant. We present a child with Ménétrier disease with edema and ascites possibly associated with a cytomegalovirus infection.

  5. Comparison of plasma PCR and bronchoalveolar lavage fluid culture for detection of cytomegalovirus infection in adult bone marrow transplant recipients.

    PubMed Central

    Aspin, M M; Gallez-Hawkins, G M; Giugni, T D; Tegtmeier, B; Lang, D J; Schmidt, G M; Forman, S J; Zaia, J A

    1994-01-01

    Plasma PCR for human cytomegalovirus (CMV) DNA was compared with bronchoalveolar lavage (BAL) fluid culture as an indicator for disseminated CMV infection. Thirteen (32.5%) of 40 consecutive bone marrow transplant (BMT) recipients were BAL fluid culture positive for CMV on day 35 post-BMT, and 9 (69%) of the 13 had positive plasma PCRs between days 28 and 49. Of the 27 with negative BAL fluid cultures, 2 (7%) had positive plasma PCRs (P < 0.001). Plasma CMV DNA in BMT recipients is a useful clinical marker for serious infection. Images PMID:7814556

  6. Adjuvant and salvage therapy with leflunomide for recalcitrant cytomegalovirus infections in hematopoietic cell transplantation recipients: A case series.

    PubMed

    El Chaer, Firas; Mori, Nobuyoshi; Shah, Dimpy; Oliver, Nora; Wang, Emily; Jan, Anna; Doan, Vi; Tverdek, Frank; Tayar, Jean; Ariza-Heredia, Ella; Chemaly, Roy F

    2016-11-01

    Cytomegalovirus (CMV) reactivation is a clinically significant complication in hematopoietic stem cell transplant (HCT) recipients. Alternative therapy for multidrug-resistant CMV is limited and often fails. Leflunomide has been used to treat resistant CMV infections, however, data on efficacy, safety, and guidance for therapeutic drug level monitoring are lacking. In this report, we describe 3 HCT recipients with multi-drug resistant CMV infections who received leflunomide as adjuvant and salvage therapy. The therapeutic effect of leflunomide as an anti-CMV agent based on virologic responses and therapeutic drug monitoring were evaluated.

  7. Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children

    PubMed Central

    Studzińska, Mirosława; Jabłońska, Agnieszka; Wiśniewska-Ligier, Małgorzata; Nowakowska, Dorota; Gaj, Zuzanna; Leśnikowski, Zbigniew J.; Woźniakowska-Gęsicka, Teresa; Wilczyński, Jan; Paradowska, Edyta

    2017-01-01

    Intracellular Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (dsRNA) and activates antiviral immune responses through the production of type I interferons (IFNs) and inflammatory cytokines. This receptor binds to dsRNA molecules produced during human cytomegalovirus (HCMV) replication. TLR7 senses viral single-stranded RNA (ssRNA) in endosomes, and it can interact with endogenous RNAs. We determined the genotype distribution of single-nucleotide polymorphisms (SNPs) within the TLR3 and TLR7 genes in children with HCMV infection and the relationship between TLR polymorphisms and viral infection. We genotyped 59 children with symptomatic HCMV infection and 78 healthy individuals for SNPs in the TLR3 (rs3775290, c.1377C>T, F459F; rs3775291, c.1234C>T, L412F; rs3775296, c.-7C>A) and TLR7 (rs179008, c.32A>T, Q11L; rs5741880, c.3+1716G>T) genes. SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and capillary electrophoresis. The HCMV DNA load was quantified by real-time PCR. We found an increased frequency of the heterozygous genotype TLR3 L412F in children with HCMV infection compared with uninfected cases. In individuals with a mutation present in at least one allele of the L412F SNP, an increased risk of HCMV disease was found, and this result remained highly significant after Bonferroni’s correction for multiple testing (Pc < 0.001). The heterozygous genotype of this SNP was associated with the increased risk of HCMV disease in an adjusted model that included the HCMV DNA copy number in whole blood and urine (P < 0.001 and P = 0.008, respectively). Moreover, those with a heterozygous genotype of rs3775296 showed an increased relative risk of HCMV infection (P = 0.042), but this association did not reach statistical significance after correction for multiple testing. In contrast, the rs3775290 SNP of TLR3 and TLR7 SNPs were not related to viral infection. A moderate linkage

  8. Haploidentical Haematopoietic Stem Cell Transplantation: Role of NK Cells and Effect of Cytomegalovirus Infections.

    PubMed

    Della Chiesa, Mariella; Moretta, Lorenzo; Muccio, Letizia; Bertaina, Alice; Moretta, Francesca; Locatelli, Franco; Moretta, Alessandro

    2016-01-01

    Natural killer cells play an important role in the immune responses against cancer and viral infections. In addition, NK cells have been shown to exert a key role in haploidentical hematopoietic stem cell (HSC) transplantation for the therapy of high-risk leukemias. The anti-leukemia effect is mostly related to the presence of "alloreactive" NK cells, i.e., mature KIR(+) NK cells that express inhibitory KIR mismatched with HLA class I (KIR-L) of the patient. In addition, an important role is played by certain activating KIR (primarily, but not only, KIR2DS1) upon interaction with their HLA class I ligand (C2 alleles). In general, the presence of activating KIR correlates with a better prognosis. Beside the infusion of "pure" CD34(+) cells, a novel protocol has been recently developed in which depletion of αβ T cells and CD19(+) B cells makes it possible to infuse into the patient, together with donor CD34(+) HSCs, important effector cells including mature PB NK cells and γδ T cells. Recent studies revealed that cytomegalovirus (CMV) infection/reactivation may induce rapid NK cell maturation and greatly influence the NK receptor repertoire. The remarkable expansion of a subset expressing the activating receptor NKG2C, together with a more efficient virus-specific effector response after rechallenge with CMV (i.e., antigen specificity), and the longevity of the expanded population are all features consistent with an adaptive type of response and support the notion of a memory-like activity of NK cells.

  9. Physical Function Impairment of Older, HIV-Infected Adults Is Associated with Cytomegalovirus Immunoglobulin Response

    PubMed Central

    Allshouse, Amanda A.; Rapaport, Eric; Palmer, Brent E.; Wilson, Cara C.; Weinberg, Adriana; MaWhinney, Samantha; Campbell, Thomas B.

    2015-01-01

    Abstract Cytomegalovirus (CMV) is associated with poor outcomes, including physical function impairment, in older HIV-uninfected adults. Whether CMV is associated with physical functional impairment in HIV-infected adults is unknown. The primary objective of this study was to determine the relationship between CMV-specific humoral and cell-mediated immune responses with functional impairment in well-controlled HIV infection. In a case-control study, low-function cases were matched by age, gender, and time from HIV diagnosis to high-function controls. Quantitative CMV IgG and %CMV-specific CD8+ and CD4+ T cells (interferon-γ expression following CMV pp65 stimulation) were used to estimate physical function. Among 30 low-function cases and 48 high-function matched controls, CMV IgG ranged from <10 to 8,830 EU/ml, including four controls with results <10 EU/ml. Each log10 increase in CMV IgG was associated with 5-fold greater odds of low function (p=0.01); these findings were robust to adjustment for concomitant CD4+ count, tobacco use, and age; to exclusion of subjects with CMV IgG <10 EU/ml; and to adjustment for hepatitis C viremia. %CMV-specific CD4+ or CD8+ T cells were not associated with low function. In bivariable models, the relationship between CMV IgG and physical function was attenuated and was no longer significant when including IL-6, CD4/CD8 ratio, or the Veterans Aging Cohort Study Index score. High levels of CMV-specific IgG were associated with impaired physical function. Attenuation of the strength of this association in bivariable models suggests an indirect relationship mediated by systemic inflammation and immune suppression. PMID:26061347

  10. γδ T Cell-Mediated Immunity to Cytomegalovirus Infection

    PubMed Central

    Khairallah, Camille; Déchanet-Merville, Julie; Capone, Myriam

    2017-01-01

    γδ T lymphocytes are unconventional immune cells, which have both innate- and adaptive-like features allowing them to respond to a wide spectrum of pathogens. For many years, we and others have reported on the role of these cells in the immune response to human cytomegalovirus in transplant patients, pregnant women, neonates, immunodeficient children, and healthy people. Indeed, and as described for CD8+ T cells, CMV infection leaves a specific imprint on the γδ T cell compartment: (i) driving a long-lasting expansion of oligoclonal γδ T cells in the blood of seropositive individuals, (ii) inducing their differentiation into effector/memory cells expressing a TEMRA phenotype, and (iii) enhancing their antiviral effector functions (i.e., cytotoxicity and IFNγ production). Recently, two studies using murine CMV (MCMV) have corroborated and extended these observations. In particular, they have illustrated the ability of adoptively transferred MCMV-induced γδ T cells to protect immune-deficient mice against virus-induced death. In vivo, expansion of γδ T cells is associated with the clearance of CMV infection as well as with reduced cancer occurrence or leukemia relapse risk in kidney transplant patients and allogeneic stem cell recipients, respectively. Taken together, all these studies show that γδ T cells are important immune effectors against CMV and cancer, which are life-threatening diseases affecting transplant recipients. The ability of CMV-induced γδ T cells to act independently of other immune cells opens the door to the development of novel cellular immunotherapies that could be particularly beneficial for immunocompromised transplant recipients. PMID:28232834

  11. Characterising variation in five genetic loci of cytomegalovirus during treatment for congenital infection.

    PubMed

    Kadambari, Seilesh; Atkinson, Claire; Luck, Suzanne; Macartney, Malcolm; Conibear, Tim; Harrison, Ian; Booth, Clare; Sharland, Mike; Griffiths, Paul D

    2017-03-01

    Cytomegalovirus (CMV) is the most common congenital infection in humans and a leading cause of sensorineural hearing loss. Ganciclovir (6 mg/kg twice daily for 42 days) has been shown to reduce hearing deterioration and is used in clinical practice. Vaccines and passive administration of antibody are being evaluated in randomized controlled trials in allograft candidates, women of childbearing age, and pregnant women with primary CMV infection. To help define genetic variation in each of the targets of these therapeutic interventions, we amplified and sequenced genes UL97 (site utilised for ganciclovir phosphorylation), UL55 (glycoprotein B (gB) vaccine target) and UL128, UL130, and UL131a (specific monoclonal antibody targets). Serial blood, saliva, and urine samples (total 120) obtained from nine infants with symptomatic congenital CMV treated with 42 days' ganciclovir were analyzed. All samples tested were UL97 wild type at baseline and none developed mutations during treatment, showing no selection of resistance. The prevalences of UL55 genotypes were 28% gB1, 22% gB2, 1% gB3, and mixed in 20% samples. No mutations were noted in UL128-131a. Phylogenetic tree analysis showed that sequences with variations were found in multiple body sites of individual patients, so there was no evidence of body site compartmentalization of particular strains of CMV. The significance of these results for changes in diagnostic practices and therapeutic interventions against CMV are discussed. J. Med. Virol. 89:502-507, 2017. © 2016 Wiley Periodicals, Inc.

  12. Role for Tumor Necrosis Factor Alpha in Murine Cytomegalovirus Transcriptional Reactivation in Latently Infected Lungs

    PubMed Central

    Simon, Christian O.; Seckert, Christof K.; Dreis, Doris; Reddehase, Matthias J.; Grzimek, Natascha K. A.

    2005-01-01

    Interstitial pneumonia is a major clinical manifestation of primary or recurrent cytomegalovirus (CMV) infection in immunocompromised recipients of a bone marrow transplant. In a murine model, lungs were identified as a prominent site of CMV latency and recurrence. Pulmonary latency of murine CMV is characterized by high viral genome burden and a low incidence of variegated immediate-early (IE) gene expression, reflecting a sporadic activity of the major IE promoters (MIEPs) and enhancer. The enhancer-flanking promoters MIEP1/3 and MIEP2 are switched on and off during latency in a ratio of ∼2:1. MIEP1/3 latency-associated activity generates the IE1 transcript of the ie1/3 transcription unit but not the alternative splicing product IE3 that encodes the essential transactivator of early gene expression. Splicing thus appeared to be an important checkpoint for maintenance of latency. In accordance with previous work of others, we show here that signaling by the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) activates IE1/3 transcription in vivo. As an addition to current knowledge, Poisson distribution analysis revealed an increased incidence of IE1/3 transcriptional events as well as a higher amount of transcripts per event. Notably, TNF-α promoted the splicing to IE3 transcripts, but transcription did not proceed to the M55/gB early gene. Moreover, the activated transcriptional state induced by TNF-α did not predispose latently infected mice to a higher incidence of virus recurrence after hematoablative treatment. In conclusion, TNF-α is an important inductor of IE gene transcriptional reactivation, whereas early genes downstream in the viral replicative cycle appear to be the rate-limiting checkpoint(s) for virus recurrence. PMID:15596827

  13. Glucocorticosteroids trigger reactivation of human cytomegalovirus from latently infected myeloid cells and increase the risk for HCMV infection in D+R+ liver transplant patients

    PubMed Central

    Van Damme, Ellen; Sauviller, Sarah; Lau, Betty; Kesteleyn, Bart; Griffiths, Paul; Burroughs, Andrew; Emery, Vincent; Sinclair, John

    2015-01-01

    Graft rejection in transplant patients is managed clinically by suppressing T-cell function with immunosuppressive drugs such as prednisolone and methylprednisolone. In such immunocompromised hosts, human cytomegalovirus (HCMV) is an important opportunistic pathogen and can cause severe morbidity and mortality. Currently, the effect of glucocorticosteroids (GCSs) on the HCMV life cycle remains unclear. Previous reports showed enhanced lytic replication of HCMV in vitro in the presence of GCSs. In the present study, we explored the implications of steroid exposure on latency and reactivation. We observed a direct effect of several GCSs used in the clinic on the activation of a quiescent viral major immediate-early promoter in stably transfected THP-1 monocytic cells. This activation was prevented by the glucocorticoid receptor (GR) antagonist Ru486 and by shRNA-mediated knockdown of the GR. Consistent with this observation, prednisolone treatment of latently infected primary monocytes resulted in HCMV reactivation. Analysis of the phenotype of these cells showed that treatment with GCSs was correlated with differentiation to an anti-inflammatory macrophage-like cell type. On the basis that these observations may be pertinent to HCMV reactivation in post-transplant settings, we retrospectively evaluated the incidence, viral kinetics and viral load of HCMV in liver transplant patients in the presence or absence of GCS treatment. We observed that combination therapy of baseline prednisolone and augmented methylprednisolone, upon organ rejection, significantly increased the incidence of HCMV infection in the intermediate risk group where donor and recipient are both HCMV seropositive (D+R+) to levels comparable with the high risk D+R− group. PMID:25312585

  14. Glucocorticosteroids trigger reactivation of human cytomegalovirus from latently infected myeloid cells and increase the risk for HCMV infection in D+R+ liver transplant patients.

    PubMed

    Van Damme, Ellen; Sauviller, Sarah; Lau, Betty; Kesteleyn, Bart; Griffiths, Paul; Burroughs, Andrew; Emery, Vincent; Sinclair, John; Van Loock, Marnix

    2015-01-01

    Graft rejection in transplant patients is managed clinically by suppressing T-cell function with immunosuppressive drugs such as prednisolone and methylprednisolone. In such immunocompromised hosts, human cytomegalovirus (HCMV) is an important opportunistic pathogen and can cause severe morbidity and mortality. Currently, the effect of glucocorticosteroids (GCSs) on the HCMV life cycle remains unclear. Previous reports showed enhanced lytic replication of HCMV in vitro in the presence of GCSs. In the present study, we explored the implications of steroid exposure on latency and reactivation. We observed a direct effect of several GCSs used in the clinic on the activation of a quiescent viral major immediate-early promoter in stably transfected THP-1 monocytic cells. This activation was prevented by the glucocorticoid receptor (GR) antagonist Ru486 and by shRNA-mediated knockdown of the GR. Consistent with this observation, prednisolone treatment of latently infected primary monocytes resulted in HCMV reactivation. Analysis of the phenotype of these cells showed that treatment with GCSs was correlated with differentiation to an anti-inflammatory macrophage-like cell type. On the basis that these observations may be pertinent to HCMV reactivation in post-transplant settings, we retrospectively evaluated the incidence, viral kinetics and viral load of HCMV in liver transplant patients in the presence or absence of GCS treatment. We observed that combination therapy of baseline prednisolone and augmented methylprednisolone, upon organ rejection, significantly increased the incidence of HCMV infection in the intermediate risk group where donor and recipient are both HCMV seropositive (D+R+) to levels comparable with the high risk D+R- group.

  15. Pneumonia associated with infection with pneumocystis, respiratory syncytial virus, chlamydia, mycoplasma, and cytomegalovirus in children in Papua New Guinea.

    PubMed Central

    Shann, F; Walters, S; Pifer, L L; Graham, D M; Jack, I; Uren, E; Birch, D; Stallman, N D

    1986-01-01

    Paired serum samples were collected from 94 children with pneumonia admitted to Goroka Hospital, Papua New Guinea. All but three of the children were aged 1-24 months. Only nine children were malnourished, with weight for age less than 70% of the Harvard median (three had weight for age less than 60% of the Harvard median). Pneumocystis carinii antigen was detected in the serum of 23 children. Twenty two children had serological evidence of recent infection with respiratory syncytial virus. Five children were probably infected with Chlamydia trachomatis at the time of the study, and there was less convincing serological evidence of current infection in a further 11 children. Five children showed a fourfold rise in antibody to Mycoplasma pneumoniae. Although only one child showed a fourfold rise in antibody to cytomegalovirus, 86 children had this antibody. No child showed a fourfold rise in antibody to Ureaplasma urealyticum or Legionella pneumophila. P carinii, respiratory syncytial virus, C trachomatis, M pneumoniae, and cytomegalovirus may be important causes of pneumonia in children in developing countries. PMID:3002538

  16. Effect of Cytomegalovirus Co-Infection on Normalization of Selected T-Cell Subsets in Children with Perinatally Acquired HIV Infection Treated with Combination Antiretroviral Therapy

    PubMed Central

    Kapetanovic, Suad; Aaron, Lisa; Montepiedra, Grace; Anthony, Patricia; Thuvamontolrat, Kasalyn; Pahwa, Savita; Burchett, Sandra; Weinberg, Adriana; Kovacs, Andrea

    2015-01-01

    Background We examined the effect of cytomegalovirus (CMV) co-infection and viremia on reconstitution of selected CD4+ and CD8+ T-cell subsets in perinatally HIV-infected (PHIV+) children ≥ 1-year old who participated in a partially randomized, open-label, 96-week combination antiretroviral therapy (cART)-algorithm study. Methods Participants were categorized as CMV-naïve, CMV-positive (CMV+) viremic, and CMV+ aviremic, based on blood, urine, or throat culture, CMV IgG and DNA polymerase chain reaction measured at baseline. At weeks 0, 12, 20 and 40, T-cell subsets including naïve (CD62L+CD45RA+; CD95-CD28+), activated (CD38+HLA-DR+) and terminally differentiated (CD62L-CD45RA+; CD95+CD28-) CD4+ and CD8+ T-cells were measured by flow cytometry. Results Of the 107 participants included in the analysis, 14% were CMV+ viremic; 49% CMV+ aviremic; 37% CMV-naïve. In longitudinal adjusted models, compared with CMV+ status, baseline CMV-naïve status was significantly associated with faster recovery of CD8+CD62L+CD45RA+% and CD8+CD95-CD28+% and faster decrease of CD8+CD95+CD28-%, independent of HIV VL response to treatment, cART regimen and baseline CD4%. Surprisingly, CMV status did not have a significant impact on longitudinal trends in CD8+CD38+HLA-DR+%. CMV status did not have a significant impact on any CD4+ T-cell subsets. Conclusions In this cohort of PHIV+ children, the normalization of naïve and terminally differentiated CD8+ T-cell subsets in response to cART was detrimentally affected by the presence of CMV co-infection. These findings may have implications for adjunctive treatment strategies targeting CMV co-infection in PHIV+ children, especially those that are now adults or reaching young adulthood and may have accelerated immunologic aging, increased opportunistic infections and aging diseases of the immune system. PMID:25794163

  17. Prevalence, Characteristics, and One-Year Follow-Up of Congenital Cytomegalovirus Infection in Isfahan City, Iran

    PubMed Central

    Yaghini, Omid; Nasr Azadani, Hossein; Mohammadizadeh, Majid; Arabzadeh, Seyed Ali Mohammad; Adibi, Atosa

    2016-01-01

    Introduction. Need of neonatal screening for Cytomegalovirus (CMV) infection is under debate, in part because of limited data on importance of the disease regarding the prevalence of congenital CMV (cCMV) infection and associated morbidity and mortality. We aimed to evaluate the prevalence and prognosis of cCMV infection in Iran, where there is high maternal seroprevalence of CMV. Methodology. This prospective study was conducted in Isfahan city, Iran, from 2014 to 2016. CMV was investigated in urine specimens by using the real-time polymerase chain reaction (RT-PCR) method. CMV-infected infants were examined for clinical and laboratory findings attributed to CMV infection and followed up for one year. Results. Among 1617 studied neonates, eight (0.49%) were positive for CMV infection. CMV-infected neonates were more likely to be preterm than noninfected ones (25% versus 4.5%, p = 0.0508), and they had lower birth weight. Three out of the eight CMV-infected neonates had transient symptoms at birth. At follow-up, one case had mild hearing loss. Most patients had impaired growth during the one-year follow-up. Conclusions. The primary object of this study was determination of prevalence of cCMV infection in Iran as a developing country, which was at the lower range compared with other such countries. cCMV infection may result in short-term impairment in growth. PMID:28070187

  18. Selective impairment of T lymphocyte activation through the T cell receptor/CD3 complex after cytomegalovirus infection.

    PubMed Central

    Timón, M; Arnaiz-Villena, A; Ruiz-Contreras, J; Ramos-Amador, J T; Pacheco, A; Regueiro, J R

    1993-01-01

    Cytomegalovirus (CMV) infection is reported to cause transient immunosuppression in man. In this study we have analysed the effect of CMV on T lymphocyte function in 29 children diagnosed for acute CMV infection. Peripheral blood mononuclear cells (PBMC) obtained from the patients showed a significant specific impairment in their proliferative response to enterotoxins A and C1, to concanavalin A and to the anti-CD3 MoAb OKT3. The impaired responses were corrected with exogenous IL-2. In contrast, stimulation using phytohaemagglutinin, as well as activation signals delivered through the surface molecules CD26 or CD28, elicited normal proliferative responses in CMV PBMC. The results indicate that the T cell anergy associated with CMV infection is restricted to the T cell receptor/CD3 activation pathway. PMID:8403514

  19. Congenital Cytomegalovirus Infection: A Significant Cause of Deafness and Mental Deficiency.

    ERIC Educational Resources Information Center

    Eichhorn, Sarah K.

    1982-01-01

    Research on cytomegalovirus (CMV), a herpes virus causing neurological damage (hearing problems and/or mental retardation) in 10 percent of infants born with the condition, is reviewed. Incidence of hearing and retardation in CMV cases is reported and current treatment described. (CL)

  20. Protection against lethal cytomegalovirus infection by a recombinant vaccine containing a single nonameric T-cell epitope.

    PubMed Central

    Del Val, M; Schlicht, H J; Volkmer, H; Messerle, M; Reddehase, M J; Koszinowski, U H

    1991-01-01

    The regulatory immediate-early (IE) protein pp89 of murine cytomegalovirus induces CD8+ T lymphocytes that protect against lethal murine cytomegalovirus infection. The IE1 epitope is the only epitope of pp89 that is recognized by BALB/c cytolytic T lymphocytes (CTL). Using synthetic peptides, the optimal and minimal antigenic sequences of the IE1 epitope have been defined. To evaluate the predictive value of data obtained with synthetic peptides, recombinant vaccines encoding this single T-cell epitope were constructed using as a vector the hepatitis B virus core antigen encoded in recombinant vaccinia virus. In infected cells expressing the chimeric proteins, only IE1 epitope sequences that were recognized as synthetic peptides at concentrations lower than 10(-6) M were presented to CTL. Vaccination of mice with the recombinant vaccinia virus that encoded a chimeric protein carrying the optimal 9-amino-acid IE1 epitope sequence elicited CD8+ T lymphocytes with antiviral activity and, furthermore, protected against lethal disease. The results thus show for the first time that recombinant vaccines containing a single foreign nonameric CTL epitope can induce T-lymphocyte-mediated protective immunity. Images PMID:1710286

  1. A novel flow cytometry-based tool for determining the efficiency of human cytomegalovirus infection in THP-1 derived macrophages.

    PubMed

    Li, Huifen; Mao, Genxiang; Carlson, Joshua; Leng, Sean X

    2015-09-01

    Human cytomegalovirus (hCMV) is a ubiquitous pathogen that causes congenital infection and severe infections in immunocompromised patients. Chronic hCMV infection may also play an important role in immunosenescence and adverse health outcomes in older adults. THP-1, a human monocytic cell line and its derived macrophages serve as a useful cell culture model for mechanistic studies of hCMV infection and its underlying biology. A major methodological challenge is the lack of a quick and reliable tool to accurately determine the efficiency of hCMV infection in THP-1 derived macrophages. In this study, we developed a flow cytometry based method using commercially available monoclonal antibody (MAb) against hCMV immediate early (IE) antigen that can accurately determine infection efficiency. We used 0.5% formaldehyde for fixation, 90% methanol for permeabilization, and incubation with FITC conjugated MAb at 37°C. The method was tested by hCMV infection with laboratory Towne strain in the presence or absence of hydrocortisone. It was also compared with the routine flow cytometry protocol using Cytofix/Cytoperm solution and with immunofluorescence. The results indicate that this new method is reliable and time saving for accurate determination of infection efficiency. It may facilitate further investigations into the underlying biological mechanisms of hCMV infection.

  2. Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii.

    PubMed

    Carter, C J

    2009-11-01

    Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind

  3. Dual Intravitreal Injections With Foscarnet and Ganciclovir for Ganciclovir-Resistant Recurrent Cytomegalovirus Retinitis in a Congenitally Infected Infant.

    PubMed

    Boss, Joseph D; Rosenberg, Kevin; Shah, Rajiv

    2016-10-22

    Resistant strains of cytomegalovirus can be difficult to treat in cases of congenital cytomegalovirus retinitis. The authors describe a case of recurrent bilateral congenital cytomegalovirus retinitis in an immunocompetent newborn with ganciclovir resistance successfully treated uniquely with dual therapy of intravenous ganciclovir and foscarnet and dual intravitreal injections with ganciclovir and foscarnet. [J Pediatr Ophthalmol Strabismus. 2016;53:e58-e60.].

  4. Late-onset cytomegalovirus infection complicated by Guillain-Barre syndrome in a kidney transplant recipient: case report and review of the literature.

    PubMed

    Shaban, E; Gohh, R; Knoll, B M

    2016-04-01

    Cytomegalovirus (CMV) infection remains a common infection after solid-organ transplantation. In the general population CMV disease is associated with Guillain-Barre syndrome (GBS), an autoimmune disease leading to an acute peripheral neuropathy, in 1 of 1000 cases. Interestingly, GBS is a rarely observed complication in solid-organ transplant recipients, possibly related to maintenance immunosuppression. We describe a case of CMV infection complicated by GBS in a kidney transplant recipient and review the literature.

  5. Acute Cytomegalovirus (CMV) Infection Associated with Hemophagocytic Lymphohistiocytosis (HLH) in an Immunocompetent Host Meeting All Eight HLH 2004 Diagnostic Criteria

    PubMed Central

    Willeford, Wesley G; Lichstein, Peter; Ohar, Jill

    2017-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a rare and often deadly syndrome characterized by severe inflammation and cytokine dysregulation. The disease is defined by the HLH-2004 criteria, requiring five of eight findings, and is further differentiated into either primary or secondary causes. Primary HLH tends to be of genetic etiology, while secondary HLH results from other insults such as infection. Secondary HLH is most commonly associated with viral infections in immunocompromised patients. Acute cytomegalovirus (CMV) associated HLH in the immunocompetent host is exceedingly rare and only documented in four case reports to date. We describe the fifth documented case of CMV-associated HLH in an immunocompetent patient, and furthermore, we demonstrate that this patient is the first published case of its type to satisfy all eight of HLH-2004 criteria.

  6. A Homolog Pentameric Complex Dictates Viral Epithelial Tropism, Pathogenicity and Congenital Infection Rate in Guinea Pig Cytomegalovirus

    PubMed Central

    McGregor, Alistair

    2016-01-01

    In human cytomegalovirus (HCMV), tropism to epithelial and endothelial cells is dependent upon a pentameric complex (PC). Given the structure of the placenta, the PC is potentially an important neutralizing antibody target antigen against congenital infection. The guinea pig is the only small animal model for congenital CMV. Guinea pig cytomegalovirus (GPCMV) potentially encodes a UL128-131 HCMV PC homolog locus (GP128-GP133). In transient expression studies, GPCMV gH and gL glycoproteins interacted with UL128, UL130 and UL131 homolog proteins (designated GP129 and GP131 and GP133 respectively) to form PC or subcomplexes which were determined by immunoprecipitation reactions directed to gH or gL. A natural GP129 C-terminal deletion mutant (aa 107–179) and a chimeric HCMV UL128 C-terminal domain swap GP129 mutant failed to form PC with other components. GPCMV infection of a newly established guinea pig epithelial cell line required a complete PC and a GP129 mutant virus lacked epithelial tropism and was attenuated in the guinea pig for pathogenicity and had a low congenital transmission rate. Individual knockout of GP131 or 133 genes resulted in loss of viral epithelial tropism. A GP128 mutant virus retained epithelial tropism and GP128 was determined not to be a PC component. A series of GPCMV mutants demonstrated that gO was not strictly essential for epithelial infection whereas gB and the PC were essential. Ectopic expression of a GP129 cDNA in a GP129 mutant virus restored epithelial tropism, pathogenicity and congenital infection. Overall, GPCMV forms a PC similar to HCMV which enables evaluation of PC based vaccine strategies in the guinea pig model. PMID:27387220

  7. Adoptive transfer of cytomegalovirus-specific effector CD4+ T cells provides antiviral protection from murine CMV infection.

    PubMed

    Jeitziner, Sanja Mandaric; Walton, Senta M; Torti, Nicole; Oxenius, Annette

    2013-11-01

    Cytomegalovirus (CMV) infects a majority of the human population and establishes a life-long persistence. CMV infection is usually asymptomatic but the virus carries pathogenic potential and causes severe disease in immunocompromised individuals. T-cell-mediated immunity plays an essential role in control of CMV infection and adoptive transfer of CMV-specific CD8(+) T cells restores viral immunity in immunosuppressed patients but a role for CD4(+) T cells remains elusive. Here, we analyzed in adoptive transfer studies the features and antiviral functions of virus-specific CD4(+) T cells during primary murine CMV (MCMV) infection. MCMV-specific CD4(+) T cells expanded upon MCMV infection and displayed an effector phenotype and function. Adoptive transfer of in vivo activated MCMV-specific CD4(+) T cells to immune-compromised mice was protective during pathogenic MCMV infection and IFN-γ was a crucial mediator of this protective capacity. Moreover, co-transfer of low doses of both MCMV-specific CD4(+) T cells and CD8(+) T cells synergized in control of lytic viral replication in immune-compromised mice. Our data reveal a pivotal antiviral role for virus-specific CD4(+) T cells in protection from pathogenic CMV infection and provide evidence for their antiviral therapeutic potential.

  8. Evaluation of a quantitative plasma PCR plate assay for detecting cytomegalovirus infection in marrow transplant recipients.

    PubMed Central

    Gallez-Hawkins, G M; Tegtmeier, B R; ter Veer, A; Niland, J C; Forman, S J; Zaia, J A

    1997-01-01

    A plasma PCR test, using a nonradioactive PCR plate assay, was evaluated for detection of human cytomegalovirus reactivation. This assay was compared to Southern blotting and found to perform well. As a noncompetitive method of quantitation, it was similar to a competitive method for detecting the number of genome copies per milliliter of plasma in marrow transplant recipients. This is a technically simplified assay with potential for adaptation to automation. PMID:9041438

  9. Activation of Langerhans-Type Dendritic Cells Alters Human Cytomegalovirus Infection and Reactivation in a Stimulus-Dependent Manner

    PubMed Central

    Coronel, Roxanne; Jesus, Desyree M.; Dalle Ore, Lucia; Mymryk, Joe S.; Hertel, Laura

    2016-01-01

    Oral mucosal Langerhans cells (LC) are likely to play important roles in host defense against infection by human cytomegalovirus (CMV). We previously showed that in vitro-differentiated immature LC (iLC) populations contain smaller amounts of infected cells but produce higher yields than mature LC (mLC) cultures, obtained by iLC stimulation with fetal bovine serum (FBS), CD40 ligand (CD40L) and lipopolysaccharide (LPS). Here, we sought to determine if exposure to select stimuli can improve LC permissiveness to infection, if specific components of the mLC cocktail are responsible for lowering viral yields, if this is due to defects in progeny production or release, and if these restrictions are also effective against reactivated virus. None of the stimuli tested extended the proportion of infected cells to 100%, suggesting that the block to infection onset cannot be fully removed. While CD40L and FBS exerted positive effects on viral progeny production per cell, stimulation with LPS alone or in combination with CD40L was detrimental. Reductions in viral titers were not due to defects in progeny release, and the permissive or restrictive intracellular environment established upon exposure to each stimulus appeared to act in a somewhat similar way toward lytic and latent infections. PMID:27683575

  10. Cytomegalovirus Infection May Contribute to the Reduced Immune Function, Growth, Development, and Health of HIV-Exposed, Uninfected African Children

    PubMed Central

    Filteau, Suzanne; Rowland-Jones, Sarah

    2016-01-01

    With increasing access to antiretroviral therapy (ART) in Africa, most children born to HIV-infected mothers are not themselves HIV-infected. These HIV-exposed, uninfected (HEU) children are at increased risk of mortality and have immune, growth, development, and health deficits compared to HIV-unexposed children. HEU children are known to be at higher risk than HIV-unexposed children of acquiring cytomegalovirus (CMV) infection in early life. This risk is largely unaffected by ART and is increased by breastfeeding, which itself is critically important for child health and survival. Early CMV infection, namely in utero or during early infancy, may contribute to reduced growth, altered or impaired immune functions, and sensory and cognitive deficits. We review the evidence that CMV may be responsible for the health impairments of HEU children. There are currently no ideal safe and effective interventions to reduce postnatal CMV infection. If a clinical trial showed proof of the principle that decreasing early CMV infection improved health and development of HEU children, this could provide the impetus needed for the development of better interventions to improve the health of this vulnerable population. PMID:27446087

  11. Control of human cytomegalovirus gene expression by differential histone modifications during lytic and latent infection of a monocytic cell line.

    PubMed

    Ioudinkova, Elena; Arcangeletti, Maria Cristina; Rynditch, Alla; De Conto, Flora; Motta, Federica; Covan, Silvia; Pinardi, Federica; Razin, Sergey V; Chezzi, Carlo

    2006-12-15

    Non-differentiated THP-1 cells can be infected by human cytomegalovirus (HCMV) Towne strain, which persists in these cells in a non-active (latent) form without undergoing a productive cycle. The same cells become permissive for HCMV lytic infection after induction of cell differentiation by treatment with 12-O-tetradecanoylphorbol-13-acetate. We used this cellular model to study the possible role of histone modifications in the control of HCMV latency. Using chromatin immunoprecipitation with antibodies against histone H3 acetylated or dimethylated in position K9, we demonstrated that in lytically infected cells the HCMV enhancer was associated with heavy acetylated but not dimethylated H3. In the case of latent infection, the HCMV enhancer was associated with neither acetylated nor dimethylated H3. HCMV genes encoding DNA polymerase (early), pp65 (early-late) and pp150 (late) proteins were associated preferentially with acetylated H3 in lytically infected cells and with dimethylated H3 in latently infected cells. These data strongly suggest that K9 methylation of H3 is involved in HCMV gene repression, while association of the above genes with acetylated histones is likely to be necessary for active transcription. It can be postulated that the same histone modifications are used to mark active and repressed genes in both cellular and viral chromatin.

  12. Relevance of maintenance triple-drug immunosuppression to bridle the amplification of rat cytomegalovirus infection after experimental lung transplantation.

    PubMed

    Lehle, K; von Suesskind-Schwendi, M; Diez, C; Michl, M; Geissler, E K; Wottge, H U; Schmid, C; Hirt, S W

    2012-12-01

    Immunosuppressive therapy required to treat rejection after lung transplantation (LTx) contributes significantly to the pathogenesis of cytomegalovirus (CMV) infection and disease. In a weak allogeneic left LTx model in the rat (Fisher 344 [F344] to Wistar Kyoto [WKY] rats) we analyzed the influence of acute CMV infection on postoperative day (POD) 3, with application of standard triple-drug immunosuppression (TD-IS) (cyclosporin A, azathioprine, prednisolone) on late outcome after LTx. Native right lungs and syngeneic grafts (WKY to WKY) served as controls. Rats were sacrificed on POD 15, 30, 60, and 100. TD-IS completely prevented acute and chronic rejection in non-infected rats. Allografts of CMV-infected rats treated with TD-IS showed only mild perivascular infiltrations in 6/10 rats (POD 15 and 30), which persisted up to POD 100 in 4/10 rats. In the long-term course, mild isolated interstitial and alveolar changes were found in 40% of these animals. In conclusion, rat CMV infection partially neutralized the immunosuppressive effect of TD-IS. However, an amplification of CMV infection under TD-IS can be controlled and does not result in fatal outcome.

  13. A Novel Non-Replication-Competent Cytomegalovirus Capsid Mutant Vaccine Strategy Is Effective in Reducing Congenital Infection

    PubMed Central

    Choi, K. Yeon; Root, Matthew

    2016-01-01

    ABSTRACT Congenital cytomegalovirus (CMV) infection is a leading cause of mental retardation and deafness in newborns. The guinea pig is the only small animal model for congenital CMV infection. A novel CMV vaccine was investigated as an intervention strategy against congenital guinea pig cytomegalovirus (GPCMV) infection. In this disabled infectious single-cycle (DISC) vaccine strategy, a GPCMV mutant virus was used that lacked the ability to express an essential capsid gene (the UL85 homolog GP85) except when grown on a complementing cell line. In vaccinated animals, the GP85 mutant virus (GP85 DISC) induced an antibody response to important glycoprotein complexes considered neutralizing target antigens (gB, gH/gL/gO, and gM/gN). The vaccine also generated a T cell response to the pp65 homolog (GP83), determined via a newly established guinea pig gamma interferon enzyme-linked immunosorbent spot assay. In a congenital infection protection study, GP85 DISC-vaccinated animals and a nonvaccinated control group were challenged during pregnancy with wild-type GPCMV (105 PFU). The pregnant animals carried the pups to term, and viral loads in target organs of pups were analyzed. Based on live pup births in the vaccinated and control groups (94.1% versus 63.6%), the vaccine was successful in reducing mortality (P = 0.0002). Additionally, pups from the vaccinated group had reduced CMV transmission, with 23.5% infected target organs versus 75.9% in the control group. Overall, these preliminary studies indicate that a DISC CMV vaccine strategy has the ability to induce an immune response similar to that of natural virus infection but has the increased safety of a non-replication-competent virus, which makes this approach attractive as a CMV vaccine strategy. IMPORTANCE Congenital CMV infection is a leading cause of mental retardation and deafness in newborns. An effective vaccine against CMV remains an elusive goal despite over 50 years of CMV research. The guinea pig, with

  14. The impact of cytomegalovirus infection on new-onset diabetes mellitus after kidney transplantation: a review on current findings

    PubMed Central

    Einollahi, Behzad; Motalebi, Mohsen; Salesi, Mahmood; Ebrahimi, Mehrdad; Taghipour, Mehrdad

    2014-01-01

    Context: New onset diabetes mellitus after transplantation (NODAT) increases the risk of cardiovascular disease, rate of infections, graft rejection and graft loss as well as decreases patient and graft survival rates. There is a controversy surrounding the impact of cytomegalovirus (CMV) infection in the development of NODAT. This meta-analysis aims to identify the role of CMV infection leading to the development of NODAT in kidney recipient patients. Evidence Acquisitions: We searched several electronic databases, including PubMed, Embase, Medline, Scopus, Trip Database and Google Scholar for studies that completely fulfill our criteria between January 1990 and January 2014 Results: Seven studies with 1389 kidney transplant patients were included in this metaanalysis.The mean age of patients ranged from 42.8 to 48.8 years and males made up 53% to 75% of patients in the cohort studies. The incidence of NODAT varies from 14.3% to 27.1% in these studies. Overall adj OR was 1.94 [exp (0.66)] with a 95% CI of 1.26-2.98 [exp (0.23) and (1.09)]. There was no significant publication bias based on the Begg’s and Egger’s test (p value = 0.17 and 0.54, respectively). Conclusions: Our study showed that CMV infection is a risk factor for increasing incidence of NODAT. Thus, prophylaxis against CMV infection after kidney transplantation is strongly suggested. However, further clinical trials and cohorts are needed to confirm this association. PMID:25374883

  15. The antiviral restriction factors IFITM1, 2 and 3 do not inhibit infection of human papillomavirus, cytomegalovirus and adenovirus.

    PubMed

    Warren, Cody J; Griffin, Laura M; Little, Alexander S; Huang, I-Chueh; Farzan, Michael; Pyeon, Dohun

    2014-01-01

    Type I interferons (IFN-α and β) induce dynamic host defense mechanisms to inhibit viral infections. It has been recently recognized that the interferon-inducible transmembrane proteins (IFITM) 1, 2 and 3 can block entry of a broad spectrum of RNA viruses. However, no study to date has focused on the role of IFITM proteins in DNA virus restriction. Here, we demonstrate that IFN-α or -β treatment of keratinocytes substantially decreases human papillomavirus 16 (HPV16) infection while robustly inducing IFITM1, 2 and 3 expression. However, IFITM1, 2 and 3 overexpression did not inhibit HPV16 infection; rather, IFITM1 and IFITM3 modestly enhanced HPV16 infection in various cell types including primary keratinocytes. Moreover, IFITM1, 2 and 3 did not inhibit infection by two other DNA viruses, human cytomegalovirus (HCMV) and adenovirus type 5 (Ad5). Taken together, we reveal that the entry of several DNA viruses, including HPV, HCMV, and Ad5 is not affected by IFITM1, 2 and 3 expression. These results imply that HPV, and other DNA viruses, may bypass IFITM restriction during intracellular trafficking.

  16. Cytomegalovirus IgG Level and Avidity in Breastfeeding Infants of HIV-Infected Mothers in Malawi.

    PubMed

    Kourtis, Athena P; Wiener, Jeffrey; Chang, Tiffany S; Dollard, Sheila C; Amin, Minal M; Ellington, Sascha; Kayira, Dumbani; van der Horst, Charles; Jamieson, Denise J

    2015-12-01

    Cytomegalovirus (CMV) infection is common among infants of HIV-infected mothers in resource-limited settings. We examined the prevalence and timing of infant CMV infection during the first year of life using IgG antibody and avidity among HIV-exposed infants in Malawi and correlated the results with the presence of detectable CMV DNA in the blood. The Breastfeeding, Antiretrovirals and Nutrition (BAN) study randomized 2,369 mothers and their infants to maternal antiretrovirals, infant nevirapine, or neither for 28 weeks of breastfeeding, followed by weaning. Stored plasma specimens were tested for CMV IgG and antibody avidity from a random subset of infants who had been previously tested with blood CMV PCR and had available specimens at birth and at 24 and 48 weeks of age. Ninety-four of 127 infants (74.0%) tested at 24 weeks of age had CMV IgG of low or intermediate avidity, signifying primary CMV infections. An additional 22 infants (17.3%) had IgG of high avidity; 19 of them had CMV DNA detected in their blood, indicating infant infections. Taken together, these results show that the estimated prevalence of CMV infection at 24 weeks was 88.9%. By 48 weeks of age, 81.3% of infants had anti-CMV IgG; most of them (70.9%) had IgG of high avidity. The CMV serology and avidity testing, combined with the PCR results, confirmed a high rate of primary CMV infection by 6 months of life among breastfeeding infants of HIV-infected mothers. The CMV PCR in blood detected most, but not all, infant CMV infections.

  17. New Strategies for Prevention and Therapy of Cytomegalovirus Infection and Disease in Solid-Organ Transplant Recipients

    PubMed Central

    Sia, Irene G.; Patel, Robin

    2000-01-01

    In the past three decades since the inception of human organ transplantation, cytomegalovirus (CMV) has gained increasing clinical import because it is a common pathogen in the immunocompromised transplant recipient. Patients may suffer from severe manifestations of this infection along with the threat of potential fatality. Additionally, the dynamic evolution of immunosuppressive and antiviral agents has brought forth changes in the natural history of CMV infection and disease. Transplant physicians now face the daunting task of recognizing and managing the changing spectrum of CMV infection and its consequences in the organ recipient. For the microbiology laboratory, the emphasis has been geared toward the development of more sophisticated detection assays, including methods to detect emerging antiviral resistance. The discovery of novel antiviral chemotherapy is an important theme of clinical research. Investigations have also focused on preventative measures for CMV disease in the solid-organ transplant population. In all, while much has been achieved in the overall management of CMV infection, the current understanding of CMV pathogenesis and therapy still leaves much to be learned before success can be claimed. PMID:10627493

  18. Self-Injurious Behavior Secondary to Cytomegalovirus-Induced Neuropathy in an SIV-Infected Rhesus Macaque (Macaca mulatta).

    PubMed

    Clemmons, Elizabeth A; Gumber, Sanjeev; Strobert, Elizabeth; Bloomsmith, Mollie A; Jean, Sherrie M

    2015-06-01

    A 3.5-y-old, female rhesus macaque (Macaca mulatta) inoculated with SIVmac239 presented 8 mo later for inappetence and facial bruising. Physical examination revealed a superficial skin abrasion below the left eye, bruising below the left brow, and epistaxis of the left nostril. There were no significant findings on CBC, serum chemistry, urinalysis, or radiographs. Differential diagnoses included infectious etiologies, self-injurious behavior, immune-mediated dermatitis, and neoplasia. Lack of response to antibiotic and analgesic therapy and observations of the macaque made it apparent that the skin lesions were self-inflicted. The excoriations rapidly progressed to extend over the nose, and the left palpebrae became edematous. Euthanasia was elected because the macaque appeared to be experiencing continued discomfort despite analgesic therapy. Histopathologic examination revealed systemic cytomegalovirus (CMV) infection involving the facial nerves, periocular nerves, meninges, and perimesenteric lymph nodes. CMV is a common infection in macaques, with adult seroprevalence close to 100% in most colonies. Infection in immunocompetent animals is usually asymptomatic but can cause significant clinical disease in immunodeficient hosts. CMV is associated with a painful peripheral neuropathy in human AIDS patients, and analgesic treatment is often unsatisfactory. Peripheral neuropathy secondary to CMV should be considered as an underlying cause of self-injurious behavior in SIV-infected macaques. Macaques affected by other diseases and disorders may also be at risk for development of painful peripheral neuropathies.

  19. Self-Injurious Behavior Secondary to Cytomegalovirus-Induced Neuropathy in an SIV-Infected Rhesus Macaque (Macaca mulatta)

    PubMed Central

    Clemmons, Elizabeth A; Gumber, Sanjeev; Strobert, Elizabeth; Bloomsmith, Mollie A; Jean, Sherrie M

    2015-01-01

    A 3.5-y-old, female rhesus macaque (Macaca mulatta) inoculated with SIVmac239 presented 8 mo later for inappetence and facial bruising. Physical examination revealed a superficial skin abrasion below the left eye, bruising below the left brow, and epistaxis of the left nostril. There were no significant findings on CBC, serum chemistry, urinalysis, or radiographs. Differential diagnoses included infectious etiologies, self-injurious behavior, immune-mediated dermatitis, and neoplasia. Lack of response to antibiotic and analgesic therapy and observations of the macaque made it apparent that the skin lesions were self-inflicted. The excoriations rapidly progressed to extend over the nose, and the left palpebrae became edematous. Euthanasia was elected because the macaque appeared to be experiencing continued discomfort despite analgesic therapy. Histopathologic examination revealed systemic cytomegalovirus (CMV) infection involving the facial nerves, periocular nerves, meninges, and perimesenteric lymph nodes. CMV is a common infection in macaques, with adult seroprevalence close to 100% in most colonies. Infection in immunocompetent animals is usually asymptomatic but can cause significant clinical disease in immunodeficient hosts. CMV is associated with a painful peripheral neuropathy in human AIDS patients, and analgesic treatment is often unsatisfactory. Peripheral neuropathy secondary to CMV should be considered as an underlying cause of self-injurious behavior in SIV-infected macaques. Macaques affected by other diseases and disorders may also be at risk for development of painful peripheral neuropathies. PMID:26141451

  20. Analysis of leukocyte activation during acute rejection of pulmonary allografts in noninfected and cytomegalovirus-infected rats.

    PubMed

    Steinmüller, C; Steinhoff, G; Bauer, D; You, X M; Denzin, H; Franke-Ullmann, G; Hausen, B; Bruggemann, C; Wagner, T O; Lohmann-Matthes, M L; Emmendörffer, A

    1997-01-01

    After human lung transplantation acute rejection and cytomegalovirus (CMV) infections may occur, probably contributing to the development of chronic rejection. We established a model of subacute allograft rejection in rats to analyze leukocyte activation and effects of a CMV infection. Histoincompatible lung transplants (BN/LEW) without immunosuppression (group A) and lungs of initially immunosuppressed animals (group B) were analyzed. The production of inflammatory mediators (interleukin-6, tumor necrosis factor alpha, nitric oxides) and the expression of MHC class II antigens by alveolar and lung tissue macrophages were significantly enhanced during the alloresponse. In recipients without immunosuppression (group A) allograft necrosis was detected by day 6, whereas group B allografts were fully rejected by day 25. In allografts of immunosuppressed, CMV-infected animals (group C) the CMV infection was clearly aggravated and the number of activated lung tissue macrophages was increased when compared with noninfected allografts or isografts. The subacute model provides the advantage of allowing us to study mechanisms of acute rejection without the effects of reperfusion injury. Furthermore these findings underline the role of inflammatory mediators produced by macrophages during rejection.

  1. Active human cytomegalovirus infection and glycoprotein b genotypes in brazilian pediatric renal or hematopoietic stem cell transplantation patients

    PubMed Central

    de Campos Dieamant, Débora; Bonon, Sandra Helena Alves; Prates, Liliane Cury; Belangelo, Vera Maria Santoro; Pontes, Erika R.; Costa, Sandra Cecília Botelho

    2010-01-01

    A prospective analysis of active Human Cytomegalovirus infection (HCMV) was conducted on 33 pediatric renal or hematopoietic stem cell post-transplant patients. The HCMV-DNA positive samples were evaluated for the prevalence of different gB subtypes and their subsequent correlation with clinical signs. The surveillance of HCMV active infection was based on the monitoring of antigenemia (AGM) and on a nested polymerase chain reaction (N-PCR) for the detection of HCMV in the patients studied. Using restriction analysis of the gB gene sequence by PCR-RFLP (Restriction Fragment Length Polymorphism), different HCMV strains could be detected and classified in at least four HCMV genotypes. Thirty-three pediatric recipients of renal or bone marrow transplantation were monitored. Twenty out of thirty-three (60.6%) patients demonstrated active HCMV infection. gB1 and gB2 genotypes were more frequent in this population. In this study, we observed that gB2 had correlation with reactivation of HCMV infection and that patients with mixture of genotypes did not show any symptoms of HCMV disease. Future studies has been made to confirm this. PMID:24031463

  2. [Consensus document from the Spanish Society of Paediatric Infectious Diseases (SEIP) on the diagnosis and treatment of congenital cytomegalovirus infection].

    PubMed

    Baquero-Artigao, F

    2009-12-01

    Cytomegalovirus (CMV) is the leading cause of congenital infection in developed countries, affecting 0.3 to 0.6% of all live births in Europe. Primary CMV infection occurs in 1 to 4% of seronegative women during pregnancy and may be transmitted to the fetus in 40% of cases. Up to 10% of intrauterine CMV infections result in symptomatic congenital disease at birth. Half of these children and 13% of those born with asymptomatic infection will develop long-term sequelae, especially neurosensory hearing loss and mental retardation. Accurate diagnosis of primary maternal and fetal infection is now possible using the avidity index of anti-CMV IgG and virological testing to detect the virus in amniotic fluid. Symptomatic congenital infection may be preventable using CMV hyperimmune globulin during pregnancy. The gold standard for diagnosis of congenital CMV infection is the detection of the virus in urine within the first 2 weeks of life by rapid cell culture techniques (shell vial) or nucleic acid amplification of viral DNA (PCR). Retrospective diagnosis can be achieved by detection of viral DNA by PCR in dried blood spots (Guthrie card) collected on filter paper in the first days of life. Currently available drugs for the treatment of congenital CMV include ganciclovir and its oral prodrug valganciclovir. Treatment with intravenous ganciclovir for six weeks may prevent hearing deterioration in children with symptomatic congenital CMV infection and central nervous system involvement. Valganciclovir may be an excellent alternative because of its good bio-availability, providing plasma concentrations similar to those achieved with intravenous ganciclovir.

  3. Cytomegalovirus iritis.

    PubMed

    Cheng, L; Rao, N A; Keefe, K S; Avila, C P; Macdonald, J C; Freeman, W R

    1998-11-01

    We describe a case of focal cytomegalovirus iritis in a patient with acquired immunodeficiency syndrome (AIDS) who had CMV retinitis. The autopsy showed histologic evidence of focal iritis in the left eye. This iritis was characterized by infiltration of acute inflammatory cells mixed with cytomegalic cells, which was confirmed by CMV-specific immunohistochemical staining. The case suggested that cytomegalovirus could be a direct causative agent of infectious iritis in AIDS patients.

  4. Controversies in the natural history of congenital human cytomegalovirus infection: the paradox of infection and disease in offspring of women with immunity prior to pregnancy.

    PubMed

    Britt, William

    2015-06-01

    Human cytomegalovirus (HCMV) is the most common virus infection in the developing fetus. A fraction of infants infected in utero develop significant life-threatening and organ-threatening disease with over 90% of infected infants exhibiting no clinical evidence of infection in the newborn period. However, about 10% of all infected infants will develop long-term sequelae. Early studies stressed the importance of primary maternal HCMV infection during pregnancy as a critical determinant of intrauterine transmission and outcome. This concept serves as the foundation for the development of prophylactic vaccines and biologics such as HCMV immune globulins. More recently, studies in maternal populations with high HCMV seroprevalence have challenged the concept of protective maternal immunity. Findings from multiple studies suggest that preexisting maternal HCMV immunity provides at best, partial protection from disease in the infected offspring and similarly may have limited impact on intrauterine transmission. This brief review will provide some considerations about the apparent paradox of maternal HCMV immunity and congenital infection.

  5. Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

    PubMed Central

    Collins-McMillen, Donna; Kim, Jung Heon; Nogalski, Maciej T.; Stevenson, Emily V.; Caskey, Joshua R.; Cieply, Stephen J.

    2015-01-01

    ABSTRACT Monocytes play a key role in the hematogenous dissemination of human cytomegalovirus (HCMV) to target organ systems. To infect monocytes and reprogram them to deliver infectious virus, HCMV must overcome biological obstacles, including the short life span of monocytes and their antiviral proapoptotic response to infection. We have shown that virally induced upregulation of cellular Mcl-1 promotes early survival of HCMV-infected monocytes, allowing cells to overcome an early apoptotic checkpoint at around 48 h postinfection (hpi). Here, we demonstrate an HCMV-dependent shift from Mcl-1 as the primary antiapoptotic player to the related protein, Bcl-2, later during infection. Bcl-2 was upregulated in HCMV-infected monocytes beginning at 48 hpi. Treatment with the Bcl-2 antagonist ABT-199 only reduced the prosurvival effects of HCMV in target monocytes beginning at 48 hpi, suggesting that Mcl-1 controls survival prior to 48 hpi, while Bcl-2 promotes survival after 48 hpi. Although Bcl-2 was upregulated following viral binding/signaling through cellular integrins (compared to Mcl-1, which is upregulated through binding/activation of epidermal growth factor receptor [EGFR]), it functioned similarly to Mcl-1, adopting the early role of Mcl-1 in preventing caspase-3 cleavage/activation. This distinct, HCMV-induced shift from Mcl-1 to Bcl-2 occurs in response to a cellular upregulation of proapoptotic Bax, as small interfering RNA (siRNA)-mediated knockdown of Bax reduced the upregulation of Bcl-2 in infected monocytes and rescued the cells from the apoptotic effects of Bcl-2 inhibition. Our data demonstrate a distinct survival strategy whereby HCMV induces a biphasic regulation of cellular Bcl-2 proteins to promote host cell survival, leading to viral dissemination and the establishment of persistent HCMV infection. IMPORTANCE Hematogenous dissemination of HCMV via infected monocytes is a crucial component of the viral survival strategy and is required for the

  6. Detection of congenital cytomegalovirus infection by real-time polymerase chain reaction analysis of saliva or urine specimens.

    PubMed

    Ross, Shannon A; Ahmed, Amina; Palmer, April L; Michaels, Marian G; Sánchez, Pablo J; Bernstein, David I; Tolan, Robert W; Novak, Zdenek; Chowdhury, Nazma; Fowler, Karen B; Boppana, Suresh B

    2014-11-01

    Viral culture of urine or saliva has been the gold standard technique for the diagnosis of congenital cytomegalovirus (CMV) infection. Results of rapid culture and polymerase chain reaction (PCR) analysis of urine and saliva specimens from 80 children were compared to determine the clinical utility of a real-time PCR assay for diagnosis of congenital CMV infection. Results of urine PCR were positive in 98.8% of specimens. Three PCR-positive urine samples were culture negative. Results of saliva PCR and culture were concordant in 78 specimens (97.5%). Two PCR-positive saliva samples were culture negative. These findings demonstrate that PCR performs as well as rapid culture of urine or saliva specimens for diagnosing congenital CMV infection and saliva specimens are easier to collect. Because PCR also offers more rapid turnaround, is unlikely to be affected by storage and transport conditions, has lower cost, and may be adapted to high-throughput situations, it is well suited for targeted testing and large-scale screening for CMV.

  7. Oral ulceration associated with concurrent herpes simplex virus, cytomegalovirus, and Epstein-Barr virus infection in an immunocompromised patient.

    PubMed

    Mainville, Gisele N; Marsh, William L; Allen, Carl M

    2015-06-01

    In immunocompromised patients, oral ulcerations are common and have a wide spectrum of causes, including herpesvirus infection. We report on a case in which an oral ulcer was simultaneously infected by herpes simplex (HSV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) in a kidney-pancreas transplant recipient. A 46-year-old woman presented with a clinically nonspecific dorsal tongue ulcer of 3 months duration. Histopathologic evaluation indicated keratinocytes exhibiting herpetic viral cytopathic effect. Nuclear and cytologic alterations suggestive of CMV infection were found in endothelial cells subjacent to the ulcer. Immunohistochemistry testing for HSV and CMV was positive in these cells. Large atypical mononuclear cells were also evident in the ulcer bed's inflammatory infiltrate, which had intense nuclear positivity for Epstein-Barr encoding region in situ hybridization. We believe this is the first well-documented report of the definitive concomitant presence of HSV, CMV, and EBV in an immunocompromised patient. Although the pathogenesis of coinfected ulcers remains unknown, a synergistic effect is possible.

  8. Vaccine Therapy in Preventing Cytomegalovirus Infection in Patients With Hematological Malignancies Undergoing Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-11-23

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Nodular Lymphocyte Predominant Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; B-cell Adult Acute Lymphoblastic Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cytomegalovirus Infection; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Isolated Plasmacytoma of Bone; Monoclonal Gammopathy of Undetermined Significance; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously

  9. Human cytomegalovirus infection leads to elevated levels of transplant arteriosclerosis in a humanized mouse aortic xenograft model.

    PubMed

    Abele-Ohl, S; Leis, M; Wollin, M; Mahmoudian, S; Hoffmann, J; Müller, R; Heim, C; Spriewald, B M; Weyand, M; Stamminger, T; Ensminger, S M

    2012-07-01

    Recent findings emphasized an important role of human cytomegalovirus (HCMV) infection in the development of transplant arteriosclerosis. Therefore, the aim of this study was to develop a human peripheral blood lymphocyte (hu-PBL)/Rag-2(-/-) γc(-/-) mouse-xenograft-model to investigate both immunological as well as viral effector mechanisms in the progression of transplant arteriosclerosis. For this, sidebranches from the internal mammary artery were recovered during coronary artery bypass graft surgery, tissue-typed and infected with HCMV. Then, size-matched sidebranches were implanted into the infrarenal aorta of Rag-2(-/-) γc(-/-) mice. The animals were reconstituted with human peripheral blood mononuclear cells (PBMCs) 7 days after transplantation. HCMV-infection was confirmed by Taqman-PCR and immunofluorescence analyses. Arterial grafts were analyzed by histology on day 40 after transplantation. PBMC-reconstituted Rag-2(-/-) γc(-/-) animals showed splenic chimerism levels ranging from 1-16% human cells. After reconstitution, Rag-2(-/-) γc(-/-) mice developed human leukocyte infiltrates in their grafts and vascular lesions that were significantly elevated after infection. Cellular infiltration revealed significantly increased ICAM-1 and PDGF-R-β expression after HCMV-infection of the graft. Arterial grafts from unreconstituted Rag-2(-/-) γc(-/-) recipients showed no vascular lesions. These data demonstrate a causative relationship between HCMV-infection as an isolated risk factor and the development of transplant-arteriosclerosis in a humanized mouse arterial-transplant-model possibly by elevated ICAM-1 and PDGF-R-β expression.

  10. Dual Role of Natural Killer Cells on Graft Rejection and Control of Cytomegalovirus Infection in Renal Transplantation

    PubMed Central

    López-Botet, Miguel; Vilches, Carlos; Redondo-Pachón, Dolores; Muntasell, Aura; Pupuleku, Aldi; Yélamos, José; Pascual, Julio; Crespo, Marta

    2017-01-01

    Allograft rejection constitutes a major complication of solid organ transplantation requiring prophylactic/therapeutic immunosuppression, which increases susceptibility of patients to infections and cancer. Beyond the pivotal role of alloantigen-specific T cells and antibodies in the pathogenesis of rejection, natural killer (NK) cells may display alloreactive potential in case of mismatch between recipient inhibitory killer-cell immunoglobulin-like receptors (KIRs) and graft HLA class I molecules. Several studies have addressed the impact of this variable in kidney transplant with conflicting conclusions; yet, increasing evidence supports that alloantibody-mediated NK cell activation via FcγRIIIA (CD16) contributes to rejection. On the other hand, human cytomegalovirus (HCMV) infection constitutes a risk factor directly associated with the rate of graft loss and reduced host survival. The levels of HCMV-specific CD8+ T cells have been reported to predict the risk of posttransplant infection, and KIR-B haplotypes containing activating KIR genes have been related with protection. HCMV infection promotes to a variable extent an adaptive differentiation and expansion of a subset of mature NK cells, which display the CD94/NKG2C-activating receptor. Evidence supporting that adaptive NKG2C+ NK cells may contribute to control the viral infection in kidney transplant recipients has been recently obtained. The dual role of NK cells in the interrelation of HCMV infection with rejection deserves attention. Further phenotypic, functional, and genetic analyses of NK cells may provide additional insights on the pathogenesis of solid organ transplant complications, leading to the development of biomarkers with potential clinical value. PMID:28261220

  11. TLR9 -1486T/C and 2848C/T SNPs Are Associated with Human Cytomegalovirus Infection in Infants

    PubMed Central

    Paradowska, Edyta; Jabłońska, Agnieszka; Studzińska, Mirosława; Skowrońska, Katarzyna; Suski, Patrycja; Wiśniewska-Ligier, Małgorzata; Woźniakowska-Gęsicka, Teresa; Nowakowska, Dorota; Gaj, Zuzanna; Wilczyński, Jan; Leśnikowski, Zbigniew J.

    2016-01-01

    Toll-like receptor 9 (TLR9) recognizes non-methylated viral CpG-containing DNA and serves as a pattern recognition receptor that signals the presence of human cytomegalovirus (HCMV). Here, we present the genotype distribution of single-nucleotide polymorphisms (SNPs) of the TLR9 gene in infants and the relationship between TLR9 polymorphisms and HCMV infection. Four polymorphisms (-1237T/C, rs5743836; -1486T/C, rs187084; 1174G/A, rs352139; and 2848C/T, rs352140) in the TLR9 gene were genotyped in 72 infants with symptomatic HCMV infection and 70 healthy individuals. SNP genotyping was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Digested fragments were separated and identified by capillary electrophoresis. The HCMV DNA copy number was measured by a quantitative real-time PCR assay. We found an increased frequency of heterozygous genotypes TLR9 -1486T/C and 2848C/T in infants with HCMV infection compared with uninfected cases. Heterozygous variants of these two SNPs increased the risk of HCMV disease in children (P = 0.044 and P = 0.029, respectively). In infants with a mutation present in at least one allele of -1486T/C and 2848C/T SNPs, a trend towards increased risk of cytomegaly was confirmed after Bonferroni’s correction for multiple testing (Pc = 0.063). The rs352139 GG genotype showed a significantly reduced relative risk for HCMV infection (Pc = 0.006). In contrast, the -1237T/C SNP was not related to viral infection. We found no evidence for linkage disequilibrium with the four examined TLR9 SNPs. The findings suggest that the TLR9 -1486T/C and 2848C/T polymorphisms could be a genetic risk factor for the development of HCMV disease. PMID:27105145

  12. Primary Cytomegalovirus Infection in Seronegative Kidney Transplant Patients Is Associated with Protracted Cold Ischemic Time of Seropositive Donor Organs

    PubMed Central

    Hoffmann, Dieter; Matevossian, Edouard; Lutz, Jens; Heemann, Uwe; Hösel, Volker; Busch, Dirk H.; Renders, Lutz; Neuenhahn, Michael

    2017-01-01

    Human Cytomegalovirus (CMV) can lead to primary infection or reactivation in CMV-seronegative or -seropositive kidney transplant recipients, respectively. Complications comprise severe end-organ diseases and acute or chronic transplant rejection. Risk for CMV manifestation is stratified according to the CMV-IgG-serostatus, with donor+/recipient- (D+/R-) patients carrying the highest risk for CMV-replication. However, risk factors predisposing for primary infection in CMV-seronegative recipients are still not fully elucidated. Therefore, we monitored D+/R- high-risk patients undergoing kidney transplantation in combination with antiviral prophylaxis for the incidence of CMV-viremia for a median follow-up time of 784 days (156–1155 days). In this period, we analyzed the functional CMV-specific T cell response by intracellular cytokine staining and CMV-serology by ELISA. Only four of eight D+/R- patients developed clinically relevant CMV-viremia followed by seroconversion. Viremia triggered expansion of functional CMV-specific T cells correlating with protection against secondary CMV-reactivations. In contrast, all other patients remained permanently aviremic and showed no immunological correlate of infection after discontinuation of antiviral prophylaxis for up to three years. Comparing cold ischemic times (CIT) of viremic (median = 1020 min; 720–1080 min) and aviremic patients (median = 335 min; 120–660 min) revealed significantly (p = 0.0286) protracted CIT in patients with primary CMV-infection. Taken together, primary CMV-infection affects only a subgroup of D+/R- patients correlating with length of CIT. Therefore, patients with extended CIT should be thoroughly monitored for CMV-replication well beyond discontinuation of antiviral prophylaxis. In contrast, patients with short CIT remained permanently uninfected and might benefit from shorter prophylactic treatment. PMID:28129395

  13. History of the molecular biology of cytomegaloviruses.

    PubMed

    Stinski, Mark F

    2014-01-01

    The history of the molecular biology of cytomegaloviruses from the purification of the virus and the viral DNA to the cloning and expression of the viral genes is reviewed. A key genetic element of cytomegalovirus (the CMV promoter) contributed to our understanding of eukaryotic cell molecular biology and to the development of lifesaving therapeutic proteins. The study of the molecular biology of cytomegaloviruses also contributed to the development of antivirals to control the viral infection.

  14. Infection and Cardiovascular Disease

    ClinicalTrials.gov

    2016-02-17

    Cardiovascular Diseases; Coronary Disease; Cerebrovascular Accident; Heart Diseases; Myocardial Infarction; Infection; Chlamydia Infections; Cytomegalovirus Infections; Helicobacter Infections; Atherosclerosis

  15. Diagnostic value of amplification of human cytomegalovirus DNA from gastrointestinal biopsies from human immunodeficiency virus-infected patients.

    PubMed Central

    Cotte, L; Drouet, E; Bissuel, F; Denoyel, G A; Trepo, C

    1993-01-01

    In order to assess the value of human cytomegalovirus (HCMV) DNA amplification of gastrointestinal biopsies, we studied 57 human immunodeficiency virus-infected patients with and without gastrointestinal HCMV diseases. After DNA extraction, a 406-bp fragment from the unique short region of the HCMV genome was amplified by 35 cycles of polymerase chain reaction (PCR) and semiquantified from 80 to 80,000 HCMV genomic copies. Among 12 non-AIDS patients, the PCR assay was negative for 11 of 12 duodenal and 8 of 8 colorectal samples. It was also negative for 28 of 31 duodenal and 12 of 15 colorectal samples from 31 AIDS patients without gastrointestinal HCMV diseases. Among 14 AIDS patients with gastrointestinal HCMV diseases, the PCR assay was positive for 12 of 12 patients with HCMV duodenitis and for 13 of 13 patients with HCMV colitis. Results were dichotomized between high and low HCMV-DNA copy numbers. For duodenitis, sensitivity was 92% and specificity was 100%. For colitis, sensitivity was 92% and specificity was 93%. Specificity and sensitivity were not influenced by shedding status for HCMV or by other gastrointestinal infections. HCMV DNA amplification of gastrointestinal biopsies is a sensitive and specific tool for the diagnosis of gastrointestinal HCMV diseases in AIDS patients. Images PMID:8396587

  16. Developing a Vaccine against Congenital Cytomegalovirus (CMV) Infection: What Have We Learned from Animal Models? Where Should We Go Next?

    PubMed

    Schleiss, Mark R

    2013-12-01

    Congenital human cytomegalovirus (HCMV) infection can lead to long-term neurodevelopmental sequelae, including mental retardation and sensorineural hearing loss. Unfortunately, CMVs are highly adapted to their specific species, precluding the evaluation of HCMV vaccines in animal models prior to clinical trials. Several species-specific CMVs have been characterized and developed in models of pathogenesis and vaccine-mediated protection against disease. These include the murine CMV (MCMV), the porcine CMV (PCMV), the rhesus macaque CMV (RhCMV), the rat CMV (RCMV), and the guinea pig CMV (GPCMV). Because of the propensity of the GPCMV to cross the placenta, infecting the fetus in utero, it has emerged as a model of particular interest in studying vaccine-mediated protection of the fetus. In this paper, a review of these various models, with particular emphasis on the value of the model in the testing and evaluation of vaccines against congenital CMV, is provided. Recent exciting developments and advances in these various models are summarized, and recommendations offered for high-priority areas for future study.

  17. Non-hematopoietic cells in lymph nodes drive memory CD8 T cell inflation during murine cytomegalovirus infection.

    PubMed

    Torti, Nicole; Walton, Senta M; Brocker, Thomas; Rülicke, Thomas; Oxenius, Annette

    2011-10-01

    During human and murine cytomegalovirus (MCMV) infection an exceptionally large virus-specific CD8 T cell pool is maintained in the periphery lifelong. This anomalous response is only seen for specific subsets of MCMV-specific CD8 T cells which are referred to as 'inflationary T cells'. How memory CD8 T cell inflation is induced and maintained is unclear, though their activated phenotype strongly suggests an involvement of persistent antigen encounter during MCMV latency. To dissect the cellular and molecular requirements for memory CD8 T cell inflation, we have generated a transgenic mouse expressing an MHC class I-restricted T cell receptor specific for an immunodominant inflationary epitope of MCMV. Through a series of adoptive transfer experiments we found that memory inflation was completely dependent on antigen presentation by non-hematopoietic cells, which are also the predominant site of MCMV latency. In particular, non-hematopoietic cells selectively induced robust proliferation of inflationary CD8 T cells in lymph nodes, where a majority of the inflationary CD8 T cells exhibit a central-memory phenotype, but not in peripheral tissues, where terminally differentiated inflationary T cells accumulate. These results indicate that continuous restimulation of central memory CD8 T cells in the lymph nodes by infected non-hematopoietic cells ensures the maintenance of a functional effector CD8 T pool in the periphery, providing protection against viral reactivation events.

  18. Developing a Vaccine against Congenital Cytomegalovirus (CMV) Infection: What Have We Learned from Animal Models? Where Should We Go Next?

    PubMed Central

    Schleiss, Mark R.

    2014-01-01

    Summary Congenital human cytomegalovirus (HCMV) infection can lead to long-term neurodevelopmental sequelae, including mental retardation and sensorineural hearing loss. Unfortunately, CMVs are highly adapted to their specific species, precluding the evaluation of HCMV vaccines in animal models prior to clinical trials. Several species-specific CMVs have been characterized and developed in models of pathogenesis and vaccine-mediated protection against disease. These include the murine CMV (MCMV), the porcine CMV (PCMV), the rhesus macaque CMV (RhCMV), the rat CMV (RCMV), and the guinea pig CMV (GPCMV). Because of the propensity of the GPCMV to cross the placenta, infecting the fetus in utero, it has emerged as a model of particular interest in studying vaccine-mediated protection of the fetus. In this paper, a review of these various models, with particular emphasis on the value of the model in the testing and evaluation of vaccines against congenital CMV, is provided. Recent exciting developments and advances in these various models are summarized, and recommendations offered for high-priority areas for future study. PMID:24523827

  19. [The role of virological tests in the diagnosis of cytomegalovirus infection in pregnant women].

    PubMed

    Mihály, Ilona; Arányi, Zsuzsanna; Prinz, Gyula; Lukács, Adrienne; Kolozsi, Tímea; Liptai, Zoltán; Bábinszky, Agota; Kodaj, Imre; Petik, Dóra; Lázár, Gábor

    2014-10-12

    Bevezetés: A leggyakoribb magzatkárosító ágens a cytomegalovirus. A diagnosztika eszközeinek és a terápiás lehetőségeknek a fejlődése új perspektívát nyitott a terhességi cytomegalovirusfertőzések kiderítésében és kezelésében. Célkitűzés: A 2007 és 2012 közötti hat év terhességi cytomegalovirus szűrővizsgálati eredményeinek elemzése. Módszer: 956 várandós klinikai adatainak és virológiai eredményeinek retrospektív analízise. Eredmények: 65,4%-uk védett, 33,3%-uk fogékony volt cytomegalovirusfertőzés iránt. A szerzők 10 primer fertőzést igazoltak, három esetben kétes eredményt találtak. A 13 várandós közül hat tünetmentes, öt beteg, kettőnek magzati ultrahangeltérése volt. A négy követett terhes közül egy spontán elvetélt, kettő gyermekénél igazolódott, egynél kizárható volt a congenitalis fertőzés. Következtetések: A magyarországi terhességi cytomegalovirusátvészeltségi arány a magas higiénés viszonyokra jellemző. Klinikai gyanú esetén és enzimimmunoassay típusú vizsgálattal talált IgM-pozitív esetekben kötelező a konfirmációs vizsgálatok elvégzése. A szűrővizsgálatot a terhességvállalást megelőzően kellene beiktatni. Szükség van az érintett szakmák közötti szorosabb együttműködésre a kiszámíthatatlan szűrővizsgálati kérelmek szabályozása és az indokolatlan terhességmegszakítások megelőzése érdekében. Orv. Hetil., 2014, 155(41), 1632–1642.

  20. Vaccine-Derived Neutralizing Antibodies to the Human Cytomegalovirus gH/gL Pentamer Potently Block Primary Cytotrophoblast Infection

    PubMed Central

    Chiuppesi, Flavia; Wussow, Felix; Johnson, Erica; Bian, Chao; Zhuo, Meng; Rajakumar, Augustine; Barry, Peter A.; Britt, William J.; Chakraborty, Rana

    2015-01-01

    ABSTRACT Human cytomegalovirus (HCMV) elicits neutralizing antibodies (NAb) of various potencies and cell type specificities to prevent HCMV entry into fibroblasts (FB) and epithelial/endothelial cells (EpC/EnC). NAb targeting the major essential envelope glycoprotein complexes gB and gH/gL inhibit both FB and EpC/EnC entry. In contrast to FB infection, HCMV entry into EpC/EnC is additionally blocked by extremely potent NAb to conformational epitopes of the gH/gL/UL128/130/131A pentamer complex (PC). We recently developed a vaccine concept based on coexpression of all five PC subunits by a single modified vaccinia virus Ankara (MVA) vector, termed MVA-PC. Vaccination of mice and rhesus macaques with MVA-PC resulted in a high titer and sustained NAb that blocked EpC/EnC infection and lower-titer NAb that inhibited FB entry. However, antibody function responsible for the neutralizing activity induced by the MVA-PC vaccine is uncharacterized. Here, we demonstrate that MVA-PC elicits NAb with cell type-specific neutralization potency and antigen recognition pattern similar to human NAb targeting conformational and linear epitopes of the UL128/130/131A subunits or gH. In addition, we show that the vaccine-derived PC-specific NAb are significantly more potent than the anti-gH NAb to prevent HCMV spread in EpC and infection of human placental cytotrophoblasts, cell types thought to be of critical importance for HCMV transmission to the fetus. These findings further validate MVA-PC as a clinical vaccine candidate to elicit NAb that resembles those induced during HCMV infection and provide valuable insights into the potency of PC-specific NAb to interfere with HCMV cell-associated spread and infection of key placental cells. IMPORTANCE As a consequence of the leading role of human cytomegalovirus (HCMV) in causing permanent birth defects, developing a vaccine against HCMV has been assigned a major public health priority. We have recently introduced a vaccine strategy based

  1. The Mouse Cytomegalovirus Gene m42 Targets Surface Expression of the Protein Tyrosine Phosphatase CD45 in Infected Macrophages

    PubMed Central

    Thiel, Nadine; Keyser, Kirsten A.; Oduro, Jennifer D.; Wagner, Karen; Halenius, Anne; Lenac Roviš, Tihana; Brinkmann, Melanie M.; Jonjić, Stipan; Cicin-Sain, Luka

    2016-01-01

    The receptor-like protein tyrosine phosphatase CD45 is expressed on the surface of cells of hematopoietic origin and has a pivotal role for the function of these cells in the immune response. Here we report that following infection of macrophages with mouse cytomegalovirus (MCMV) the cell surface expression of CD45 is drastically diminished. Screening of a set of MCMV deletion mutants allowed us to identify the viral gene m42 of being responsible for CD45 down-modulation. Moreover, expression of m42 independent of viral infection upon retroviral transduction of the RAW264.7 macrophage cell line led to comparable regulation of CD45 expression. In immunocompetent mice infected with an m42 deletion mutant lower viral titers were observed in all tissues examined when compared to wildtype MCMV, indicating an important role of m42 for viral replication in vivo. The m42 gene product was identified as an 18 kDa protein expressed with early kinetics and is predicted to be a tail-anchored membrane protein. Tracking of surface-resident CD45 molecules revealed that m42 induces internalization and degradation of CD45. The observation that the amounts of the E3 ubiquitin ligases Itch and Nedd4 were diminished in cells expressing m42 and that disruption of a PY motif in the N-terminal part of m42 resulted in loss of function, suggest that m42 acts as an activator or adaptor for these Nedd4-like ubiquitin ligases, which mark CD45 for lysosomal degradation. In conclusion, the down-modulation of CD45 expression in MCMV-infected myeloid cells represents a novel pathway of virus-host interaction. PMID:27926943

  2. Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+ NK cells in healthy humans.

    PubMed

    Bigley, A B; Rezvani, K; Shah, N; Sekine, T; Balneger, N; Pistillo, M; Agha, N; Kunz, H; O'Connor, D P; Bollard, C M; Simpson, R J

    2016-08-01

    Cytomegalovirus (CMV) infection markedly expands NKG2C+/NKG2A- NK cells, which are potent killers of infected cells expressing human leucocyte antigen (HLA)-E. As HLA-E is also over-expressed in several haematological malignancies and CMV has been linked to a reduced risk of leukaemic relapse, we determined the impact of latent CMV infection on NK cell cytotoxicity against four tumour target cell lines with varying levels of HLA-E expression. NK cell cytotoxicity against K562 (leukaemia origin) and U266 (multiple myeloma origin) target cells was strikingly greater in healthy CMV-seropositive donors than seronegative donors and was associated strongly with target cell HLA-E and NK cell NKG2C expression. NK cell cytotoxicity against HLA-E transfected lymphoma target cells (221.AEH) was ∼threefold higher with CMV, while NK cell cytotoxicity against non-transfected 721.221 cells was identical between the CMV groups. NK cell degranulation (CD107a(+) ) and interferon (IFN)-γ production to 221.AEH cells was localized almost exclusively to the NKG2C subset, and antibody blocking of NKG2C completely eliminated the effect of CMV on NK cell cytotoxicity against 221.AEH cells. Moreover, 221.AEH feeder cells and interleukin (IL)-15 were found to expand NKG2C(+) /NKG2A(-) NK cells preferentially from CMV-seronegative donors and increase NK cell cytotoxicity against HLA-E(+) tumour cell lines. We conclude that latent CMV infection enhances NK cell cytotoxicity through accumulation of NKG2C(+) NK cells, which may be beneficial in preventing the initiation and progression of haematological malignancies characterized by high HLA-E expression.

  3. Clinical features of late cytomegalovirus infection after hematopoietic stem cell transplantation.

    PubMed

    Asano-Mori, Yuki; Kanda, Yoshinobu; Oshima, Kumi; Kako, Shinichi; Shinohara, Akihito; Nakasone, Hideki; Sato, Hiroyuki; Watanabe, Takuro; Hosoya, Noriko; Izutsu, Koji; Asai, Takashi; Hangaishi, Akira; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo

    2008-04-01

    Late cytomegalovirus (CMV) disease beyond day 100 after hematopoietic stem cell transplantation (HSCT) has become an increasing problem after the introduction of preemptive ganciclovir (GCV) administration. To clarify the risk factors and outcome for late CMV reactivation and disease, we retrospectively analyzed the records of 101 Japanese adult patients who underwent allogeneic HSCT between 1998 and 2005 at our hospital. Fifty-one developed late positive CMV antigenemia, with a cumulative incidence of 53%. Recipient CMV seropositivity, the use of alemtuzumab, chronic GVHD, and high-dose steroids were significantly associated with late positive antigenemia. Eight patients developed late CMV disease, with a cumulative incidence of 8%, including retinitis and gastrointestinal disease. None progressed to a fatal disease. The use of alemtuzumab was identified as an independent significant risk factor for late CMV disease, although it was not associated with increased non-relapse mortality. Among the 51 patients with late positive antigenemia, 28 had consistently less than three positive cells, 25 of whom showed negative conversion without antiviral agents. In conclusion, late CMV antigenemia appeared to develop frequently, especially in patients with profound immune suppression; however, a fatal outcome could be prevented by optimal preemptive therapy. Low-level antigenemia may not require antiviral treatments.

  4. Xenotransplantation and porcine cytomegalovirus.

    PubMed

    Denner, Joachim

    2015-01-01

    Porcine microorganisms may be transmitted to the human recipient when xenotransplantation with pig cells, tissues, and organs will be performed. Most of such microorganisms can be eliminated from the donor pig by specified or designated pathogen-free production of the animals. As human cytomegalovirus causes severe transplant rejection in allotransplantation, considerable concern is warranted on the potential pathogenicity of porcine cytomegalovirus (PCMV) in the setting of xenotransplantation. On the other hand, despite having a similar name, PCMV is different from HCMV. The impact of PCMV infection on pigs is known; however, the influence of PCMV on the human transplant recipient is unclear. However, first transplantations of pig organs infected with PCMV into non-human primates were associated with a significant reduction of the survival time of the transplants. Sensitive detection methods and strategies for elimination of PCMV from donor herds are required.

  5. The Expression of Human Cytomegalovirus MicroRNA MiR-UL148D during Latent Infection in Primary Myeloid Cells Inhibits Activin A-triggered Secretion of IL-6

    PubMed Central

    Lau, Betty; Poole, Emma; Krishna, Benjamin; Sellart, Immaculada; Wills, Mark R.; Murphy, Eain; Sinclair, John

    2016-01-01

    The successful establishment and maintenance of human cytomegalovirus (HCMV) latency is dependent on the expression of a subset of viral genes. Whilst the exact spectrum and functions of these genes are far from clear, inroads have been made for protein-coding genes. In contrast, little is known about the expression of non-coding RNAs. Here we show that HCMV encoded miRNAs are expressed de novo during latent infection of primary myeloid cells. Furthermore, we demonstrate that miR-UL148D, one of the most highly expressed viral miRNAs during latent infection, directly targets the cellular receptor ACVR1B of the activin signalling axis. Consistent with this, we observed upregulation of ACVR1B expression during latent infection with a miR-UL148D deletion virus (ΔmiR-UL148D). Importantly, we observed that monocytes latently infected with ΔmiR-UL148D are more responsive to activin A stimulation, as demonstrated by their increased secretion of IL-6. Collectively, our data indicates miR-UL148D inhibits ACVR1B expression in latently infected cells to limit proinflammatory cytokine secretion, perhaps as an immune evasion strategy or to postpone cytokine-induced reactivation until conditions are more favourable. This is the first demonstration of an HCMV miRNA function during latency in primary myeloid cells, implicating that small RNA species may contribute significantly to latent infection. PMID:27491954

  6. Inflammatory monocytes and NK cells play a crucial role in DNAM-1–dependent control of cytomegalovirus infection

    PubMed Central

    Kaynan, Noa; Jordan, Stefan; Messerle, Martin; Mandelboim, Ofer

    2016-01-01

    The poliovirus receptor (PVR) is a ubiquitously expressed glycoprotein involved in cellular adhesion and immune response. It engages the activating receptor DNAX accessory molecule (DNAM)-1, the inhibitory receptor TIGIT, and the CD96 receptor with both activating and inhibitory functions. Human cytomegalovirus (HCMV) down-regulates PVR expression, but the significance of this viral function in vivo remains unknown. Here, we demonstrate that mouse CMV (MCMV) also down-regulates the surface PVR. The m20.1 protein of MCMV retains PVR in the endoplasmic reticulum and promotes its degradation. A MCMV mutant lacking the PVR inhibitor was attenuated in normal mice but not in mice lacking DNAM-1. This attenuation was partially reversed by NK cell depletion, whereas the simultaneous depletion of mononuclear phagocytes abolished the virus control. This effect was associated with the increased expression of DNAM-1, whereas TIGIT and CD96 were absent on these cells. An increased level of proinflammatory cytokines in sera of mice infected with the virus lacking the m20.1 and an increased production of iNOS by inflammatory monocytes was observed. Blocking of CCL2 or the inhibition of iNOS significantly increased titer of the virus lacking m20.1. In this study, we have demonstrated that inflammatory monocytes, together with NK cells, are essential in the early control of CMV through the DNAM-1–PVR pathway. PMID:27503073

  7. Reduced dose of foscarnet as preemptive therapy for cytomegalovirus infection following reduced-intensity cord blood transplantation.

    PubMed

    Narimatsu, H; Kami, M; Kato, D; Matsumura, T; Murashige, N; Kusumi, E; Yuji, K; Hori, A; Shibata, T; Masuoka, K; Wake, A; Miyakoshi, S; Morinaga, S; Taniguchi, S

    2007-03-01

    Although foscarnet is a promising alternative for the treatment of cytomegalovirus (CMV) infection, its toxicity can be significant in patients with advanced age. We retrospectively reviewed medical records of 123 patients (median age of 55; range, 17-79) who received reduced-intensity cord blood transplantation (RI-CBT). Patients preemptively received reduced-dose foscarnet 30 mg/kg twice daily when CMV antigenemia exceeded 10/50,000. Sixty-three patients developed CMV antigenemia on a median of day 34, and 29 received foscarnet preemptively. The median level of CMV antigenemia at the initiation of foscarnet was 30. Median duration of foscarnet administration was 24 days. Adverse effects included electrolyte abnormalities (n=19), renal impairment (n=13), and skin eruption requiring discontinuation of foscarnet (n=1). Preemptive therapy of foscarnet was completed in 18 patients. Seven patients died during foscarnet use without developing CMV disease. The remaining 3 developed CMV enterocolitis 5, 14, and 17 days after initiation of foscarnet. All of them were successfully treated with ganciclovir or foscarnet. Reduced dose of foscarnet is beneficial to control CMV reactivation following RI-CBT; however, it has considerable toxicities in RI-CBT recipients with advanced age. Further studies are warranted to minimize toxicities and identify optimal dosages.

  8. Diagnosis of children’s attention deficit hyperactivity disorder (ADHD) and its association with cytomegalovirus infection with ADHD: a historical review

    PubMed Central

    Zhou, Rui; Xia, Qun; Shen, Huaiyun; Yang, Xiaoyun; Zhang, Yongli; Xu, Jiali

    2015-01-01

    As the most common mental disorder identified in children and teenagers, attention deficit hyperactivity disorder (ADHD) affects millions of children and their families, making it a critical health issue worldwide. This article reviewed the historical opinions about the diagnosis of ADHD and defined different subtypes of this disorder. It also summarized the current diagnostic criteria and available medications. After re-visiting the etiology of ADHD in the sense of both genetic and environment factors, it was further hypothesized that viral infection might be involved in ADHD pathogenesis. Human cytomegalovirus (HCMV) infection may be associated with ADHD, although both clinical observations and animal studies need to be performed for validation. PMID:26550354

  9. Management of Developmentally Disabled Children with Chronic Infections.

    ERIC Educational Resources Information Center

    Andersen, Richard D.

    1988-01-01

    The nature of chronic infections in developmentally disabled children is reviewed, along with appropriate management strategies for care providers and implications for other children. Discussed are herpes simplex virus, cytomegalovirus, hepatitis B virus, and human immunodeficiency virus. (Author/JDD)

  10. Analytical Performance and Clinical Utility of a Nucleic Acid Sequence-Based Amplification Assay for Detection of Cytomegalovirus Infection

    PubMed Central

    Witt, Donald J.; Kemper, M.; Stead, Andrew; Sillekens, P.; Ginocchio, Christine C.; Espy, Mark J.; Paya, Carlos V.; Smith, Thomas F.; Roeles, Frits; Caliendo, Angela M.

    2000-01-01

    A nucleic acid sequence-based amplification (NASBA) assay for qualitative detection of human cytomegalovirus (CMV) pp67 mRNA was evaluated in a multicenter study. Negative results were obtained for all specimens from 50 CMV-seronegative and 50 CMV-seropositive low-risk whole-blood donors. No interference with CMV mRNA amplification was observed in the testing of 288 specimens containing various potential interfering substances, nonspecifically reacting substances (including mRNA from other herpesviruses), and three anticoagulants. A total of 95% (50 of 51) of CMV-positive (cell culture- and antigenemia immunofluorescence [AG-IFA]-positive) clinical specimens were positive by the NASBA assay. Results from different operators over multiple testing days were consistent for each of four panel members containing different concentrations of CMV mRNA, indicating the reproducibility of the assay. The estimated 95% reliable upper detection limit of the assay was 600 mRNA copies; the lower limit of detection was less than 25 mRNA copies. The clinical utility of the assay was evaluated with longitudinally collected specimens from solid-organ transplant patients (n = 21). A total of 98% (81 of 83) of the specimens from CMV-negative patients were negative by the NASBA assay, while 90% (10 of 11) of patient specimens that were positive by cell culture or AG-IFA were positive by the NASBA assay. Positive NASBA assay results were obtained earlier than AG-IFA or cell culture results for 55% of the patients and at the same time for the remainder of the patients (45%). The overall agreement between the NASBA assay and current reference tests was 86% when active CMV infection was present. These studies indicate that the CMV pp67 mRNA NASBA assay has reproducible and sensitive performance characteristics that should enable more rapid diagnosis of CMV infection. PMID:11060058

  11. Human Cytomegalovirus Infant Infection Adversely Affects Growth and Development in Maternally HIV-Exposed and Unexposed Infants in Zambia

    PubMed Central

    Larke, N.; Sanz-Ramos, M.; Bates, M.; Musonda, K.; Manno, D.; Siame, J.; Monze, M.; Filteau, S.

    2012-01-01

    Background. Human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV) coinfections have been shown to increase infant morbidity, mortality, and AIDS progression. In HIV-endemic regions, maternal HIV-exposed but HIV-uninfected infants, which is the majority of children affected by HIV, also show poor growth and increased morbidity. Although nutrition has been examined, the effects of HCMV infection have not been evaluated. We studied the effects of HCMV infection on the growth, development, and health of maternally HIV-exposed and unexposed infants in Zambia. Methods. Infants were examined in a cohort recruited to a trial of micronutrient-fortified complementary foods. HIV-infected mothers and infants had received perinatal antiretroviral therapy to prevent mother-to-child HIV transmission. Growth, development, and morbidity were analyzed by linear regression analyses in relation to maternal HIV exposure and HCMV infection, as screened by sera DNA for viremia at 6 months of age and by antibody for infection at 18 months. Results. All HCMV-seropositive infants had decreased length-for-age by 18 months compared with seronegative infants (standard deviation [z]-score difference: −0.44 [95% confidence interval {CI}, −.72 to −.17]; P = .002). In HIV-exposed infants, those who were HCMV positive compared with those who were negative, also had reduced head size (mean z-score difference: −0.72 [95% CI, −1.23 to −.22]; P = .01) and lower psychomotor development (Bayley test score difference: −4.1 [95% CI, −7.8 to −.5]; P = .03). HIV-exposed, HCMV-viremic infants were more commonly referred for hospital treatment than HCMV-negative infants. The effects of HCMV were unaffected by micronutrient fortification. Conclusion. HCMV affects child growth, development, and morbidity of African infants, particularly in those maternally exposed to HIV. HCMV is therefore a risk factor for child health in this region. PMID:22247303

  12. Diagnostic significance and clinical impact of quantitative assays for diagnosis of human cytomegalovirus infection/disease in immunocompromised patients.

    PubMed

    Gerna, G; Percivalle, E; Baldanti, F; Sarasini, A; Zavattoni, M; Furione, M; Torsellini, M; Revello, M G

    1998-07-01

    In recent years several assays have been developed for quantitation of human cytomegalovirus (HCMV) in blood of immunocompromised (transplanted and AIDS) patients. It is currently agreed that the only reliable indication of the degree of dissemination of HCMV infection/disease is the measurement of HCMV in blood. Diagnosis of HCMV end-organ disease (organ localizations) often does not benefit from quantitation of virus in blood, but requires detection and quantification of virus in samples taken locally. The most important and clinically useful diagnostic assays for HCMV quantitation in blood are: i) viremia, quantifying infectious HCMV carried by peripheral blood leukocytes (PBL); ii) pp65-antigenemia, quantifying the number of PBL positive for HCMV pp65 in the nucleus; iii) circulating cytomegalic endothelial cell (CEC) viremia (CEC-viremia) measuring the number of circulating CEC carrying infectious HCMV (during the antigenemia assay); iv) leuko- and plasma-DNAemia, quantifying the number of HCMV genome equivalents present in PBL or plasma, respectively, by quantitative polymerase chain reaction (Q-PCR). Other less widely used assays are: i) determination of immediate early and late gene transcripts (mRNA) to detect active viral infection; ii) in situ hybridization to detect viral nucleic acid (DNA or RNA) in tissue sections or cell smears; iii) in situ PCR to detect a low DNA copy number in single cells. Monitoring of HCMV infection/disease in transplant recipients and AIDS patients has established threshold values for different assays above which HCMV-related clinical symptoms are likely to appear. These values are approximately 10 for viremia, 100 for antigenemia and 1,000 GE for leukoDNAemia, and are valid for both solid organ and bone marrow transplant recipients as well as AIDS patients, whereas presence of even a single circulating CEC is sufficient to suggest the presence of a disseminated HCMV infection with potential organ involvement. Monitoring of

  13. Opportunistic infections (non-cytomegalovirus) in live related renal transplant recipients

    PubMed Central

    Vinod, P. B.; Sharma, Raj Kumar

    2009-01-01

    The purpose of review was increasing number of opportunistic infections with use of newer immunosuppression and difficulty in diagnosis and management of such patients. For this review, MEDLINE database was searched from 2000 to 2006 with the keywords of opportunistic infections in renal transplantation. Opportunistic infection is a serious clinical complication in patients receiving immunosuppressive therapy after kidney transplantation. The two major factors for successful renal transplantation are better control of rejection and better prevention and treatment of infection. In renal allograft recipient, immunosuppressive drug therapy is the major cause of immunocompromised status and occurrence of infections, which arise most commonly as a result of invasion by endogenous opportunists. The opportunistic infections with varicella zoster viruses, parvovirus B-19, polyomavirus, nocardia and mucormycosis in immunosuppressed patients were present with severe complications that are reviewed in this article. As a result of use of strong immunosuppressive drugs like tacrolimus, mycophenolate mofetyl and antirejection therapy with antithymocyte globulins, these infections are now seen frequently, so they should always be included in differential diagnostic consideration. New diagnostic procedures and new treatment strategies are required to allow early detection and successful treatment of opportunistic infections in kidney transplant recipients. PMID:19672339

  14. Analysis of cytomegalovirus and Epstein-Barr virus antibody responses in treated hemophiliacs. Implications for the study of acquired immune deficiency syndrome.

    PubMed

    Cheeseman, S H; Sullivan, J L; Brettler, D B; Levine, P H

    1984-07-06

    One hundred hemophiliacs were studied for serological evidence of infection with cytomegalovirus (CMV), Epstein-Barr virus (EBV), and hepatitis B virus. Ninety-eight percent had markers of hepatitis B infection, while 69% had antibody to EBV and only 42% had antibody to CMV, suggesting that factor VIII preparations do not transmit EBV and CMV efficiently. Seventy-one percent of those seropositive to EBV had an antibody pattern suggestive of active infection, as compared with 23% of healthy young adult blood donors. These findings make the patients with hemophilia an unusually favorable population for the study of the role of persistent viral infection in the immunodeficiency now found to be widespread in groups at high risk for acquired immune deficiency syndrome (AIDS) and for the contribution of CMV and EBV to AIDS itself.

  15. Expression of a human cytomegalovirus late gene is posttranscriptionally regulated by a 3'-end-processing event occurring exclusively late after infection.

    PubMed Central

    Goins, W F; Stinski, M F

    1986-01-01

    A phenomenon of posttranscriptional regulation has been previously identified in cytomegalovirus-infected human fibroblast cells (Wathen and Stinski, J. Virol. 41:462, 1982). A region typifying this phenomenon has been located within the large unique component of the viral genome (map units 0.408 to 0.423). Even though this transcriptional unit was highly transcribed at early times after infection, mRNAs from this region were only detectable on the polyribosomes after viral DNA replication. Thus, this region is believed to code for a late gene. Single-strand-specific nuclease mapping experiments of viral transcripts established that the transcriptional initiation sites and the 5' ends of a downstream exon were identical at early and late times. However, the late transcripts differed from the early transcripts by the processing of the 3' end of the viral RNAs. This involved either the removal of a distinct region of the transcript by the selection of an upstream cleavage and polyadenylation site or the differential splicing of the RNA molecule. The upstream cleavage and polyadenylation site was identified by nuclease mapping analyses and DNA sequencing. The 3'-end processing of these transcripts is necessary for the detection of these viral RNAs within the cytoplasm of the infected cell. We propose that human cytomegalovirus either codes for a factor(s) that is involved in the 3'-end-processing event at late times after infection or stimulates the synthesis of a host cell factor(s) involved in this complex regulatory event. This level of regulation may have an influence on the types of cells that permit productive cytomegalovirus replication. Images PMID:3025644

  16. Human cytomegalovirus and Epstein-Barr virus infection in inflammatory bowel disease: Need for mucosal viral load measurement

    PubMed Central

    Ciccocioppo, Rachele; Racca, Francesca; Paolucci, Stefania; Campanini, Giulia; Pozzi, Lodovica; Betti, Elena; Riboni, Roberta; Vanoli, Alessandro; Baldanti, Fausto; Corazza, Gino Roberto

    2015-01-01

    AIM: To evaluate the best diagnostic technique and risk factors of the human Cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) infection in inflammatory bowel disease (IBD). METHODS: A cohort of 40 IBD patients (17 refractory) and 40 controls underwent peripheral blood and endoscopic colonic mucosal sample harvest. Viral infection was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry, and correlations with clinical and endoscopic indexes of activity, and risk factors were investigated. RESULTS: All refractory patients carried detectable levels of HCMV and/or EBV mucosal load as compared to 13/23 (56.5%) non-refractory and 13/40 (32.5%) controls. The median DNA value was significantly higher in refractory (HCMV 286 and EBV 5.440 copies/105 cells) than in non-refractory (HCMV 0 and EBV 6 copies/105 cells; P < 0.05 and < 0.001) IBD patients and controls (HCMV and EBV 0 copies/105 cells; P < 0.001 for both). Refractory patients showed DNA peak values ≥ 103 copies/105 cells in diseased mucosa in comparison to non-diseased mucosa (P < 0.0121 for HCMV and < 0.0004 for EBV), while non-refractory patients and controls invariably displayed levels below this threshold, thus allowing us to differentiate viral colitis from mucosal infection. Moreover, the mucosal load positively correlated with the values found in the peripheral blood, whilst no correlation with the number of positive cells at immunohistochemistry was found. Steroid use was identified as a significant risk factor for both HCMV (P = 0.018) and EBV (P = 0.002) colitis. Finally, a course of specific antiviral therapy with ganciclovir was successful in all refractory patients with HCMV colitis, whilst refractory patients with EBV colitis did not show any improvement despite steroid tapering and discontinuation of the other medications. CONCLUSION: Viral colitis appeared to contribute to mucosal lesions in refractory IBD, and its correct diagnosis and management require

  17. Enhancerless cytomegalovirus is capable of establishing a low-level maintenance infection in severely immunodeficient host tissues but fails in exponential growth.

    PubMed

    Podlech, Jürgen; Pintea, Rares; Kropp, Kai A; Fink, Annette; Lemmermann, Niels A W; Erlach, Katja C; Isern, Elena; Angulo, Ana; Ghazal, Peter; Reddehase, Matthias J

    2010-06-01

    Major immediate-early transcriptional enhancers are genetic control elements that act, through docking with host transcription factors, as a decisive regulatory unit for efficient initiation of the productive virus cycle. Animal models are required for studying the function of enhancers paradigmatically in host organs. Here, we have sought to quantitatively assess the establishment, maintenance, and level of in vivo growth of enhancerless mutants of murine cytomegalovirus in comparison with those of an enhancer-bearing counterpart in models of the immunocompromised or immunologically immature host. Evidence is presented showing that enhancerless viruses are capable of forming restricted foci of infection but fail to grow exponentially.

  18. Latent infection of myeloid progenitors by human cytomegalovirus protects cells from FAS-mediated apoptosis through the cellular IL-10/PEA-15 pathway.

    PubMed

    Poole, Emma; Lau, Jonathan C H; Sinclair, John

    2015-08-01

    Latent infection of primary CD34(+) progenitor cells by human cytomegalovirus (HCMV) results in their increased survival in the face of pro-apoptotic signals. For instance, we have shown previously that primary myeloid cells are refractory to FAS-mediated killing and that cellular IL-10 (cIL-10) is an important survival factor for this effect. However, how cIL-10 mediates this protection is unclear. Here, we have shown that cIL-10 signalling leading to upregulation of the cellular factor PEA-15 mediates latency-associated protection of CD34(+) progenitor cells from the extrinsic death pathway.

  19. Prevalence of cytomegalovirus infection in different patient groups of an urban university in Brazil.

    PubMed

    Suassuna, J H; Leite, L L; Villela, L H

    1995-01-01

    This study sought for evidence of previous CMV infection in patients of a general hospital serving the low income population of Rio de Janeiro. An enzyme immunoassay was used to detect anti-CMV antibodies in 713 typical hospital patients classified into eight different groups. Positive tests were found in 87% of pregnant women, 85% of newborns, 61% of pediatric patients, 77% of adolescent patients, 81% of adult patients, 87% of dialysed transplant candidates, 89% of kidney donors, and 92% of patients after transplantation. Depending of the subgroup studied these results carry different meanings and necessitate different clinical approaches. The risk of congenital disease is probably low in view of the reduced number of pregnant women still susceptible to primary infection. The number of primary infections will also be low in transplant recipients. However, those still susceptible will almost certainly acquire the infection from their donor. Prophylactic CMV matching in kidney transplantation is not a realistic approach due to the low probability of finding pairs of seronegative donors and recipients.

  20. Cytomegalovirus Infection during Pregnancy and Its Impact on the Intrauterine Fetal Development – Case Report

    PubMed Central

    Angelova, Mariya; Kovachev, Emil; Todorov, Nikolai

    2016-01-01

    AIM: The aim of this publication is to present a case of CMV infection during pregnancy, with clinical manifestations of the development of microcephaly and simultaneous dilatation of the 3rd and 4th brain ventricle at 23 weeks gestation. This article discusses the role of ultrasound screening in the second trimester of pregnancy. CASE PRESENTATION: We present the case of a 25-year-old woman with the initials S.K. in her second pregnancy that came to our antenatal Consulting Centre. The first screening for blood count, blood group, biochemistry and serology showed results within the reference range. The patient came for a second comprehensive biochemical screening at 17 – 18 weeks gestation. The results showed the low genetic risk of congenital anomalies. Fetal morphology of the fetus was normal. S.K. came again for consultation at 22 weeks gestation in connection with the admittance of her first 3-year-old child to the hospital because of pneumonia. Serological tests of the child had shown elevated CMV titer - specific IgM. Then we made new serological tests of the patient and the results have shown that the patient was most likely infected by CMV primarily in the first trimester of pregnancy. After consulting about the risk of transmission of CMV to the fetus, the woman chose monthly ultrasound scans and refused amniocentesis. At 36 weeks gestation, in addition to the microcephaly already established, enlargement of the IV brain ventricle at the expense of underdevelopment of the cerebellum was noticed. Also, 2nd to 3rd stage of placenta maturity and low quantity of amniotic fluid was established. A male fetus of weight 2,890 g and height 50 cm was delivered. The fetus was with skin petechiae and hepatosplenomegaly. Neurological examination showed no abnormalities. CONCLUSIONS: In the described case the time interval between infection and ultrasonic manifestations is more than 17 weeks. The long interval between infection and occurrence of ultrasound markers

  1. Single Chain Antibodies Against gp55 of Human Cytomegalovirus (HCMV) for Prophylaxis and Treatment of HCMV Infections

    PubMed Central

    Moazen, Bahareh; Ebrahimi, Elahe; Nejatollahi, Foroogh

    2016-01-01

    Background: Immunotherapy is a promising prospective new treatment for cytomegalovirus (CMV) infections. Neutralizing effects have been reported using monoclonal antibodies. Recombinant single chain antibodies (scFvs) due to their advantages over monoclonal antibodies are potential alternatives and provide valuable clinical agents. Objectives: The aim of this study was to select specific single chain antibodies against gp55 of CMV and to evaluate their neutralizing effects. In the present study, we selected specific single chain antibodies against glycoprotein 55 (gp55) of CMV for their use in treatment and diagnosis. Materials and Methods: Single chain antibodies specific against an epitope located in the C-terminal part of gp55 were selected from a phage antibody display library. After four rounds of panning, twenty clones were amplified by the polymerase chain reaction (PCR) and fingerprinted by MvaI restriction enzyme. The reactivities of the specific clones were tested by the enzyme-linked immunosorbent assay (ELISA) and the neutralizing effects were evaluated by the plaque reduction assay. Results: Fingerprinting of selected clones revealed three specific single chain antibodies (scFv1, scFv2 and scFv3) with frequencies 25%, 20 and 20%. The clones produced positive ELISA with the corresponding peptide. The percentages of plaque reduction for scFv1, scFv2 and scFv3 were 23.7, 68.8 and 11.6, respectively. Conclusions: Gp55 of human CMV is considered as an important candidate for immunotherapy. In this study, we selected three specific clones against gp55. The scFvs reacted only with the corresponding peptide in a positive ELISA. The scFv2 with 68.8% neutralizing effect showed the potential to be considered for prophylaxis and treatment of CMV infections, especially in solid organ transplant recipients, for whom treatment of CMV is urgently needed. The scFv2 with neutralizing effect of 68.8%, has the potential to be considered for treatment of these patients

  2. DRIED BLOOD SPOT REAL-TIME POLYMERASE CHAIN REACTION ASSAYS TO SCREEN NEWBORNS FOR CONGENITAL CYTOMEGALOVIRUS INFECTION

    PubMed Central

    Boppana, Suresh B.; Ross, Shannon A.; Novak, Zdenek; Shimamura, Masako; Tolan, Robert W.; Palmer, April L.; Ahmed, Amina; Michaels, Marian G.; Sánchez, Pablo J.; Bernstein, David I.; Britt, William J.; Fowler, Karen B.

    2010-01-01

    Context Reliable methods to screen newborns for congenital cytomegalovirus (CMV) infection are needed for identification of infants at increased risk for hearing loss. Since dried blood spots (DBS) are routinely collected for metabolic screening from all newborns in the United States, there has been interest in using DBS polymerase chain reaction (PCR)-based methods for newborn CMV screening. Objective To determine the diagnostic accuracy of DBS real-time PCR assays for newborn CMV screening Design, Setting, and Participants Between March 2007 and May 2008, infants born at seven medical centers in the U.S. were enrolled in the CMV and Hearing Multicenter Screening (CHIMES) study. Newborn saliva specimens were tested for the detection of early antigen fluorescent foci (DEAFF). Results of saliva DEAFF were compared with a single-primer (from 03/07 to 12/07) and a two-primer (from 01/08 to 05/08) DBS real-time PCR. Infants positive by screening DEAFF or PCR were enrolled in follow-up to confirm congenital infection by the reference standard method, DEAFF on saliva or urine. Main Outcome Measures Sensitivity, specificity and positive and negative likelihood ratios (LRs) of single-primer and two-primer DBS real-time PCR assays for identifying infants with confirmed congenital CMV infection. Results Congenital CMV infection was confirmed in 92 of 20,448 (0.45%; 95% CI, 0.36–0.55) infants. Ninety-one of 92 infants were saliva DEAFF positive on screening. Of the 11,422 infants screened using the single-primer DBS PCR, 17 of 60 (28%) infants were positive with this assay, whereas, among the 9,026 infants screened using the two-primer DBS PCR, 11 of 32 (34%) infants were positive. The single-primer DBS PCR identified congenital CMV infection with a sensitivity of 28.3% (95% CI, 17.4–41.4%), specificity, 99.9% (95% CI, 99.9–100%), positive LR, 803.7 (95% CI, 278.7–2317.9), and negative LR, 0.7 (95% CI, 0.6–0.8). The positive and negative predictive values of the

  3. Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice.

    PubMed

    Seleme, Maria C; Kosmac, Kate; Jonjic, Stipan; Britt, William J

    2017-04-15

    Congenital human cytomegalovirus (HCMV) infection is a significant cause of abnormal neurodevelopment and long-term neurological sequelae in infants and children. Resident cell populations of the developing brain have been suggested to be more susceptible to virus-induced cytopathology, a pathway thought to contribute to the clinical outcomes following intrauterine HCMV infection. However, recent findings in a newborn mouse model of the infection in the developing brain have indicated that elevated levels of proinflammatory mediators leading to mononuclear cell activation and recruitment could underlie the abnormal neurodevelopment. In this study, we demonstrate that treatment with tumor necrosis factor alpha (TNF-α)-neutralizing antibodies decreased the frequency of CD45(+) Ly6C(hi) CD11b(+) CCR2(+) activated myeloid mononuclear cells (MMCs) and the levels of proinflammatory cytokines in the blood and the brains of murine CMV-infected mice. This treatment also normalized neurodevelopment in infected mice without significantly impacting the level of virus replication. These results indicate that TNF-α is a major component of the inflammatory response associated with altered neurodevelopment that follows murine CMV infection of the developing brain and that a subset of peripheral blood myeloid mononuclear cells represent a key effector cell population in this model of virus-induced inflammatory disease of the developing brain.IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the most common viral infection of the developing human fetus and can result in neurodevelopmental sequelae. Mechanisms of disease leading to neurodevelopmental deficits in infected infants remain undefined, but postulated pathways include loss of neuronal progenitor cells, damage to the developing vascular system of the brain, and altered cellular positioning. Direct virus-mediated cytopathic effects cannot explain the phenotypes of brain damage in most infected infants. Using a

  4. Congenital TORCH Infections in Infants and Young Children: Neurodevelopmental Sequelae and Implications for Intervention.

    ERIC Educational Resources Information Center

    Hutchinson, M. Katherine; Sandall, Susan R.

    1995-01-01

    This article describes TORCH infections, a congenital cluster of infections including toxoplasmosis, syphilis, rubella, cytomegalovirus, and herpes which often results in developmental disabilities for infected children. Methods of transmission, incidence, and developmental outcomes for common TORCH infections are described, as are program…

  5. Cytomegalovirus (CMV) IE1- and pp65-specific CD8+ T cell responses broaden over time after primary CMV infection in infants.

    PubMed

    Gibson, Laura; Dooley, Sheryl; Trzmielina, Sonia; Somasundaran, Mohan; Fisher, Donna; Revello, Maria Grazia; Luzuriaga, Katherine

    2007-06-15

    Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in young children. We have previously shown that CD8+ T cell responses to CMV pp65 or IE1 protein were readily detectable in children with congenital or postnatal CMV infection. Here, we have further characterized the evolution of the peptide specificity of these responses in 7 infants<6 months of age at the start of the study. Thirteen pp65 and 15 IE1 peptides (median, 5 peptides/infant) were targeted, and most (61%) represented sequences not previously reported. Peptide specificity remained stable or broadened over time despite the clearance of CMV viremia. Loss of peptide recognition was not observed. Responses with the highest functional peptide avidity were not necessarily detected earliest. These data provide additional evidence that young infants can generate diverse CMV-specific CD8+ T cell responses but show that early responses may exhibit relatively focused peptide specificity and lower peptide avidity.

  6. Open reading frames carried on UL/b' are implicated in shedding and horizontal transmission of rhesus cytomegalovirus in rhesus monkeys.

    PubMed

    Oxford, Kristie L; Strelow, Lisa; Yue, Yujuan; Chang, W L William; Schmidt, Kimberli A; Diamond, Don J; Barry, Peter A

    2011-05-01

    Implicit with the use of animal models to test human cytomegalovirus (HCMV) vaccines is the assumption that the viral challenge of vaccinated animals reflects the anticipated virus-host interactions following exposure of vaccinated humans to HCMV. Variables of animal vaccine studies include the route of exposure to and the titer of challenge virus, as well as the genomic coding content of the challenge virus. This study was initiated to provide a better context for conducting vaccine trials with nonhuman primates by determining whether the in vivo phenotype of culture-passaged strains of rhesus cytomegalovirus (RhCMV) is comparable to that of wild-type RhCMV (RhCMV-WT), particularly in relation to the shedding of virus into bodily fluids and the potential for horizontal transmission. Results of this study demonstrate that two strains containing a full-length UL/b' region of the RhCMV genome, which encodes proteins involved in epithelial tropism and immune evasion, were persistently shed in large amounts in bodily fluids and horizontally transmitted, whereas a strain lacking a complete UL/b' region was not shed or transmitted to cagemates. Shedding patterns exhibited by strains encoding a complete UL/b' region were consistent with patterns observed in naturally infected monkeys, the majority of whom persistently shed high levels of virus in saliva for extended periods of time after seroconversion. Frequent viral shedding contributed to a high rate of infection, with RhCMV-infected monkeys transmitting virus to one naïve animal every 7 weeks after introduction of RhCMV-WT into an uninfected cohort. These results demonstrate that the RhCMV model can be designed to rigorously reflect the challenges facing HCMV vaccine trials, particularly those related to horizontal transmission.

  7. Proteomic analyses of human cytomegalovirus strain AD169 derivatives reveal highly conserved patterns of viral and cellular proteins in infected fibroblasts.

    PubMed

    Reyda, Sabine; Büscher, Nicole; Tenzer, Stefan; Plachter, Bodo

    2014-01-07

    Human cytomegalovirus (HCMV) particle morphogenesis in infected cells is an orchestrated process that eventually results in the release of enveloped virions. Proteomic analysis has been employed to reveal the complexity in the protein composition of these extracellular particles. Only limited information is however available regarding the proteome of infected cells preceding the release of HCMV virions. We used quantitative mass spectrometry to address the pattern of viral and cellular proteins in cells, infected with derivatives of the AD169 laboratory strain. Our analyses revealed a remarkable conservation in the patterns of viral and of abundant cellular proteins in cells, infected for 2 hours, 2 days, or 4 days. Most viral proteins increased in abundance as the infection progressed over time. Of the proteins that were reliably detectable by mass spectrometry, only IE1 (pUL123), pTRS1, and pIRS1 were downregulated at 4 days after infection. In addition, little variation of viral proteins in the virions of the different viruses was detectable, independent of the expression of the major tegument protein pp65. Taken together these data suggest that there is little variation in the expression program of viral and cellular proteins in cells infected with related HCMVs, resulting in a conserved pattern of viral proteins ultimately associated with extracellular virions.

  8. Cytomegalovirus hepatitis and myopericarditis.

    PubMed

    Zubiaurre, Leire; Zapata, Eva; Bujanda, Luis; Castillo, María; Oyarzabal, Igor; Gutiérrez-Stampa, Maria A; Cosme, Angel

    2007-01-28

    Cytomegalovirus (CMV) infection in inmunocompetent hosts generally is asymptomatic or may present as a mononucleosis syndrome but rarely can lead to severe organ complications. We report a case of simultaneous hepatic and pericardic CMV infection in a 36-year old immunocompetent man. He was admitted to coronary unit with fever, chest pain radiated to shoulders, changes on electrocardiogram with diffuse ST elevation and modest laboratory elevations in the MB fraction of creatine kinase (CK-MB) of 33.77 microg/L (0.1-6.73), serum cardiac troponin T of 0.904 ng/mL (0-0.4), creatine kinase of 454 U/L (20-195) and myoglobin of 480.4 microg/L (28-72). Routine laboratory test detected an elevation of aminotransferase level: alanine aminotransferase 1445 U/L, aspartate aminotransferase 601 U/L. We ruled out other causes of hepatitis with normal results except IgM CMV. The patient was diagnosed with myopericarditis and hepatitis caused by cytomegalovirus and started symptomatic treatment with salicylic acid. In few days the laboratory findings became normal and the patient was discharged.

  9. [Frequency of HIV-1, rubella, syphilis, toxoplasmosis, cytomegalovirus, simple herpes virus, hepatitis B, hepatitis C, Chagas disease and HTLV I/II infection in pregnant women of State of Mato Grosso do Sul].

    PubMed

    Figueiró-Filho, Ernesto Antonio; Senefonte, Flávio Renato de Almeida; Lopes, Alessandro Henrique Antunes; de Morais, Orlando Oliveira; Souza Júnior, Virgílio Gonçalves; Maia, Tamara Lemos; Duarte, Geraldo

    2007-01-01

    It was aimed to estimate the frequency of syphilis, rubella, hepatitis B, hepatitis C, toxoplasmosis, Chagas disease, HTLV I/II, simple herpes virus, HIV-1 and cytomegalovirus in pregnant women and to evaluate the relationship between age and the frequency of the infections studied. A transversal study of 32,512 pregnant women submitted to pre-natal screening in the period of November 2002 to October 2003. The frequency of the tried infections among the pregnant women were 0.2% of HIV-1, 0.03% of rubella, 0.8% of syphilis, 0.4% of toxoplasmosis, 0.05% of cytomegalovirus, 0.02% of simple herpes virus, 0.3% of HBsAg, 0.1% of hepatitis C, 0.1% of HTLV and 0.1% of Chagas disease. There was significative statistical association between age and prenatal infection of rubella, cytomegalovirus, Chagas disease and herpes virus. The rates of frequency of rubella, syphilis, toxoplasmosis, Chagas disease and cytomegalovirus in pregnant women studied were lower than the compared rates.

  10. Cytomegalovirus (CMV) Infection

    MedlinePlus

    ... of antiviral drugs. Antiviral drugs slow the virus reproduction, but can't cure it. Researchers are studying ... saliva. Practice safe sex. Wear a condom during sexual contact to prevent spreading the CMV virus through ...

  11. Cytomegalovirus infection and donor/recipient HLA antigens: interdependent co-factors in pathogenesis of vanishing bile-duct syndrome after liver transplantation.

    PubMed

    O'Grady, J G; Alexander, G J; Sutherland, S; Donaldson, P T; Harvey, F; Portmann, B; Calne, R Y; Williams, R

    1988-08-06

    The contribution of cytomegalovirus (CMV) infection and its interrelation with HLA antigens in the development of chronic rejection (vanishing bile-duct syndrome--VBDS) was investigated in 101 patients surviving for at least 3 months after liver transplantation. A 1-2 antigen match for HLA DR antigens (30.9% vs 4.5% for zero DR match; p less than 0.002), a zero match for HLA A/B antigens (27.5% vs 10.9% for 1 or more A/B match; p less than 0.05), and active CMV infection (26.3% vs 4.4% for no CMV infection; p less than 0.005) were independently associated with an increased risk of VBDS. The coexistence of a 1-2 HLA DR match and CMV infection carried the highest relative risk (10.1) of VBDS; these two variables were probably interdependent since either alone was associated with a low relative risk (0.45 and 0.5). The association between VBDS and active CMV infection was not a consequence of alterations in immunosuppressive therapy. The findings would be consistent with precipitation of chronic rejection by CMV-induced HLA antigen expression in patients rendered susceptible by the donor/recipient HLA antigen match.

  12. In situ detection of frequent and active infection of human cytomegalovirus in inflammatory abdominal aortic aneurysms: possible pathogenic role in sustained chronic inflammatory reaction.

    PubMed

    Yonemitsu, Y; Nakagawa, K; Tanaka, S; Mori, R; Sugimachi, K; Sueishi, K

    1996-04-01

    Inflammatory abdominal aortic aneurysm (IAAA) is histopathologically characterized by extensive adventitial fibrosis, mononuclear cell infiltration with lymph follicle formation, and severe atheromatous changes in the aneurysmal wall. We previously reported a frequent prevalence and immediate early gene expression of human cytomegalovirus (CMV) in IAAA by solution-phase PCR and reverse transcription PCR, respectively, and suggested that this virus might play a role in chronic inflammatory reaction in IAAA. To evaluate the pathogenic role of CMV infection, the frequency and distribution of CMV infected cells in IAAA were examined by in situ PCR, and compared with those in atherosclerotic aneurysms (AA) and control cases with minimal atherosclerotic changes. Human leukocyte antigen (HLA)-DR was simultaneously evaluated as a marker for immune response related to CMV infection. Immediate early gene expression was also detected by reverse transcription PCR and in situ hybridization, to certify whether the CMV infection in IAAA is active or latent. In the fibrously thickened adventitia of IAAA, CMV infected cells and HLA-DR-positive cells were more frequently encountered than in that of AA and control cases (p < 0.01). CMV infected cells were largely identified as macrophages, fibroblasts, endothelial cells, and lymphocytes. The expression of CMV immediate early mRNA, which suggests an active infection inducing active inflammatory reaction, was detected in most of the macrophages, endothelial cells, and fibroblasts. Our results strongly suggest that frequent and active infection of CMV in IAAA plays a significant role in the induction and acceleration of chronic inflammatory reaction in aortas of IAAA.

  13. Ablation of the Regulatory IE1 Protein of Murine Cytomegalovirus Alters In Vivo Pro-inflammatory TNF-alpha Production during Acute Infection

    PubMed Central

    Wilhelmi, Vanessa; Lisnic, Vanda Juranic; Hsieh, Wei Yuan; Blanc, Mathieu; Livingston, Andrew; Busche, Andreas; Tekotte, Hille; Messerle, Martin; Auer, Manfred; Fraser, Iain; Jonjic, Stipan; Angulo, Ana; Reddehase, Matthias J.; Ghazal, Peter

    2012-01-01

    Little is known about the role of viral genes in modulating host cytokine responses. Here we report a new functional role of the viral encoded IE1 protein of the murine cytomegalovirus in sculpting the inflammatory response in an acute infection. In time course experiments of infected primary macrophages (MΦs) measuring cytokine production levels, genetic ablation of the immediate-early 1 (ie1) gene results in a significant increase in TNFα production. Intracellular staining for cytokine production and viral early gene expression shows that TNFα production is highly associated with the productively infected MΦ population of cells. The ie1- dependent phenotype of enhanced MΦ TNFα production occurs at both protein and RNA levels. Noticeably, we show in a series of in vivo infection experiments that in multiple organs the presence of ie1 potently inhibits the pro-inflammatory cytokine response. From these experiments, levels of TNFα, and to a lesser extent IFNβ, but not the anti-inflammatory cytokine IL10, are moderated in the presence of ie1. The ie1- mediated inhibition of TNFα production has a similar quantitative phenotype profile in infection of susceptible (BALB/c) and resistant (C57BL/6) mouse strains as well as in a severe immuno-ablative model of infection. In vitro experiments with infected macrophages reveal that deletion of ie1 results in increased sensitivity of viral replication to TNFα inhibition. However, in vivo infection studies show that genetic ablation of TNFα or TNFRp55 receptor is not sufficient to rescue the restricted replication phenotype of the ie1 mutant virus. These results provide, for the first time, evidence for a role of IE1 as a regulator of the pro-inflammatory response and demonstrate a specific pathogen gene capable of moderating the host production of TNFα in vivo. PMID:22952450

  14. Human Cytomegalovirus Stimulates the Synthesis of Select Akt-Dependent Antiapoptotic Proteins during Viral Entry To Promote Survival of Infected Monocytes

    PubMed Central

    Peppenelli, Megan A.; Arend, Kyle C.; Cojohari, Olesea; Moorman, Nathaniel J.

    2016-01-01

    ABSTRACT Primary peripheral blood monocytes are responsible for the hematogenous dissemination of human cytomegalovirus (HCMV) following a primary infection. To facilitate viral spread, we have previously shown HCMV to extend the short 48-h life span of monocytes. Mechanistically, HCMV upregulated two specific cellular antiapoptotic proteins, myeloid leukemia sequence 1 (Mcl-1) and heat shock protein 27 (HSP27), to block the two proteolytic cleavages necessary for the formation of fully active caspase 3 and the subsequent initiation of apoptosis. We now show that HCMV more robustly upregulated Mcl-1 than normal myeloid growth factors and that Mcl-1 was the only myeloid survival factor to rapidly induce HSP27 prior to the 48-h cell fate checkpoint. We determined that HCMV glycoproteins gB and gH signal through the cellular epidermal growth factor receptor (EGFR) and αvβ3 integrin, respectively, during viral entry in order to drive the increase of Mcl-1 and HSP27 in an Akt-dependent manner. Although Akt is known to regulate protein stability and transcription, we found that gB- and gH-initiated signaling preferentially and cooperatively stimulated the synthesis of Mcl-1 and HSP27 through mTOR-mediated translation. Overall, these data suggest that the unique signaling network generated during the viral entry process stimulates the upregulation of select antiapoptotic proteins allowing for the differentiation of short-lived monocytes into long-lived macrophages, a key step in the viral dissemination strategy. IMPORTANCE Human cytomegalovirus (HCMV) infection is endemic within the human population. Although primary infection is generally asymptomatic in immunocompetent individuals, HCMV is a significant cause of morbidity and mortality in the immunocompromised. The multiorgan inflammatory diseases associated with symptomatic HCMV infection are a direct consequence of the monocyte-mediated systemic spread of the virus. In order for peripheral blood monocytes to

  15. Human Cytomegalovirus (HCMV)-Specific CD4(+) T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro.

    PubMed

    Jackson, Sarah E; Sedikides, George X; Mason, Gavin M; Okecha, Georgina; Wills, Mark R

    2017-03-15

    Human cytomegalovirus (HCMV) infection and periodic reactivation are generally well controlled by the HCMV-specific T cell response in healthy people. While the CD8(+) T cell response to HCMV has been extensively studied, the HCMV-specific CD4(+) T cell effector response is not as well understood, especially in the context of direct interactions with HCMV-infected cells. We screened the gamma interferon (IFN-γ) and interleukin-10 (IL-10) responses to 6 HCMV peptide pools (pp65, pp71, IE1, IE2, gB, and US3, selected because they were the peptides most frequently responded to in our previous studies) in 84 donors aged 23 to 74 years. The HCMV-specific CD4(+) T cell response to pp65, IE1, IE2, and gB was predominantly Th1 biased, with neither the loss nor the accumulation of these responses occurring with increasing age. A larger proportion of donors produced an IL-10 response to pp71 and US3, but the IFN-γ response was still dominant. CD4(+) T cells specific to the HCMV proteins studied were predominantly effector memory cells and produced both cytotoxic (CD107a expression) and cytokine (macrophage inflammatory protein 1β secretion) effector responses. Importantly, when we measured the CD4(+) T cell response to cytomegalovirus (CMV)-infected dendritic cells in vitro, we observed that the CD4(+) T cells produced a range of cytotoxic and secretory effector functions, despite the presence of CMV-encoded immune evasion molecules. CD4(+) T cell responses to HCMV-infected dendritic cells were sufficient to control the dissemination of virus in an in vitro assay. Together, the results show that HCMV-specific CD4(+) T cell responses, even those from elderly individuals, are highly functional and are directly antiviral.IMPORTANCE Human cytomegalovirus (HCMV) infection is carried for a lifetime and in healthy people is kept under control by the immune system. HCMV has evolved many mechanisms to evade the immune response, possibly explaining why the virus is never eliminated

  16. Functional interaction of nuclear domain 10 and its components with cytomegalovirus after infections: cross-species host cells versus native cells.

    PubMed

    Cosme, Ruth Cruz; Martínez, Francisco Puerta; Tang, Qiyi

    2011-04-28

    Species-specificity is one of the major characteristics of cytomegaloviruses (CMVs) and is the primary reason for the lack of a mouse model for the direct infection of human CMV (HCMV). It has been determined that CMV cross-species infections are blocked at the post-entry level by intrinsic cellular defense mechanisms, but few details are known. It is important to explore how CMVs interact with the subnuclear structure of the cross-species host cell. In our present study, we discovered that nuclear domain 10 (ND10) of human cells was not disrupted by murine CMV (MCMV) and that the ND10 of mouse cells was not disrupted by HCMV, although the ND10-disrupting protein, immediate-early protein 1 (IE1), also colocalized with ND10 in cross-species infections. In addition, we found that the UL131-repaired HCMV strain AD169 (vDW215-BADrUL131) can infect mouse cells to produce immediate-early (IE) and early (E) proteins but that neither DNA replication nor viral particles were detectable in mouse cells. Unrepaired AD169 can express IE1 only in mouse cells. In both HCMV-infected mouse cells and MCMV-infected human cells, the knocking-down of ND10 components (PML, Daxx, and SP100) resulted in significantly increased viral-protein production. Our observations provide evidence to support our hypothesis that ND10 and ND10 components might be important defensive factors against the CMV cross-species infection.

  17. Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing αβ+T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies.

    PubMed

    Muccio, Letizia; Bertaina, Alice; Falco, Michela; Pende, Daniela; Meazza, Raffaella; Lopez-Botet, Miguel; Moretta, Lorenzo; Locatelli, Franco; Moretta, Alessandro; Della Chiesa, Mariella

    2016-03-01

    We analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/β+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C(+)CD57(+) natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects.

  18. Toll-like receptor 4 is involved in the cell cycle modulation and required for effective human cytomegalovirus infection in THP-1 macrophages

    SciTech Connect

    Arcangeletti, Maria-Cristina; Germini, Diego; Rodighiero, Isabella; Mirandola, Prisco; De Conto, Flora; Medici, Maria-Cristina; Gatti, Rita; Chezzi, Carlo; Calderaro, Adriana

    2013-05-25

    Suitable host cell metabolic conditions are fundamental for the effective development of the human cytomegalovirus (HCMV) lytic cycle. Indeed, several studies have demonstrated the ability of this virus to interfere with cell cycle regulation, mainly by blocking proliferating cells in G1 or G1/S. In the present study, we demonstrate that HCMV deregulates the cell cycle of THP-1 macrophages (a cell line irreversibly arrested in G0) by pushing them into S and G2 phases. Moreover, we show that HCMV infection of THP-1 macrophages leads to Toll-like receptor 4 (TLR4) activation. Since various studies have indicated TLR4 to be involved in promoting cell proliferation, here we investigate the possible role of TLR4 in the observed HCMV-induced cell cycle perturbation. Our data strongly support TLR4 as a mediator of HCMV-triggered cell cycle activation in THP-1 macrophages favouring, in turn, the development of an efficient viral lytic cycle. - Highlights: ► We studied HCMV infection impact on THP-1 macrophage cell cycle. ► We analysed the role played by Toll-like receptor (TLR) 4 upon HCMV infection. ► HCMV pushes THP-1 macrophages (i.e. resting cells) to re-enter the cell cycle. ► TLR4 pathway inhibition strongly affects the effectiveness of HCMV replication. ► TLR4 pathway inhibition significantly decreases HCMV-induced cell cycle re-entry.

  19. Antibody Treatment Promotes Compensation for Human Cytomegalovirus-Induced Pathogenesis and a Hypoxia-Like Condition in Placentas with Congenital Infection

    PubMed Central

    Maidji, Ekaterina; Nigro, Giovanni; Tabata, Takako; McDonagh, Susan; Nozawa, Naoki; Shiboski, Stephen; Muci, Stefania; Anceschi, Maurizio M.; Aziz, Natali; Adler, Stuart P.; Pereira, Lenore

    2010-01-01

    Human cytomegalovirus (HCMV) is the major viral cause of birth defects worldwide. Affected infants can have temporary symptoms that resolve soon after birth, such as growth restriction, and permanent disabilities, including neurological impairment. Passive immunization of pregnant women with primary HCMV infection is a promising treatment to prevent congenital disease. To understand the effects of sustained viral replication on the placenta and passive transfer of protective antibodies, we performed immunohistological analysis of placental specimens from women with untreated congenital infection, HCMV-specific hyperimmune globulin treatment, and uninfected controls. In untreated infection, viral replication proteins were found in trophoblasts and endothelial cells of chorionic villi and uterine arteries. Associated damage included extensive fibrinoid deposits, fibrosis, avascular villi, and edema, which could impair placental functions. Vascular endothelial growth factor and its receptor fms-like tyrosine kinase 1 (Flt1) were up-regulated, and amniotic fluid contained elevated levels of soluble Flt1 (sFlt1), an antiangiogenic protein, relative to placental growth factor. With hyperimmune globulin treatment, placentas appeared uninfected, vascular endothelial growth factor and Flt1 expression was reduced, and sFlt1 levels in amniotic fluid were lower. An increase in the number of chorionic villi and blood vessels over that in controls suggested compensatory development for a hypoxia-like condition. Taken together the results indicate that antibody treatment can suppress HCMV replication and prevent placental dysfunction, thus improving fetal outcome. PMID:20651234

  20. Isolation of Endoplasmic Reticulum, Mitochondria, and Mitochondria-Associated Membrane and Detergent Resistant Membrane Fractions from Transfected Cells and from Human Cytomegalovirus-Infected Primary Fibroblasts.

    PubMed

    Williamson, Chad D; Wong, Daniel S; Bozidis, Petros; Zhang, Aiping; Colberg-Poley, Anamaris M

    2015-09-01

    Increasingly mechanistic virology studies require dependable and sensitive methods for isolating purified organelles containing functional cellular sub-domains. The mitochondrial network is, in part, closely apposed to the endoplasmic reticulum (ER). The mitochondria-associated membrane (MAM) fraction provides direct physical contact between the ER and mitochondria. Characterization of the dual localization and trafficking of human cytomegalovirus (HCMV) UL37 proteins required establishing protocols in which the ER and mitochondria could be reliably separated. Because of its documented role in lipid and ceramide transfer from the ER to mitochondria, a method to purify MAM from infected cells was also developed. Two robust procedures were developed to efficiently isolate mitochondria, ER, and MAM fractions while providing substantial protein yields from HCMV-infected primary fibroblasts and from transfected HeLa cells. Furthermore, this unit includes protocols for isolation of detergent resistant membranes from subcellular fractions as well as techniques that allow visualization of the mitochondrial network disruption that occurs in permissively infected cells by their optimal resolution in Percoll gradients.

  1. Isolation of Endoplasmic Reticulum, Mitochondria, and Mitochondria-Associated Membrane and Detergent Resistant Membrane Fractions from Transfected Cells and from Human Cytomegalovirus-Infected Primary Fibroblasts

    PubMed Central

    Williamson, Chad D.; Wong, Daniel S.; Bozidis, Petros; Zhang, Aiping; Colberg-Poley, Anamaris M.

    2015-01-01

    Increasingly mechanistic virology studies require dependable and sensitive methods for isolating purified organelles containing functional cellular sub-domains. The mitochondrial network is, in part, closely apposed to the endoplasmic reticulum (ER). The mitochondria-associated membrane (MAM) fraction provides direct physical contact between the ER and mitochondria. Characterization of the dual localization and trafficking of human cytomegalovirus (HCMV) UL37 proteins required establishing protocols in which the ER and mitochondria could be reliably separated. Because of its documented role in lipid and ceramide transfer from the ER to mitochondria, a method to purify MAM from infected cells was also developed. Two robust procedures were developed to efficiently isolate mitochondria, ER, and MAM fractions while providing substantial protein yields from HCMV-infected primary fibroblasts and from transfected HeLa cells. Furthermore, this unit includes protocols for isolation of detergent resistant membranes from subcellular fractions as well as techniques that allow visualization of the mitochondria network disruption that occurs in permissively infected cells by their optimal resolution in Percoll gradients. PMID:26331984

  2. The NK Cell Response to Mouse Cytomegalovirus Infection Affects the Level and Kinetics of the Early CD8+ T-Cell Response

    PubMed Central

    Mitrović, Maja; Arapović, Jurica; Jordan, Stefan; Fodil-Cornu, Nassima; Ebert, Stefan; Vidal, Silvia M.; Krmpotić, Astrid; Reddehase, Matthias J.

    2012-01-01

    Natural killer (NK) cells and CD8+ T cells play a prominent role in the clearance of mouse cytomegalovirus (MCMV) infection. The role of NK cells in modulating the CD8+ T-cell response to MCMV infection is still the subject of intensive research. For analyzing the impact of NK cells on mounting of a CD8+ T-cell response and the contribution of these cells to virus control during the first days postinfection (p.i.), we used C57BL/6 mice in which NK cells are specifically activated through the Ly49H receptor engaged by the MCMV-encoded ligand m157. Our results indicate that the requirement for CD8+ T cells in early MCMV control inversely correlates with the engagement of Ly49H. While depletion of CD8+ T cells has only a minor effect on the early control of wild-type MCMV, CD8+ T cells are essential in the control of Δm157 virus. The frequencies of virus epitope-specific CD8+ T cells and their activation status were higher in mice infected with Δm157 virus. In addition, these mice showed elevated levels of alpha interferon (IFN-α) and several other proinflammatory cytokines as early as 1.5 days p.i. Although the numbers of conventional dendritic cells (cDCs) were reduced later during infection, particularly in Δm157-infected mice, they were not significantly affected at the peak of the cytokine response. Altogether, we concluded that increased antigen load, preservation of early cDCs' function, and higher levels of innate cytokines collectively account for an enhanced CD8+ T-cell response in C57BL/6 mice infected with a virus unable to activate NK cells via the Ly49H–m157 interaction. PMID:22156533

  3. Human Cytomegalovirus miR-UL148D Facilitates Latent Viral Infection by Targeting Host Cell Immediate Early Response Gene 5

    PubMed Central

    Li, Limin; Li, Donghai; Liu, Fenyong; Zhang, Chen-Yu; Zen, Ke

    2016-01-01

    The mechanisms underlying human cytomegalovirus (HCMV) latency remain incompletely understood. Here, we showed that a HCMV-encoded miRNA, miR-UL148D, robustly accumulates during late stages of experimental latent HCMV infection in host cells and promotes HCMV latency by modulating the immediate early response gene 5 (IER5)-cell division cycle 25B (CDC25B) axis in host cells. miR-UL148D inhibited IER5 expression by directly targeting the three-prime untranslated region(3’UTR) of IER5 mRNA and thus rescued CDC25B expression during the establishment of viral latency. Infection with NR-1ΔmiR-UL148D, a derivative of the HCMV clinical strain NR-1 with a miR-UL148D knockout mutation, resulted in sustained induction of IER5 expression but decreased CDC25B expression in host cells. Mechanistically, we further showed that CDC25B plays an important role in suppressing HCMV IE1 and lytic gene transcription by activating cyclin-dependent kinase 1 (CDK-1). Both gain-of-function and lose-of-function assays demonstrated that miR-UL148D promotes HCMV latency by helping maintain CDC25B activity in host cells. These results provide a novel mechanism through which a HCMV miRNA regulates viral latency. PMID:27824944

  4. Comparison of Real-time PCR to ELISA for the detection of human cytomegalovirus infection in renal transplant patients in the Sudan

    PubMed Central

    2011-01-01

    Background This study was carried out to detect human cytomegalovirus (HCMV) IgG and IgM antibodies using an Enzyme-linked immunosorbent assay (ELISA) in renal transplant patients in Khartoum state, Sudan and to improve the diagnosis of HCMV through the introduction of Real-time Polymerase Chain Reaction (PCR) testing. A total of 98 plasma samples were collected randomly from renal transplant patients at Ibin Sina Hospital and Salma Centre for Transplantation and Haemodialysis during the period from August to September 2006. Results Among the 98 renal transplant patients, 65 were males and 33 females. The results revealed that HCMV IgG was present in all patients' plasma 98/98 (100%), while only 6/98 (6.1%) had IgM antibodies in their plasma. HCMV DNA viral loads were detected in 32 patients 32/98 (32.7%) using Real-time PCR. Conclusions The HCMV IgG results indicate a high prevalence of past HCMV infection in all tested groups, while the finding of IgM may reflect a recent infection or reactivation. HCMV detection by real-time PCR in the present study indicated a high prevalence among renal transplant patients in Khartoum. In conclusion, the prevalence of HCMV in Khartoum State was documented through detection of HCMV-specific antibodies. Further study using various diagnostic methods should be considered to determine the prevalence of HCMV disease at the national level. PMID:21569506

  5. Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1γ.

    PubMed

    Trsan, Tihana; Busche, Andreas; Abram, Maja; Wensveen, Felix M; Lemmermann, Niels A; Arapovic, Maja; Babic, Marina; Tomic, Adriana; Golemac, Mijo; Brinkmann, Melanie M; Jäger, Wiebke; Oxenius, Annette; Polic, Bojan; Krmpotic, Astrid; Messerle, Martin; Jonjic, Stipan

    2013-10-08

    Due to a unique pattern of CD8 T-cell response induced by cytomegaloviruses (CMVs), live attenuated CMVs are attractive candidates for vaccine vectors for a number of clinically relevant infections and tumors. NKG2D is one of the most important activating NK cell receptors that plays a role in costimulation of CD8 T cells. Here we demonstrate that the expression of CD8 T-cell epitope of Listeria monocytogenes by a recombinant mouse CMV (MCMV) expressing the NKG2D ligand retinoic acid early-inducible protein 1-gamma (RAE-1γ) dramatically enhanced the effectiveness and longevity of epitope-specific CD8 T-cell response and conferred protection against a subsequent challenge infection with Listeria monocytogenes. Unexpectedly, the attenuated growth in vivo of the CMV vector expressing RAE-1γ and its capacity to enhance specific CD8 T-cell response were preserved even in mice lacking NKG2D, implying additional immune function for RAE-1γ beyond engagement of NKG2D. Thus, vectors expressing RAE-1γ represent a promising approach in the development of CD8 T-cell-based vaccines.

  6. The Breadth of Synthetic Long Peptide Vaccine-Induced CD8+ T Cell Responses Determines the Efficacy against Mouse Cytomegalovirus Infection

    PubMed Central

    Panagioti, Eleni; Redeker, Anke; van Duikeren, Suzanne; Franken, Kees LMC; Drijfhout, Jan Wouter; van der Burg, Sjoerd H.

    2016-01-01

    There is an ultimate need for efficacious vaccines against human cytomegalovirus (HCMV), which causes severe morbidity and mortality among neonates and immunocompromised individuals. In this study we explored synthetic long peptide (SLP) vaccination as a platform modality to protect against mouse CMV (MCMV) infection in preclinical mouse models. In both C57BL/6 and BALB/c mouse strains, prime-booster vaccination with SLPs containing MHC class I restricted epitopes of MCMV resulted in the induction of strong and polyfunctional (i.e., IFN-γ+, TNF+, IL-2+) CD8+ T cell responses, equivalent in magnitude to those induced by the virus itself. SLP vaccination initially led to the formation of effector CD8+ T cells (KLRG1hi, CD44hi, CD127lo, CD62Llo), which eventually converted to a mixed central and effector-memory T cell phenotype. Markedly, the magnitude of the SLP vaccine-induced CD8+ T cell response was unrelated to the T cell functional avidity but correlated to the naive CD8+ T cell precursor frequency of each epitope. Vaccination with single SLPs displayed various levels of long-term protection against acute MCMV infection, but superior protection occurred after vaccination with a combination of SLPs. This finding underlines the importance of the breadth of the vaccine-induced CD8+ T cell response. Thus, SLP-based vaccines could be a potential strategy to prevent CMV-associated disease. PMID:27637068

  7. Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1γ

    PubMed Central

    Tršan, Tihana; Busche, Andreas; Abram, Maja; Wensveen, Felix M.; Lemmermann, Niels A.; Arapović, Maja; Babić, Marina; Tomić, Adriana; Golemac, Mijo; Brinkmann, Melanie M.; Jäger, Wiebke; Oxenius, Annette; Polić, Bojan; Krmpotić, Astrid; Messerle, Martin; Jonjić, Stipan

    2013-01-01

    Due to a unique pattern of CD8 T-cell response induced by cytomegaloviruses (CMVs), live attenuated CMVs are attractive candidates for vaccine vectors for a number of clinically relevant infections and tumors. NKG2D is one of the most important activating NK cell receptors that plays a role in costimulation of CD8 T cells. Here we demonstrate that the expression of CD8 T-cell epitope of Listeria monocytogenes by a recombinant mouse CMV (MCMV) expressing the NKG2D ligand retinoic acid early-inducible protein 1-gamma (RAE-1γ) dramatically enhanced the effectiveness and longevity of epitope-specific CD8 T-cell response and conferred protection against a subsequent challenge infection with Listeria monocytogenes. Unexpectedly, the attenuated growth in vivo of the CMV vector expressing RAE-1γ and its capacity to enhance specific CD8 T-cell response were preserved even in mice lacking NKG2D, implying additional immune function for RAE-1γ beyond engagement of NKG2D. Thus, vectors expressing RAE-1γ represent a promising approach in the development of CD8 T-cell–based vaccines. PMID:24052528

  8. Utility of the Enzyme-Linked Immunospot Interferon-γ–Release Assay to Predict the Risk of Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients

    PubMed Central

    Nesher, Lior; Shah, Dimpy P.; Ariza-Heredia, Ella J.; Azzi, Jacques M.; Siddiqui, Hala K.; Ghantoji, Shasank S.; Marsh, Lisa Y.; Michailidis, Lamprinos; Makedonas, George; Rezvani, Katy; Shpall, Elizabeth J.; Chemaly, Roy F.

    2016-01-01

    The ability to distinguish allogeneic hematopoietic cell transplant (allo-HCT) recipients at risk for cytomegalovirus (CMV) reactivation from those who are not is central for optimal CMV management strategies. Interferon γ (IFN-γ) produced by CMV-challenged T cells may serve as an immune marker differentiating these 2 populations. We prospectively monitored 63 CMV-seropositive allo-HCT recipients with a CMV-specific enzyme-linked immunospot (ELISPOT) assay and for CMV infection from the period before transplantation to day 100 after transplantation. Assay results above certain thresholds (50 spots per 250 000 cells for immediate early 1 or 100 spots per 250 000 cells for phosphoprotein 65) identified patients who were protected against CMV infection as long as they had no graft-versus-host disease and/or were not receiving systemic corticosteroids. Based on the multivariable Cox proportional hazards regression model, the only significant factor for preventing CMV reactivation was a CMV-specific ELISPOT response above the determined thresholds (adjusted hazard ratio, 0.21; 95% confidence interval, .05–.97; P = .046). Use of this assay as an additional tool for managing allo-HCT recipients at risk for CMV reactivation needs further validation in future studies. Application of this new approach may reduce the duration and intensity of CMV monitoring and the duration of prophylaxis or treatment with antiviral agents in those who have achieved CMV-specific immune reconstitution. PMID:26908740

  9. Natural Killer Cell Sensing of Infected Cells Compensates for MyD88 Deficiency but Not IFN-I Activity in Resistance to Mouse Cytomegalovirus.

    PubMed

    Cocita, Clément; Guiton, Rachel; Bessou, Gilles; Chasson, Lionel; Boyron, Marilyn; Crozat, Karine; Dalod, Marc

    2015-05-01

    In mice, plasmacytoid dendritic cells (pDC) and natural killer (NK) cells both contribute to resistance to systemic infections with herpes viruses including mouse Cytomegalovirus (MCMV). pDCs are the major source of type I IFN (IFN-I) during MCMV infection. This response requires pDC-intrinsic MyD88-dependent signaling by Toll-Like Receptors 7 and 9. Provided that they express appropriate recognition receptors such as Ly49H, NK cells can directly sense and kill MCMV-infected cells. The loss of any one of these responses increases susceptibility to infection. However, the relative importance of these antiviral immune responses and how they are related remain unclear. In humans, while IFN-I responses are essential, MyD88 is dispensable for antiviral immunity. Hence, a higher redundancy has been proposed in the mechanisms promoting protective immune responses against systemic infections by herpes viruses during natural infections in humans. It has been assumed, but not proven, that mice fail to mount protective MyD88-independent IFN-I responses. In humans, the mechanism that compensates MyD88 deficiency has not been elucidated. To address these issues, we compared resistance to MCMV infection and immune responses between mouse strains deficient for MyD88, the IFN-I receptor and/or Ly49H. We show that selective depletion of pDC or genetic deficiencies for MyD88 or TLR9 drastically decreased production of IFN-I, but not the protective antiviral responses. Moreover, MyD88, but not IFN-I receptor, deficiency could largely be compensated by Ly49H-mediated antiviral NK cell responses. Thus, contrary to the current dogma but consistent with the situation in humans, we conclude that, in mice, in our experimental settings, MyD88 is redundant for IFN-I responses and overall defense against a systemic herpes virus infection. Moreover, we identified direct NK cell sensing of infected cells as one mechanism able to compensate for MyD88 deficiency in mice. Similar mechanisms likely

  10. Screening for seemingly healthy newborns with congenital cytomegalovirus infection by quantitative real-time polymerase chain reaction using newborn urine: an observational study

    PubMed Central

    Yamaguchi, Akira; Oh-ishi, Tsutomu; Arai, Takashi; Sakata, Hideaki; Adachi, Nodoka; Asanuma, Satoshi; Oguma, Eiji; Kimoto, Hirofumi; Matsumoto, Jiro; Fujita, Hidetoshi; Uesato, Tadashi; Fujita, Jutaro; Shirato, Ken; Ohno, Hideki; Kizaki, Takako

    2017-01-01

    Objective Approximately 8–10% of newborns with asymptomatic congenital cytomegalovirus (cCMV) infection develop sensorineural hearing loss (SNHL). However, the relationship between CMV load, SNHL and central nervous system (CNS) damage in cCMV infection remains unclear. This study aimed to examine the relationship between urinary CMV load, SNHL and CNS damage in newborns with cCMV infection. Study design The study included 23 368 newborns from two maternity hospitals in Saitama Prefecture, Japan. Urine screening for cCMV infection (quantitative real-time PCR) and newborn hearing screening (automated auditory brainstem response (AABR) testing) were conducted within 5 days of birth to examine the incidence of cCMV infection and SNHL, respectively. CNS damage was assessed by MRI of cCMV-infected newborns. Results The incidence of cCMV infection was 60/23 368 (0.257%; 95% CI 0.192% to 0.322%). The geometric mean urinary CMV DNA copy number in newborns with cCMV was 1.79×106 copies/mL (95% CI 7.97×105 to 4.02×106). AABR testing revealed abnormalities in 171 of the 22 229 (0.769%) newborns whose parents approved hearing screening. Of these 171 newborns, 22 had SNHL (12.9%), and 5 of these 22 were infected with cCMV (22.7%). Newborns with both cCMV and SNHL had a higher urinary CMV DNA copy number than newborns with cCMV without SNHL (p=0.036). MRI revealed CNS damage, including white matter abnormalities, in 83.0% of newborns with cCMV. Moreover, newborns with CNS damage had a significantly greater urinary CMV load than newborns without CNS damage (p=0.013). Conclusions We determined the incidence of cCMV infection and urinary CMV DNA copy number in seemingly healthy newborns from two hospitals in Saitama Prefecture. SNHL and CNS damage were associated with urinary CMV DNA copy number. Quantification of urinary CMV load may effectively predict the incidence of late-onset SNHL and neurodevelopmental disorders. PMID:28110288

  11. Unusually difficult clinical presentation of an infant suffering from congenital cytomegalovirus (CMV) infection combined with alpha 1-antitrypsin (A1AT) deficiency

    PubMed Central

    Potočnjak, Ines; Tešović, Goran; Kuna, Andrea Tešija; Štefanović, Mario; Žaja, Orjena

    2014-01-01

    Congenital Cytomegalovirus (CMV) infection and alpha 1-antitrypsin (A1AT) deficiency are separately well described entities, but their simultaneous occurrence can pose a special challenge to a clinician, especially dealing with optimal diagnostic as well as therapeutic approach. Congenital CMV infection is the most common vertically transmitted infection in developed countries. In 85–95% of newborns it runs asymptomatic, while in others it is presented with jaundice, petechias, hepatosplenomegaly and central nervous system damage. A1AT deficiency is on the other hand, the most common genetic liver disease in children, and the clinical spectrum varies from the accidentally detected increased levels of transaminases through to the severe infant cholestasis that can progress to cirrhosis. The following case report describes a two-month old male with severe clinical presentation of congenital CMV infection probably exacerbated due to A1AT deficiency comorbidity. The clinical manifestations and unusually difficult clinical signs this infant presented lead to assumption that the additional liver damage exists. Extensive laboratory analyses were performed, including PCR for CMV DNA, A1AT serum concentration, A1AT genotyping, followed and confirmed with phenotyping. Patient was treated parenteral with ganciclovir, what continued with oral valganciclovir and supportive therapy. Intensive and thorough supportive treatment of the infant resulted in satisfactory progress and excellent outcome. Patient was followed-up till the age of 18 months. The presented case provides excellent example about successful overcoming obstacles in differential diagnosis of A1AT in neonates and infants. Medical charts analysis was the methodology used in making this report. PMID:25351359

  12. Enforced OX40 Stimulation Empowers Booster Vaccines to Induce Effective CD4+ and CD8+ T Cell Responses against Mouse Cytomegalovirus Infection

    PubMed Central

    Panagioti, Eleni; Boon, Louis; Arens, Ramon; van der Burg, Sjoerd H.

    2017-01-01

    There is an imperative need for effective preventive vaccines against human cytomegalovirus as it poses a significant threat to the immunologically immature, causing congenital disease, and to the immune compromised including transplant recipients. In this study, we examined the efficacy of synthetic long peptides (SLPs) as a CD4+ and CD8+ T cell-eliciting preventive vaccine approach against mouse CMV (MCMV) infection. In addition, the use of agonistic OX40 antibodies to enhance vaccine efficacy was explored. Immunocompetent C57BL/6 mice were vaccinated in a prime-boost vaccination regiment with SLPs comprising various MHC class I- and II-restricted peptide epitopes of MCMV-encoded antigens. Enforced OX40 stimulation resulted in superior MCMV-specific CD4+ as CD8+ T cell responses when applied during booster SLP vaccination. Vaccination with a mixture of SLPs containing MHC class II epitopes and OX40 agonistic antibodies resulted in a moderate reduction of the viral titers after challenge with lytic MCMV infection. Markedly, the combination of SLP vaccines containing both MHC class I and II epitopes plus OX40 activation during booster vaccination resulted in polyfunctional (i.e., IFN-γ+, TNF+, IL-2+) CD4+ and CD8+ T cell responses that were even higher in magnitude when compared to those induced by the virus, and this resulted in the best containment of virus dissemination. Our results show that the induction of strong T cell responses can be a fundamental component in the design of vaccines against persistent viral infections. PMID:28265272

  13. Evaluation of cytomegalovirus infection in low-birth weight children by breast milk using a real-time polymerase chain reaction assay.

    PubMed

    Romero-Gómez, Maria Pilar; Cabrera, Marta; Montes-Bueno, María Teresa; Cendejas-Bueno, Emilio; Segovia, Cristina; Pastrana, Natividad; Mingorance, Jesús; Omeñaca, Félix

    2015-05-01

    Human Cytomegalovirus (CMV) is the most common cause of intrauterine and perinatal infections worldwide. Postnatal CMV transmission has usually no consequences, but in some cases it may produce disease in preterm infants. Literature reports a broad range of breast milk-acquired CMV infections (5.7-58.6%), which depends on the study's design and the treatment of the milk. To evaluate CMV transmission via breast milk, a prospective study using a real-time PCR assay was performed. One hundred and thirty-one mothers (accounting for 160 children) accepted the participation in the study. Urine samples from the infants and breast milk samples from their mothers were collected at 3, 15, 30, 60, and 90 days after delivery. CMV-DNA in breast milk was analysed by quantitative real-time PCR assay Affigene® CMV Trender (Cepheid, Bromma, Sweden). The breast milk samples from 92 mothers (92 of 131, 70.2%) were positive for CMV by PCR. CMV infection was detected in thirteen children by PCR, and four of them (30.7%) had clinical symptoms. There were not significant differences in morbidity between symptomatic and non- symptomatic patients; nonetheless, the average length of hospitalization in symptomatic children was higher than that of non-symptomatic children (P < 0.05). The rtPCR technique is useful for detection of mothers with high viral loads of CMV-DNA in milk, and might be of help to decide whether to freeze the breast milk in preterm children less than 28 weeks.

  14. Mechanisms for virus-induced liver disease: tumor necrosis factor-mediated pathology independent of natural killer and T cells during murine cytomegalovirus infection.

    PubMed Central

    Orange, J S; Salazar-Mather, T P; Opal, S M; Biron, C A

    1997-01-01

    The contribution of endogenous NK cells and cytokines to virus-induced liver pathology was evaluated during murine cytomegalovirus infections of mice. In immunocompetent C57BL/6 mice, the virus induced a self-limited liver disease characterized by hepatitis, with focal inflammation, and large grossly visible subcapsular necrotic foci. The inflammatory foci were most numerous and contained the greatest number of cells 3 days after infection; they colocalized with areas of viral antigen expression. The largest number of necrotic foci was found 2 days after infection. Overall hepatic damage, assessed as increased expression of liver enzymes in serum, accompanied the development of inflammatory and necrotic foci. Experiments with neutralizing antibodies demonstrated that although virus-induced tumor necrosis factor (TNF) can have antiviral effects, it also mediated significant liver pathology. TNF was required for development of hepatic necrotic foci and increased levels of liver enzymes in serum but not for increased numbers of inflammatory foci. The necrotic foci and liver enzyme indications of pathology occurred independently of NK and T cells, because mice rendered NK-cell deficient by treatment with antibodies, T- and B-cell-deficient Rag-/- mice, and NK- and T-cell-deficient E26 mice all manifested both parameters of disease. Development of necrotic foci and maximally increased levels of liver enzymes in serum also were TNF dependent in NK-cell-deficient mice. Moreover, in the immunodeficient E26 mice, virus-induced liver disease was progressive, with eventual death of the host, and neutralization of TNF significantly increased longevity. These results establish conditions separating hepatitis from significant liver damage and demonstrate a cytokine-mediated component to viral pathogenesis. PMID:9371583

  15. Cytomegalovirus infection modulates the phenotype and functional profile of the T-cell immune response to mycobacterial antigens in older life☆

    PubMed Central

    Terrazzini, Nadia; Bajwa, Martha; Vita, Serena; Thomas, David; Smith, Helen; Vescovini, Rosanna; Sansoni, Paolo; Kern, Florian

    2014-01-01

    Infection with Cytomegalovirus is associated with accelerated immunosenescence. Expansions of CMV-specific T cell responses have previously been demonstrated to affect the ability of T cells to respond to other infections. Most people above 60 years of age display M. tuberculosis-specific immunity because of vaccination, exposure, or both. T-cell responses can be assessed by measuring intracellular IFN-γ in vitro after tuberculin stimulation. Here we investigated tuberculin-specific CD4 T-cell responses in independently living healthy older people in the South of England using flow-cytometry. Individuals were investigated for tuberculin and CMV-specific T-cell immunity using in vitro antigen stimulation followed by intracellular staining for IFN-γ, TNF-α, IL2, as well as degranulation and CD154 upregulation. We also examined a control group of younger individuals (20–35 years of age). There was no significant difference between older and young people in regards to tuberculin responsiveness of CD4 T-cells; however, older people seemed to show more outliers. Increased responsiveness to tuberculin was significantly correlated to CMV responsiveness but not age. In older donors, the memory phenotype of tuberculin-induced T-cells was significantly skewed towards a more terminal differentiation phenotype in CMV-infected compared to uninfected individuals and the degree of skewing correlated quantitatively with the size of the CMV-specific CD4 T-cell response. This is a fundamental advance over previous reports of changes of the tuberculin-specific CD4 T-cell response with CMV serostatus. Our results show that how the immune system responds to CMV has a fundamental impact on the phenotype and function of the immune response to mycobacterial antigens in older life. PMID:24370373

  16. Efficient linking of birth certificate and newborn screening databases for laboratory investigation of congenital cytomegalovirus infection and preterm birth: Florida, 2008.

    PubMed

    DePasquale, John M; Freeman, Karen; Amin, Minal M; Park, Sohyun; Rivers, Samantha; Hopkins, Richard; Cannon, Michael J; Dy, Bonifacio; Dollard, Sheila C

    2012-02-01

    The objectives of this study are (1) to design an accurate method for linking newborn screening (NBS) and state birth certificate databases to create a de-identified study database; (2) To assess maternal cytomegalovirus (CMV) seroprevalence by measuring CMV IgG in newborn dried blood spots; (3) To assess congenital CMV infection among newborns and possible association with preterm birth. NBS and birth databases were linked and patient records were de-identified. A stratified random sample of records based on gestational age was selected and used to retrieve blood spots from the state NBS laboratory. Serum containing maternal antibodies was eluted from blood spots and tested for the presence of CMV IgG. DNA was extracted from blood spots and tested for the presence of CMV DNA. Analyses were performed with bivariable and multivariable logistic regression models. Linkage rates and specimen collection exceeded 98% of the total possible yielding a final database with 3,101 newborn blood spots. CMV seroprevalence was 91% among Black mothers, 83% among Hispanic mothers, 59% among White mothers, and decreased with increasing amounts of education. The prevalence of CMV infection in newborns was 0.45% and did not vary significantly by gestational age. Successful methods for database linkage, newborn blood spots collection, and de-identification of records can serve as a model for future congenital exposure surveillance projects. Maternal CMV seroprevalence was strongly associated with race/ethnicity and educational level. Congenital CMV infection rates were lower than those reported by other studies and lacked statistical power to examine associations with preterm birth.

  17. 21 CFR 866.3175 - Cytomegalovirus serological reagents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... serum. The identification aids in the diagnosis of diseases caused by cytomegaloviruses (principally cytomegalic inclusion disease) and provides epidemiological information on these diseases. Cytomegalic inclusion disease is a generalized infection of infants and is caused by intrauterine or early...

  18. Effect of Mycoplasma hominis and cytomegalovirus infection on pregnancy outcome: A prospective study of 200 Mongolian women and their newborns

    PubMed Central

    Batbaatar, Gunchin; Tsogtsaikhan, Sandag; Enkhtsetseg, Jamsranjav; Enkhjargal, Altangerel; Pfeffer, Klaus; Adams, Ortwin; Battogtokh, Chimeddorj

    2017-01-01

    In Mongolia, diagnostic tests for the detection of the sexually transmitted mycoplasmas, ureaplasmas, Herpes simplex virus (HSV), and cytomegalovirus (CMV) are currently not routinely used in clinical settings and the frequency of these STIs are enigmatic. The prevalence of these STI pathogens were prospectively evaluated among 200 Mongolian pregnant women and their newborns and correlated with pregnancy outcome. TaqMan PCRs were used to detect bacterial and viral STI pathogens in pre-birth vaginal swabs of the pregnant women and in oral swabs of their newborns. A standardized questionnaire concerning former and present pregnancies was developed and linear regression analysis was used to correlate pathogen detection with pregnancy outcome. Ureaplasmas were the most prevalent of the tested pathogens (positive in 90.5% positive women and 47.5% newborns), followed by mycoplasmas (32.5% and 7.5%), chlamydia (14.5% and 7.5%), trichomonas (8.5% and 4.0%) and gonococcus (0.5% and 0%). CMV was found in 46.5% of the pregnant women and in 10.5% of their newborns, whereas HSV-2 was detected in only two mothers. Multiple regression analyses indicate that colonization of the mothers with U. urealyticum, M. hominis, T. vaginalis or CMV is associated with transmission to newborns and that transmission of M. hominis or CMV from Mongolian pregnant women to offspring is associated with reduced neonatal length and gestational age. Thus, diagnostic tests for their detection should be implemented in the clinical settings in Mongolia. PMID:28257513

  19. Are female daycare workers at greater risk of cytomegalovirus infection? A secondary data analysis of CMV seroprevalence between 2010 and 2013 in Hamburg, Germany

    PubMed Central

    Stranzinger, Johanna; Kozak, Agnessa; Schilgen, Benjamin; Paris, Diana; Nießen, Thomas; Schmidt, Lutz; Wille, Andreas; Wagner, Norbert L.; Nienhaus, Albert

    2016-01-01

    Background: Close contact with asymptomatic children younger than three years is a risk factor for a primary cytomegalovirus (CMV) infection. In pregnant women, such primary infection increases the risk of CMV-induced feto- or embryopathy. Daycare providers have therefore implemented working restrictions for pregnant daycare workers (DCWs) in accordance with legislation and guidelines for maternity protection. However, little is known about the infection risk for DCWs. We therefore compared the prevalence of CMV antibodies of pregnant DCWs to that of female blood donors (BDs). Method: In a secondary data analysis, the prevalence of anti-CMV IgG among pregnant DCWs (N=509) in daycare centers (DCCs) was compared to the prevalence of female first-time BDs (N=14,358) from the greater region of Hamburg, Germany. Data collection took place between 2010 and 2013. The influence of other risk factors such as age, pregnancies and place of residence was evaluated using logistic regression models. Results: The prevalence of CMV antibodies in pregnant DCWs was higher than in female BDs (54.6 vs 41.5%; OR 1.6; 95%CI 1.3–1.9). The subgroup of BDs who had given birth to at least one child and who lived in the city of Hamburg (N=2,591) had a prevalence of CMV antibodies similar to the prevalence in pregnant DCWs (53.9 vs 54.6%; OR 0.9; 95%CI 0.8–1.2). Age, pregnancy history and living in the center of Hamburg were risk factors for CMV infections. Conclusion: The comparison of pregnant DCWs to the best-matching subgroup of female first-time BDs with past pregnancies and living in the city of Hamburg does not indicate an elevated risk of CMV infection among DCWs. However, as two secondary data sets from convenience samples were used, a more detailed investigation of the risk factors other than place of residence, age and maternity was not possible. Therefore, the CMV infection risk in DCWs should be further studied by taking into consideration the potential preventive effect of

  20. Cytomegalovirus appendicitis in an immunocompetent host.

    PubMed

    Canterino, Joseph E; McCormack, Michael; Gurung, Ananta; Passarelli, James; Landry, Marie L; Golden, Marjorie

    2016-05-01

    Cytomegalovirus (CMV) is a common viral pathogen. Asymptomatic infection or a mononucleosis syndrome are the most common manifestations in otherwise healthy individuals. End-organ disease is rare in immunocompetent individuals. Here, we describe a case of CMV appendicitis in a patient without an immune-compromising condition.

  1. Regulatory T cells generated during cytomegalovirus in vitro stimulation of mononuclear cells from HIV-infected individuals on HAART correlate with decreased lymphocyte proliferation

    SciTech Connect

    Jesser, Renee D.; Li, Shaobing; Weinberg, Adriana . E-mail: Adriana.Weinberg@uchsc.edu

    2006-09-01

    HIV-infected patients fail to fully recover cell-mediated immunity despite HAART. To identify regulatory factors, we studied the phenotype and function of in vitro cytomegalovirus (CMV)-stimulated T cells from HAART recipients. CFSE-measured proliferation showed CD4{sup +} and CD8{sup +} cells dividing in CMV-stimulated cultures. Compared with healthy controls, CMV-stimulated lymphocytes from HAART recipients had lower {sup 3}H-thymidine incorporation; lower IFN{gamma} and TNF{alpha} production; higher CD4{sup +}CD27{sup -}CD28{sup -} and CD8{sup +}CD27{sup -}CD28{sup -} frequencies; lower CD4{sup +}CD25{sup hi}; and higher FoxP3 expression in CD8{sup +}CD25{sup hi} cells. CMV-specific proliferation correlated with higher IFN{gamma}, TNF{alpha} and IL10 levels and higher CD4{sup +}perforin{sup +} and CD8{sup +}perforin{sup +} frequencies. Decreased proliferation correlated with higher CD4{sup +}CD27{sup -}CD28{sup -} frequencies and TGF{beta}1 production, which also correlated with each other. Anti-TGF{beta}1 neutralizing antibodies restored CMV-specific proliferation in a dose-dependent fashion. In HIV-infected subjects, decreased proliferation correlated with higher CMV-stimulated CD8{sup +}CD25{sup hi} frequencies and their FoxP3 expression. These data indicate that FoxP3- and TGF{beta}1-expressing regulatory T cells contribute to decreased immunity in HAART recipients.

  2. Efficacy and Safety of a Preemptive Antiviral Therapy Strategy Based on Combined Virological and Immunological Monitoring for Active Cytomegalovirus Infection in Allogeneic Stem Cell Transplant Recipients

    PubMed Central

    Navarro, David; Amat, Paula; de la Cámara, Rafael; López, Javier; Vázquez, Lourdes; Serrano, David; Nieto, José; Rovira, Monserrat; Piñana, José Luis; Giménez, Estela; Solano, Carlos

    2016-01-01

    Background. Preemptive antiviral therapy for active cytomegalovirus (CMV) infection in allogeneic stem cell transplant recipients (Allo-SCT) results in overtreatment and a high rate of recurrences. Monitoring of CMV-specific T-cell immunity may help to individualize treatments and minimize these problems. Methods. We conducted a prospective, multicenter, matched comparison-group study to evaluate the efficacy and safety of a novel strategy that consisted of interrupting anti-CMV therapy upon CMV DNAemia clearance and concurrent detection of phosphoprotein 65/immediate-early-1-specific interferon-γ-producing CD8+ T cells at levels of >1 cell/µL (within 30 days after the initiation of therapy). Immunological monitoring was performed on days +7, +14, +21, and +28 after treatment initiation. The primary endpoint was the cumulative incidence of recurrent DNAemia within 2 months after treatment cessation. Secondary endpoints were the length of antiviral treatment courses and the incidence of hematological toxicity. Results. Sixty-one patients were enrolled in the study group. Fifty-six patients were included in the matched-control group. Eleven patients (18%) fulfilled the criteria for antiviral treatment interruption. The cumulative incidence of recurrent CMV DNAemia was significantly lower (P = .02) in these patients than in patients in the comparative groups. Likewise, the length of antiviral treatment courses was significantly shorter in these patients than that in patients in the matched-control group (P = .003). No significant differences in the incidence of hematological toxicity was observed between the comparative groups. Conclusions. Our data support the clinical utility of combining immunological and virological monitoring for the management of CMV infection in a subset of Allo-SCT recipients. PMID:27419179

  3. Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration

    PubMed Central

    1995-01-01

    The presence of natural killer (NK) cells contributes to early defense against murine cytomegalovirus (MCMV) infection. Although NK cells can mediate in vivo protection against MCMV, the mechanism by which they do so has not been defined. The studies presented here evaluate cytokine production by NK cells activated during MCMV infection and the role of NK cell-produced cytokines in early in vivo antiviral defenses. Experiments with normal C57BL/6, T cell-deficient C57BL/6 nude, and severe combined immunodeficient mice lacking T and B cells demonstrated that both interferon gamma (IFN-gamma) and tumor necrosis factor (TNF) production were induced at early times after infection with MCMV. Conditioned media samples prepared with cells from these mice, on day 2 after infection, produced 11-43 pg/million cells of IFN-gamma and 12-19 pg/million cells of TNF as evaluated by specific protein enzyme-linked immunosorbent assays. Studies in the NK- and T cell-deficient mouse line, E26, in mice that had been depleted in vivo of NK cells by treatment with antibodies eliminating NK cells, anti-asialo ganglio-N- tetraosylceramide or anti-NK1.1, and with populations of cells that had been depleted of NK cells by complement treatment with the anti-NK cell antibody, SW3A4, demonstrated that NK cells were solely responsible for the IFN-gamma but were not required for TNF production. The in vivo absence of NK cells was accompanied by increased viral hepatitis and viral replication in both immunocompetent and immunodeficient mice, as well as decreased survival time of immunodeficient mice. In vivo treatments with antibodies neutralizing IFN-gamma demonstrated that this factor contributed to the NK cell-mediated antiviral defense and reduced the measured parameters of viral defense to levels indistinguishable from those observed in NK cell-deficient mice. These effects appeared to be independent of cytolytic activity, as NK cells isolated from anti-IFN-gamma-treated mice mediated

  4. Infection Prophylaxis and Management in Treating Cytomegalovirus (CMV) Infection in Patients With Hematologic Malignancies Previously Treated With Donor Stem Cell Transplant

    ClinicalTrials.gov

    2015-06-03

    Hematopoietic/Lymphoid Cancer; Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Aplastic Anemia; Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Cytomegalovirus Infection; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma

  5. The latent cytomegalovirus decreases telomere length by microcompetition

    PubMed Central

    Javaherian, Adrian

    2015-01-01

    Reduced telomere length has been associated with aging and age-related diseases. Latent infection with the Cytomegalovirus (CMV) induces telomere shortening in the infected cells. Latent CMV infection may cause reduced telomere length via GABP transcription factor deficiency, according to the Microcompetition Theory. Microcompetition and viral-induced transcription factor deficiency is important since most people harbor a latent viral infection.

  6. Cytomegalovirus Infection Leads to Development of High Frequencies of Cytotoxic Virus-Specific CD4+ T Cells Targeted to Vascular Endothelium

    PubMed Central

    Begum, Jusnara; Lal, Neeraj; Zuo, Jianmin; Beggs, Andrew; Moss, Paul

    2016-01-01

    Cytomegalovirus (CMV) infection elicits a very strong and sustained intravascular T cell immune response which may contribute towards development of accelerated immune senescence and vascular disease in older people. Virus-specific CD8+ T cell responses have been investigated extensively through the use of HLA-peptide tetramers but much less is known regarding CMV-specific CD4+ T cells. We used a range of HLA class II-peptide tetramers to investigate the phenotypic and transcriptional profile of CMV-specific CD4+ T cells within healthy donors. We show that such cells comprise an average of 0.45% of the CD4+ T cell pool and can reach up to 24% in some individuals (range 0.01–24%). CMV-specific CD4+ T cells display a highly differentiated effector memory phenotype and express a range of cytokines, dominated by dual TNF-α and IFN-γ expression, although substantial populations which express IL-4 were seen in some donors. Microarray analysis and phenotypic expression revealed a profile of unique features. These include the expression of CX3CR1, which would direct cells towards fractalkine on activated endothelium, and the β2-adrenergic receptor, which could permit rapid response to stress. CMV-specific CD4+ T cells display an intense cytotoxic profile with high level expression of granzyme B and perforin, a pattern which increases further during aging. In addition CMV-specific CD4+ T cells demonstrate strong cytotoxic activity against antigen-loaded target cells when isolated directly ex vivo. PD-1 expression is present on 47% of cells but both the intensity and distribution of the inhibitory receptor is reduced in older people. These findings reveal the marked accumulation and unique phenotype of CMV-specific CD4+ T cells and indicate how such T cells may contribute to the vascular complications associated with CMV in older people. PMID:27606804

  7. The Memory Cytotoxic T-Lymphocyte (CTL) Response to Human Cytomegalovirus Infection Contains Individual Peptide-Specific CTL Clones That Have Undergone Extensive Expansion In Vivo

    PubMed Central

    Weekes, Michael P.; Wills, Mark R.; Mynard, Kim; Carmichael, Andrew J.; Sissons, J. G. Patrick

    1999-01-01

    Human cytomegalovirus (HCMV)-specific CD8+ cytotoxic T lymphocytes (CTL) appear to play an important role in the control of virus replication and in protection against HCMV-related disease. We have previously reported high frequencies of memory CTL precursors (CTLp) specific to the HCMV tegument protein pp65 in the peripheral blood of healthy virus carriers. In some individuals, the CTL response to this protein is focused on only a single epitope, whereas in other virus carriers CTL recognized multiple epitopes which we identified by using synthetic peptides. We have analyzed the clonal composition of the memory CTL response to four of these pp65 epitopes by sequencing the T-cell receptors (TCR) of multiple independently derived epitope-specific CTL clones, which were derived by formal single-cell cloning or from clonal CTL microcultures. In all cases, we have observed a high degree of clonal focusing: the majority of CTL clones specific to a defined pp65 peptide from any one virus carrier use only one or two different TCRs at the level of the nucleotide sequence. Among virus carriers who have the same major histocompatibility complex (MHC) class I allele, we observed that CTL from different donors that recognize the same peptide-MHC complex often used the same Vβ segment, although other TCR gene segments and CDR3 length were not in general conserved. We have also examined the clonal composition of CTL specific to pp65 peptides in asymptomatic human immunodeficiency virus-infected individuals. We have observed a similarly focused peptide-specific CTL response. Thus, the large population of circulating HCMV peptide-specific memory CTLp in virus carriers in fact contains individual CTL clones that have undergone extensive clonal expansion in vivo. PMID:9971792

  8. Inhibition of IKKα by BAY61-3606 Reveals IKKα-Dependent Histone H3 Phosphorylation in Human Cytomegalovirus Infected Cells

    PubMed Central

    Ho, Catherine M. K.; Donovan-Banfield, I’ah Z.; Tan, Li; Zhang, Tinghu; Gray, Nathanael S.; Strang, Blair L.

    2016-01-01

    Protein kinase inhibitors can be used as tools to identify proteins and pathways required for virus replication. Using virus replication assays and western blotting we found that the widely used protein kinase inhibitor BAY61-3606 inhibits replication of human cytomegalovirus (HCMV) strain AD169 and the accumulation of HCMV immediate-early proteins in AD169 infected cells, but has no effect on replication of HCMV strain Merlin. Using in vitro kinase assays we found that BAY61-3606 is a potent inhibitor of the cellular kinase IKKα. Infection of cells treated with siRNA targeting IKKα indicated IKKα was required for efficient AD169 replication and immediate-early protein production. We hypothesized that IKKα was required for AD169 immediate-early protein production as part of the canonical NF-κB signaling pathway. However, although BAY61-3606 inhibited phosphorylation of the IKKα substrate IκBα, we found no canonical or non-canonical NF-κB signaling in AD169 infected cells. Rather, we observed that treatment of cells with BAY61-3606 or siRNA targeting IKKα decreased phosphorylation of histone H3 at serine 10 (H3S10p) in western blotting assays. Furthermore, we found treatment of cells with BAY61-3606, but not siRNA targeting IKKα, inhibited the accumulation of histone H3 acetylation (H3K9ac, H3K18ac and H3K27ac) and tri-methylation (H3K27me3 and H3K36me3) modifications. Therefore, the requirement for IKKα in HCMV replication was strain-dependent and during replication of an HCMV strain requiring IKKα, IKKα-dependent H3S10 phosphorylation was associated with efficient HCMV replication and immediate-early protein production. Plus, inhibition of HCMV replication by BAY61-3606 is associated with acetylation and tri-methylation modifications of histone H3 that do not involve IKKα. PMID:26930276

  9. Salivary shedding of Epstein-Barr virus and cytomegalovirus in people infected or not by human immunodeficiency virus 1.

    PubMed

    de França, Talita Ribeiro Tenório; de Albuquerque Tavares Carvalho, Alessandra; Gomes, Valder Barbosa; Gueiros, Luiz Alcino; Porter, Stephen Ross; Leao, Jair Carneiro

    2012-04-01

    The purpose of this study is to determine the frequency of EBV and CMV DNA detection in saliva of HIV infected and non-HIV individuals and their siblings. The study group comprised 240 individuals. Group 1 comprised of 40 HIV-infected patients, group 2 40 non-HIV individuals, group 3 two siblings for each patient from group 1 (n = 80), and group 4 two siblings for each individual from group 2 (n = 80). Non-stimulated whole saliva was collected, DNA was extracted, and amplification was performed using a nested PCR protocol. EBV and CMV DNA was detected in 7/40 (17.5%) and 5/40 (12.5%) individuals from group 1, 8/40 (20%) and 3/40 (7.5%) from group 2, 11/80 (13.8%) and 2/80 (2.5%) from group 3, and 8/80 (10%) and 1/80 (1.3%) from group 4, respectively. Five (71.4%) out of seven HIV/EBV coinfected individuals of group 1 had a relative also infected with EBV (OR = 11.25, CI [1.75-72.5], p = 0.011). Regarding group 2, among the eight non-HIV and EBV-infected individuals, three (37.5%) had a relative also positive to EBV (p = 0.320). No individual HIV/CMV coinfected had a relative CMV infected (p = 1.00). Also, only one non-HIV and CMV-infected individual had a relative also positive to CMV (p = 0.075). EBV and CMV DNA was detected mainly in those who had HIV viral load counts <400/mL (71%, p = 0.2 and 100%, p = 1, respectively) and those who had CD4 T cells counts between 200 and 400/mm(3) (57%, p = 0.544 and 60%, p = 0.249, respectively). HIV-infected individuals and healthy controls showed a similar frequency of viral DNA detection. EBV DNA was significantly amplified in saliva of household members of HIV/EBV coinfected individuals.

  10. Cytomegalovirus Colitis in Immunocompetent Patients

    PubMed Central

    Hussain, Qulsoom; Shafique, Khurram; Tasleem, Syed H; Hurairah, Abu

    2016-01-01

    Cytomegalovirus colitis is common in immunocompromised patients, but rare in immunocompetent patients. The present study not only represents the colonoscopy and pathological findings, but also applies the method of diagnosing and treating cytomegalovirus colitis in immunocompetent patients. PMID:27980888

  11. Detection of Cytomegalovirus (CMV) Infection in Wheezing Infants by Urine DNA and Serum IgG Testing

    PubMed Central

    Zeng, Zhao-cheng; Chang, Qing; Sun, Zhi-wei; Song, Ming-mei; Jin, Xin-ling; Jiang, Shu-ya; Yang, Xia

    2017-01-01

    Background The aim of this study was to investigate the involvement of CMV infection in wheezing infants and the association between CMV-DNA and immunoglobulins (Igs). Material/Methods A total of 243 wheezing infants and 3,000 parturients were enrolled in this study. The infants were randomly grouped to receive blood HCMV-DNA tests (n=46) or urine HCMV-DNA tests (n=197). Furthermore, all participants had serum CMV-specific IgM and IgG testing. Afterwards, 10 HCMV-IgG positive infants were randomly selected for simultaneous blood and urine HCMV-DNA tests, and 25 HCMV-IgG positive puerperants were randomly selected for urine HCMV-DNA tests. Results The detection rate of urine HCMV-DNA was significantly higher than that of blood HCMV-DNA (67.5% vs. 13.0%, p<0.001). Fifteen (6.2%) and 190 (80.0%) infants showed positive CMV-specific IgM and IgG results (p<0.001), respectively. Among the 10 HCMV-IgG positive infants tested further, only two infants had positive HCMV-DNA blood tests, while all of the 10 infants had positive HCMV-DNA urine tests. However, HCMV-DNA was not detected in the urine of the 25 randomly selected parturients positive for HCMV-IgG. Conclusions CMV infection may be one of the causes of wheezing in infants; CMV infection can be detected by urine-HCMV-DNA and serum HCMV-IgG testing. Infants were more susceptible to CMV infection than parturients. PMID:28283676

  12. Repair of a Mutation Disrupting the Guinea Pig Cytomegalovirus Pentameric Complex Acquired during Fibroblast Passage Restores Pathogenesis in Immune-Suppressed Guinea Pigs and in the Context of Congenital Infection

    PubMed Central

    McVoy, Michael A.; Wang, Jian Ben; Dittmer, Dirk P.; Swanson, Elizabeth C.; Fernández-Alarcón, Claudia; Hernandez-Alvarado, Nelmary; Zabeli, Jason C.

    2016-01-01

    encoding components of the pentameric complex (PC), in particular homologs of human cytomegalovirus (HCMV) proteins UL128, UL130, and UL131A. These mutations can attenuate the course of infection when the virus is reintroduced into animals for vaccine and pathogenesis studies. This study demonstrates that a deletion that arose during the process of tissue culture passage can be repaired, with subsequent restoration of pathogenicity, using BAC-based mutagenesis. Restoration of pathogenicity by repair of a frameshift mutation in GPCMV gene GP129 using this approach provides a valuable genetic platform for future studies using the guinea pig model of congenital CMV infection. PMID:27307567

  13. Infrequency of cytomegalovirus genome in coronary arteriopathy of human heart allografts.

    PubMed Central

    Gulizia, J. M.; Kandolf, R.; Kendall, T. J.; Thieszen, S. L.; Wilson, J. E.; Radio, S. J.; Costanzo, M. R.; Winters, G. L.; Miller, L. L.; McManus, B. M.

    1995-01-01

    In heart transplantation, long-term engraftment success is severely limited by the rapid development of obliterative disease of the coronary arteries. Data from various groups have been suggestive of a pathogenetic role of herpesviruses, particularly human cytomegalovirus, in accelerated allograft coronary artery disease; however, results are not yet conclusive. This study examines the hypothesis that human cytomegalovirus infection of allograft tissues is related pathogenetically and directly to accelerated coronary artery disease. Using in situ DNA hybridization and polymerase chain reaction, we examined particular coronary artery segments from 41 human heart allografts (ranging from 4 days to greater than 4 years after transplantation; mean, 457 days) and 22 donor age- and gender-comparable, coronary site-matched trauma victims for presence of human cytomegalovirus DNA. Human cytomegalovirus genome was detected in 8 of 41 (19.5%) allografts and in 1 of 22 (4.5%) control hearts. This difference in positivity was not statistically significant (P = 0.10). In the human cytomegalovirus-positive hearts, viral genome was localized to perivascular myocardium or coronary artery media or adventitia. Human cytomegalovirus genome was not detected in arterial intima of any allograft or control heart, although human cytomegalovirus genome was readily identified within intima of small pulmonary arteries from lung tissue with human cytomegalovirus pneumonitis. By statistical analyses, the presence of human cytomegalovirus genome was not associated with the nature or digitized extent of transplant arteriopathy, evidence of rejection, allograft recipient or donor serological data suggestive of human cytomegalovirus infection, duration of allograft implantation, or causes of death or retransplantation. Thus, our data indicate a low frequency of detectable human cytomegalovirus genome in accelerated coronary artery disease and do not support a direct role for human cytomegalovirus

  14. Molecular Detection of Human Cytomegalovirus (HCMV) Among Infants with Congenital Anomalies in Khartoum State, Sudan

    PubMed Central

    Ebrahim, Maha G.; Ali, Aisha S.; Mustafa, Mohamed O.; Musa, Dalal F.; El Hussein, Abdel Rahim M.; Elkhidir, Isam M.; Enan, Khalid A.

    2015-01-01

    Human Cytomegalovirus (HCMV) infection still represents the most common potentially serious viral complication in humans and is a major cause of congenital anomalies in infants. This study is aimed to detect HCMV in infants with congenital anomalies. Study subjects consisted of infants born with neural tube defect, hydrocephalus and microcephaly. Fifty serum specimens (20 males, 30 females) were collected from different hospitals in Khartoum State. The sera were investigated for cytomegalovirus specific immunoglobin M (IgM) antibodies using enzyme-linked immunosorbent assay (ELISA), and for Cytomegalovirus DNA using polymerase chain reaction (PCR). Out of the 50 sera tested, one patient’s (2%) sample showed HCMV IgM, but with no detectable DNA, other 4(8.2 %) sera were positive for HCMV DNA but with no detectable IgM. Various diagnostic techniques should be considered to evaluate HCMV disease and routine screening for HCMV should be introduced for pregnant women in this setting. It is vital to initiate further research work with many samples from different area to assess prevalence and characterize HCMV and evaluate its maternal health implications. PMID:26862356

  15. Acute appendicitis due to Cytomegalovirus in an apparently immunocompetent patient: a case report

    PubMed Central

    2014-01-01

    Introduction In healthy subjects, Cytomegalovirus infection can be asymptomatic or manifest as mononucleosis syndrome, but organ disease has also been reported. However, in immunocompromised patients this infection can lead to its most significant and severe disease and even mortality. When Cytomegalovirus causes a gastrointestinal tract infection, it more commonly manifests with luminal tract disease and is usually characterized by ulcerative lesions. Appendicitis is a rare manifestation, and has been reported mainly in human immunodeficiency virus-infected patients or patients with other causes of immunocompromise. Case presentation The authors report on a case of acute primary Cytomegalovirus infection complicated with acute appendicitis due to Cytomegalovirus in an apparently immunocompetent 24-year-old Caucasian man also suffering from primary sclerosing cholangitis and ulcerative colitis. Diagnosis was based on clinical manifestations, serology results, as well as microbiological and histological findings. Treatment consisted of surgery and anti-Cytomegalovirus therapy. Conclusions Cytomegalovirus should be included among the etiologic agents of acute appendicitis in patients with primary sclerosing cholangitis and ulcerative colitis. Currently, there are no definitive data regarding the frequency of Cytomegalovirus appendicitis and the role of anti-Cytomegalovirus treatment in human immunodeficiency virus-negative and apparently immunocompetent subjects. PMID:24612821

  16. Distinctive in vitro effects of T-cell growth cytokines on cytomegalovirus-stimulated T-cell responses of HIV-infected HAART recipients

    SciTech Connect

    Patterson, Julie; Jesser, Renee; Weinberg, Adriana

    2008-08-15

    Functional immune reconstitution is limited after HAART, maintaining the interest in adjunctive immune-modulators. We compared in vitro the effects of the {gamma}-chain T-cell growth cytokines IL-2, IL-4, IL-7 and IL-15 on cytomegalovirus-stimulated cell-mediated immunity. IL-2 and IL-15 increased cytomegalovirus-specific lymphocyte proliferation in HAART recipients, whereas IL-4 and IL-7 did not. The boosting effect of IL-2 and IL-15 on proliferation correlated with their ability to prevent late apoptosis. However, IL-2 increased the frequency of cells in early apoptosis, whereas IL-15 increased the frequency of fully viable cells. Both IL-2 and IL-15 increased cytomegalovirus-induced CD4{sup +} and CD8{sup +} T-cell proliferation and the synthesis of Th1 and pro-inflammatory cytokines and chemokines. However, only IL-2 increased the frequency of regulatory T cells and Th2 cytokine production, both of which have the potential to attenuate antiviral immune responses. Overall, compared to other {gamma}-chain cytokines, IL-15 had the most favorable profile for boosting antiviral cell-mediated immunity.

  17. Dual-color bioluminescent assay using infected HepG2 cells sheds new light on Chlamydia pneumoniae and human cytomegalovirus effects on human cholesterol 7α-hydroxylase (CYP7A1) transcription.

    PubMed

    Michelini, Elisa; Donati, Manuela; Aldini, Rita; Cevenini, Luca; Mezzanotte, Laura; Nardini, Paola; Foschi, Claudio; Zvi, Ido Ben; Cevenini, Monica; Montagnani, Marco; Marangoni, Antonella; Roda, Aldo; Cevenini, Roberto

    2012-11-01

    Chlamydia pneumoniae and human cytomegalovirus (HCMV) are intracellular pathogens able to infect hepatocytes, causing an increase in serum triglycerides and cholesterol levels due to the production of inflammatory cytokines. We investigated whether these pathogens could interfere with cholesterol metabolism by affecting activity of hepatic cholesterol 7α-hydroxylase (CYP7A1) promoter. CYP7A1 is the rate-limiting enzyme responsible for conversion of cholesterol to bile acids, which represents the main route of cholesterol catabolism. A straightforward dual-reporter bioluminescent assay was developed to simultaneously monitor CYP7A1 transcriptional regulation and cell viability in infected human hepatoblastoma HepG2 cells. C. pneumoniae and HCMV infection significantly decreased CYP7A1 promoter activity in a dose-dependent manner, with maximal inhibitions of 33±10% and 32±4%, respectively, at a multiplicity of infection of 1. To support in vitro experiments, serum cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and glucose levels were also measured in Balb/c mice infected with C. pneumoniae. Serum cholesterol and triglycerides also increased in infected mice compared with controls. Although further investigation is required, this work presents the first experimental evidence that C. pneumoniae and HCMV inhibit CYP7A1 gene transcription in the cultured human hepatoblastoma cell line.

  18. Evaluation of a standardised real-time PCR based DNA-detection method (Realstar®) in whole blood for the diagnosis of primary human cytomegalovirus (CMV) infections in immunocompetent patients.

    PubMed

    Berth, M; Benoy, I; Christensen, N

    2016-02-01

    Cytomegalovirus (CMV) DNA detection in blood could, as a supplementary test to serology, improve the accuracy and speed of diagnosis of an acute CMV infection. In this study we evaluated the performance of a commercially available and standardised CMV PCR assay in whole blood for the diagnosis of a primary infection in immunocompetent adults. Moreover, the kinetics of viral DNA was evaluated in order to provide a time frame in which viral DNA could be detected during an acute primary infection. Whole blood samples were collected from 66 patients with an acute CMV infection, 65 patients with an acute Epstein-Barr virus infection, 27 patients with various other acute infections (parvovirus B19, HIV, Toxoplasma gondii), 20 patients with past CMV infections (>1 year) and 20 apparently healthy persons. For CMV DNA detection and quantification a commercially available real-time PCR was applied (RealStar®, altona Diagnostics). The clinical sensitivity of CMV PCR in whole blood for the diagnosis of a recent primary CMV infection was 93.9 % and the diagnostic specificity 99.2 %. In the majority of the patients CMV DNA was not detectable anymore approximately within 4 weeks after the first blood sample was taken. From these data we concluded that, together with a suggestive serological profile, a positive CMV PCR result in whole blood can be regarded as a diagnostic confirmation of a recent CMV infection on a single blood sample in an immunocompetent patient. However, a negative CMV PCR result does not exclude a recent CMV infection.

  19. Diverse immune evasion strategies by human cytomegalovirus.

    PubMed

    Noriega, Vanessa; Redmann, Veronika; Gardner, Thomas; Tortorella, Domenico

    2012-12-01

    Members of the Herpesviridae family have the capacity to undergo both lytic and latent infection to establish a lifelong relationship with their host. Following primary infection, human cytomegalovirus (HCMV) can persist as a subclinical, recurrent infection for the lifetime of an individual. This quiescent portion of its life cycle is termed latency and is associated with periodic bouts of reactivation during times of immunosuppression, inflammation, or stress. In order to exist indefinitely and establish infection, HCMV encodes a multitude of immune modulatory mechanisms devoted to escaping the host antiviral response. HCMV has become a paradigm for studies of viral immune evasion of antigen presentation by both major histocompatibility complex (MHC) class I and II molecules. By restricting the presentation of viral antigens during both productive and latent infection, HCMV limits elimination by the human immune system. This review will focus on understanding how the virus manipulates the pathways of antigen presentation in order to modulate the host response to infection.

  20. Predictive value of human cytomegalovirus (HCMV) T-cell response in the control of HCMV infection by seropositive solid-organ transplant recipients according to different assays and stimuli.

    PubMed

    Gabanti, Elisa; Bruno, Francesca; Scaramuzzi, Lucia; Mangione, Filippo; Zelini, Paola; Gerna, Giuseppe; Lilleri, Daniele

    2016-10-01

    Human cytomegalovirus (HCMV) is still the most common viral infection in solid-organ transplant recipients (SOTR). Our study aimed to identify the predictive values of the T-cell response able to protect from HCMV disease, according to different assays. Viral DNA was determined by real-time PCR. The T-cell immune response to HCMV infection was investigated in SOTR according to the following assays and stimuli: cytokine flow cytometry (CFC) after peripheral blood mononuclear cell (PBMC) stimulation with autologous HCMV-infected dendritic cells (iDC) vs three ELISPOT assays using PBMCs stimulated with: 1. HCMV-infected cell lysate (iCL); 2. a pool of 34 epitopic peptides (PP) from different HCMV proteins; 3. a commercial pp65 peptide pool (CPM). ELISPOT results were normalized to T-cell counts. Overall, 51 SOTR were enrolled: 29 (57%) had low viral load (LVL) self-resolving infections, 19 (37%) high viral load (HVL) infections treated with antiviral drugs, and 3 (6%) tissue-invasive disease (TID). At DNAemia peak, ROC analysis showed that CFC-iDC CD4+ and the ELISPOT-iCL assays yielded overlapping area under the curve (AUC) results. The time needed to reconstitute protective T-cell immunity in SOTR with HVL infections was significantly longer with each assay compared to LVL infections. Using the CFC-iDC assay as a reference test (requiring 7 days to complete), the 24h ELISPOT-iCL assay provides similar results in terms of protection prediction from HCMV infection.

  1. Innate Nuclear Sensor IFI16 Translocates into the Cytoplasm during the Early Stage of In Vitro Human Cytomegalovirus Infection and Is Entrapped in the Egressing Virions during the Late Stage

    PubMed Central

    Dell'Oste, Valentina; Gatti, Deborah; Gugliesi, Francesca; De Andrea, Marco; Bawadekar, Mandar; Lo Cigno, Irene; Biolatti, Matteo; Vallino, Marta; Marschall, Manfred; Gariglio, Marisa

    2014-01-01

    ABSTRACT Intrinsic immune mechanisms mediated by constitutively expressed proteins termed “restriction factors” provide frontline antiviral defense. We recently demonstrated that the DNA sensor IFI16 restricts human cytomegalovirus (HCMV) replication by downregulating viral early and late but not immediate-early mRNAs and their protein expression. We show here that at an early time point during the in vitro infection of low-passage-number human embryonic lung fibroblasts, IFI16 binds to HCMV DNA. However, during a later phase following infection, IFI16 is mislocalized to the cytoplasmic virus assembly complex (AC), where it colocalizes with viral structural proteins. Indeed, upon its binding to pUL97, IFI16 undergoes phosphorylation and relocalizes to the cytoplasm of HCMV-infected cells. ESCRT (endosomal sorting complex required for transport) machinery regulates the translocation of IFI16 into the virus AC by sorting and trafficking IFI16 into multivesicular bodies (MVB), as demonstrated by the interaction of IFI16 with two MVB markers: Vps4 and TGN46. Finally, IFI16 becomes incorporated into the newly assembled virions as demonstrated by Western blotting of purified virions and electron microscopy. Together, these results suggest that HCMV has evolved mechanisms to mislocalize and hijack IFI16, trapping it within mature virions. However, the significance of this IFI16 trapping following nuclear mislocalization remains to be established. IMPORTANCE Intracellular viral DNA sensors and restriction factors are critical components of host defense, which alarm and sensitize immune system against intruding pathogens. We have recently demonstrated that the DNA sensor IFI16 restricts human cytomegalovirus (HCMV) replication by downregulating viral early and late but not immediate-early mRNAs and their protein expression. However, viruses are known to evolve numerous strategies to cope and counteract such restriction factors and neutralize the first line of host

  2. Cytomegalovirus in pregnancy and the neonate

    PubMed Central

    Emery, Vincent C.; Lazzarotto, Tiziana

    2017-01-01

    Congenital cytomegalovirus (CMV) remains a leading cause of disability in children. Understanding the pathogenesis of infection from the mother via the placenta to the neonate is crucial if we are to produce new interventions and provide supportive mechanisms to improve the outcome of congenitally infected children. In recent years, some major goals have been achieved, including the diagnosis of primary maternal CMV infection in pregnant women by using the anti-CMV IgG avidity test and the diagnosis and prognosis of foetal CMV infection by using polymerase chain reaction real-time tests to detect and quantify the virus in amniotic fluid. This review summarises recent advances in our understanding and highlights where challenges remain, especially in vaccine development and anti-viral therapy of the pregnant woman and the neonate. Currently, no therapeutic options during pregnancy are available except those undergoing clinical trials, whereas valganciclovir treatment is recommended for congenitally infected neonates with moderately to severely symptomatic disease. PMID:28299191

  3. [Acute abdomen due to cytomegalovirus in AIDS patients. Apropos 2 cases].

    PubMed

    Ferré, C; Mascaró, J; Benasco, C; Ramos, E; Pérez, J L; Podzamczer, D

    1994-07-09

    Two cases of acute abdomen--because of acute appendicitis and paralytic ileus--due to cytomegalovirus infection in AIDS patients are reported. In both patients evolution was subacute and cytomegalic inclusions were seen in the histologic examination of the surgical samples. The two patients died after surgery. The possibility of cytomegalovirus infection must be kept in mind in AIDS patients who undergo urgent abdominal laparatomy and early treatment should be instituted.

  4. Human immune responses to major human cytomegalovirus glycoprotein complexes.

    PubMed Central

    Liu, Y N; Kari, B; Gehrz, R C

    1988-01-01

    Sera from both human cytomegalovirus (HCMV)-seropositive adults and infants with congenital HCMV infection recognized two major HCMV glycoprotein complexes. However, proliferative responses of peripheral blood mononuclear cells to these complexes varied among seropositive adults and were not detected in any of the infants. Thus, these glycoproteins alone may not be sufficient to develop a subviral HCMV vaccine. Images PMID:2828655

  5. Evaluation of cytomegalovirus (CMV)-specific T-cell immunity for the assessment of the risk of active CMV infection in non-immunosuppressed surgical and trauma intensive care unit patients.

    PubMed

    Clari, María A; Aguilar, Gerardo; Benet, Isabel; Belda, Javier; Giménez, Estela; Bravo, Dayana; Carbonell, José A; Henao, Liliana; Navarro, David

    2013-10-01

    The current study was designed to assess the predictive value of the evaluation of cytomegalovirus (CMV)-specific T-cell immunity early following admission to the intensive care unit for inferring the risk of active CMV infection in non-immunosuppressed surgical and trauma patients. A total of 31 CMV-seropositive patients were included. Patients were screened for the presence of CMV DNA in plasma and in tracheal aspirates by real-time PCR. Enumeration of CMV pp65 and IE-1-specific IFN-γ CD8(+) and CD4(+) T cells was performed by flow cytometry for intracellular cytokine staining. Virological and immunological monitoring was conducted once or twice a week. Active CMV infection occurred in 17 out of 31 patients. Undetectable levels of pp65 and IE-1-specific IFN-γ CD8(+) and CD4(+) T-cell subsets cells were observed in 10 patients who developed active CMV infection and in one who did not (at a median of 2 days following ICU admission). Peak CMV DNA loads in both tracheal aspirates and plasma were substantially higher (P = 0.018 and P = 0.091, respectively) in patients with undetectable IFN-γ T-cell responses than in patients with detectable responses. The expansion of both CMV-specific T-cell subsets following detection of active CMV infection was demonstrated in 9 out of 14 patients with active CMV infection. In conclusion, the evaluation of CMV pp65 and IE-1-specific IFN-γ-producing CD8(+) and CD4(+) T cells early following ICU admission may allow the identification of patients most at risk of either having or developing an episode of active CMV infection, particularly those associated with high-level virus replication.

  6. Reconstitution of Human Cytomegalovirus-Specific CD4+ T Cells is Critical for Control of Virus Reactivation in Hematopoietic Stem Cell Transplant Recipients but Does Not Prevent Organ Infection.

    PubMed

    Gabanti, Elisa; Lilleri, Daniele; Ripamonti, Francesco; Bruno, Francesca; Zelini, Paola; Furione, Milena; Colombo, Anna A; Alessandrino, Emilio P; Gerna, Giuseppe

    2015-12-01

    The relative contribution of human cytomegalovirus (HMCV)-specific CD4(+) and CD8(+) T cells to the control of HCMV infection in hematopoietic stem cell transplant (HSCT) recipients is still controversial. HCMV reactivation and HCMV-specific CD4(+) and CD8(+) T cell reconstitution were monitored for 1 year in 63 HCMV-seropositive patients receiving HSCT. HCMV reactivation was detected in all but 2 patients. In 20 of 63 (31.7%) patients (group 1) HCMV infection resolved spontaneously, whereas 32 of 63 (50.8%) patients (group 2) controlled the infection after a single short-course of pre-emptive therapy and the remaining 9 (14.3%) patients (group 3) suffered from relapsing episodes of HCMV infection, requiring multiple courses of antiviral therapy. The kinetics and magnitude of HCMV-specific CD8(+) T cell reconstitution were comparable among the 3 groups, but HCMV-specific CD4(+) T cells were lower in number in patients requiring antiviral treatment. HCMV-seronegative donors, as well as unrelated donors (receiving antithymocyte globulin) and acute graft-versus-host disease (GVHD) were associated with both delayed HCMV-specific CD4(+) T cell reconstitution and severity of infection. Conversely, these risk factors had no impact on HCMV-specific CD8(+) T cells. Eight patients with previous GVHD suffered from HCMV gastrointestinal disease, although in the presence of HCMV-specific CD4(+) and CD8(+) systemic immunity and undetectable HCMV DNA in blood. Reconstitution of systemic HCMV-specific CD4(+) T cell immunity is required for control of HCMV reactivation in adult HSCT recipients, but it may not be sufficient to prevent late-onset organ localization in patients with GVHD. HCMV-specific CD8(+) T cells contribute to control of HCMV infection, but only after HCMV-specific CD4(+) T cell reconstitution.

  7. Killer-cell immunoglobulin-like receptors and cytomegalovirus reactivation during late pregnancy.

    PubMed

    Alvarado-Hernández, D L; Benítez-Sánchez, A; Rodríguez-Cuevas, J S; Rosales-Saavedra, T; Guerra-Palomares, S E; Comas-García, A; Noyola, D E; García-Sepúlveda, C A

    2016-08-01

    Human cytomegalovirus (CMV) represents an important public health concern as it is associated with severe morbidity and mortality in transplant recipients, HIV-infected individuals and pregnant women given the risk of congenital infection. Congenital CMV is a leading cause of neurological sequelae, developmental delay and birth defects worldwide. Cytomegalovirus can be transmitted to the foetus following maternal infection or reactivation. NK cells expressing killer-cell immunoglobulin-like receptors (KIR) are part of the innate immune system and the first line of defence against viral incursions. Previous reports have shown that KIR genes are associated with CMV infections in the post-transplant setting. In this study, we set out to determine whether a protective effect of KIR genes over CMV infection is seen in Mexican pregnant women. Cytomegalovirus infection was assessed through nucleic acid testing in 200 pregnant women and 600 healthy blood donors comprising the Mexican mestizo reference population. Killer-cell immunoglobulin-like receptors and HLA-C genotypes were obtained from 200 pregnant women and 300 reference samples using a comprehensive PCR-SSP approach. We observed statistically lower carrier frequencies of cB03|tA01 gene-content haplotype, of cB03 haplotype motif, of the KIR2DL5 + 2DS3/2DS5 gene pair and of KIR2DL5 amongst CMV-positive pregnant women in comparison with those CMV negative. None of these were associated with CMV status in the reference population. Logistic regression analysis revealed that the most important factor determining CMV status during third-trimester pregnancies was the KIR2DL5 + 2DS3/2DS5 gene pair (OR 0.376 (95%CI 0.174, 0.811, P = 0.013). Our results indicate that CMV-protective KIR gene associations described in Caucasoid populations are also present in the genetically distinct Mexican mestizo population. Our results suggest that certain KIR gene combinations provide protection against CMV infections occurring

  8. Cytomegalovirus myelitis in perinatally acquired HIV.

    PubMed Central

    Güngör, T; Funk, M; Linde, R; Jacobi, G; Horn, M; Kreuz, W

    1993-01-01

    A 7 year old child perinatally infected with HIV who died from progressive muscular paralysis and central nervous respiratory failure is described. Cytomegalovirus (CMV) prophylaxis with a special intravenous CMV hyper-immunoglobulin had been successfully conducted for more than four years. Macroscopic and microscopic immunohistochemical examination of the spinal cord revealed a diffuse CMV infiltration of the entire myelon. CMV infected cells were identified as astrocytes, oligodendrocytes, neurons, macrophages, ependymal, endothelial, and Schwann cells. Other organs had no signs of CMV infection. Central nervous spinal CMV infection was most probably due to insufficient penetration of the blood-brain barrier by the CMV hyper-immunoglobulin. In suspicious cases early spinal magnetic resonance imaging (1.5 tesla) combined with an examination of urine and cerebrospinal fluid for CMV is recommended. Images Figure 1 Figure 2 Figure 3 PMID:8385439

  9. Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2)

    ClinicalTrials.gov

    2016-04-13

    Acquired Immunodeficiency Syndrome; Lung Diseases; Cardiovascular Diseases; Heart Diseases; Heart Failure; HIV Infections; Cytomegalovirus Infections; Pneumocystis Carinii Infections; Ebstein-Barr Virus Infections

  10. Sensitivity of the Cytomegalovirus Antigenemia Assay to Diagnose Cytomegalovirus Retinitis

    PubMed Central

    Lee, Joo Yong; Chong, Yong Phil; Sung, Heungsup; Lee, Sang-Oh; Choi, Sang-Ho; Kim, Yang Soo; Woo, Jun Hee

    2016-01-01

    Background Cytomegalovirus (CMV) retinitis is one of the most important tissue-invasive CMV diseases in immunocompromised patients. Since 1980, non-invasive diagnostic methods, notably the CMV antigenemia assay, have been widely used as adjunct tests to diagnose tissue-invasive CMV diseases. However, there are limited data on the diagnostic value of the CMV antigenemia assay for diagnosing CMV retinitis. Materials and Methods We performed a retrospective review of all cases of CMV retinitis at Asan Medical Center, Seoul, South Korea over a 9-year period. The diagnosis of CMV retinitis was made by experienced ophthalmologists according to medical history and an ophthalmoscopic appearance of typical retinopathy, together with absence of an alternative diagnosis. Results We analyzed 44 patients with CMV retinitis (affecting 57 eyes) for whom the CMV antigenemia assay was performed. Of the 44 patients, 31 (70%) were HIV-uninfected and 13 (30%) were HIV-infected. The overall sensitivity of the CMV antigenemia assay was 66% (95% confidence interval [CI] 50–80%). The test’s sensitivity showed a non-significant trend towards being higher in HIV-infected patients than in HIV-uninfected patients (sensitivity 85% vs 58%, respectively, P = 0.16). In a subgroup analysis of the 35 patients without other concurrent tissue-invasive CMV disease, the sensitivity of the CMV antigenemia assay was 57% (95% CI 40–74%). Conclusions The CMV antigenemia assay has limited value as a non-invasive diagnostic adjunct test for CMV retinitis. Therefore, the results of the assay need to be interpreted in the context of underlying disease, clinical presentation, and ophthalmoscopic findings. PMID:27883376

  11. Detection of Human Cytomegalovirus pp67 Late Gene Transcripts in Cerebrospinal Fluid of Human Immunodeficiency Virus Type 1-Infected Patients by Nucleic Acid Sequence-Based Amplification

    PubMed Central

    Zhang, Fan; Tetali, Surya; Wang, Xue Ping; Kaplan, Mark H.; Cromme, Frans V.; Ginocchio, Christine C.

    2000-01-01

    This study examined the clinical correlation between the presence of human cytomegalovirus (HCMV) pp67 mRNA in cerebrospinal fluid (CSF) and active HCMV central nervous system (CNS) disease in patients with human immunodeficiency virus type 1 (HIV-1). In total, 76 CSF specimens collected from 65 HIV-1-positive patients diagnosed with HCMV CNS disease, other non-HCMV-related CNS diseases, or no CNS disease were tested for the presence of HCMV pp67 mRNA using the NucliSens cytomegalovirus (CMV) pp67 assay (Organon Teknika, Durham, N.C.). The results were compared to those of a nested PCR for the detection of HCMV glycoprotein B DNA and to those obtained by viral culture (54 samples). CSF specimens collected from patients without HCMV CNS disease yielded the following results: pp67 assay negative, 62 of 62 specimens; culture negative, 41 of 41 specimens; and PCR negative, 56 of 62 specimens (6 specimens were positive). CSF specimens collected from patients with HCMV CNS disease yielded the following results: pp67 assay positive, 9 of 13 specimens; PCR positive, 13 of 13 specimens; and culture positive, 2 of 13 specimens. After resolution of the discordant results, the following positive and negative predictive values (PPV and NPV, respectively) for the diagnosis of HCMV CNS disease were determined. The PPV for PCR, pp67 assay, and culture were 68.4, 100, and 100%, respectively, and the NPV for PCR, pp67 assay, and culture were 100, 97.0, and 82.7%, respectively. The sensitivities for DNA PCR, pp67 assay, and culture for the detection of HCMV were 100, 84.6, and 18%, respectively, and the clinical specificities were 90.5, 100, and 100%, respectively. This study indicates that the detection of HCMV pp67 mRNA in CSF has good correlation with active HCMV CNS disease, whereas CSF culture is insensitive and qualitative DNA PCR may detect latent nonreplicating virus in CSF from patients without HCMV CNS disease. PMID:10790122

  12. Detection of human cytomegalovirus pp67 late gene transcripts in cerebrospinal fluid of human immunodeficiency virus type 1-infected patients by nucleic acid sequence-based amplification.

    PubMed

    Zhang, F; Tetali, S; Wang, X P; Kaplan, M H; Cromme, F V; Ginocchio, C C

    2000-05-01

    This study examined the clinical correlation between the presence of human cytomegalovirus (HCMV) pp67 mRNA in cerebrospinal fluid (CSF) and active HCMV central nervous system (CNS) disease in patients with human immunodeficiency virus type 1 (HIV-1). In total, 76 CSF specimens collected from 65 HIV-1-positive patients diagnosed with HCMV CNS disease, other non-HCMV-related CNS diseases, or no CNS disease were tested for the presence of HCMV pp67 mRNA using the NucliSens cytomegalovirus (CMV) pp67 assay (Organon Teknika, Durham, N.C.). The results were compared to those of a nested PCR for the detection of HCMV glycoprotein B DNA and to those obtained by viral culture (54 samples). CSF specimens collected from patients without HCMV CNS disease yielded the following results: pp67 assay negative, 62 of 62 specimens; culture negative, 41 of 41 specimens; and PCR negative, 56 of 62 specimens (6 specimens were positive). CSF specimens collected from patients with HCMV CNS disease yielded the following results: pp67 assay positive, 9 of 13 specimens; PCR positive, 13 of 13 specimens; and culture positive, 2 of 13 specimens. After resolution of the discordant results, the following positive and negative predictive values (PPV and NPV, respectively) for the diagnosis of HCMV CNS disease were determined. The PPV for PCR, pp67 assay, and culture were 68.4, 100, and 100%, respectively, and the NPV for PCR, pp67 assay, and culture were 100, 97.0, and 82. 7%, respectively. The sensitivities for DNA PCR, pp67 assay, and culture for the detection of HCMV were 100, 84.6, and 18%, respectively, and the clinical specificities were 90.5, 100, and 100%, respectively. This study indicates that the detection of HCMV pp67 mRNA in CSF has good correlation with active HCMV CNS disease, whereas CSF culture is insensitive and qualitative DNA PCR may detect latent nonreplicating virus in CSF from patients without HCMV CNS disease.

  13. Rationally designed chemokine-based toxin targeting the viral G protein-coupled receptor US28 potently inhibits cytomegalovirus infection in vivo

    PubMed Central

    Spiess, Katja; Jeppesen, Mads G.; Malmgaard-Clausen, Mikkel; Krzywkowski, Karen; Dulal, Kalpana; Cheng, Tong; Hjortø, Gertrud M.; Larsen, Olav; Burg, John S.; Jarvis, Michael A.; Christopher Garcia, K.; Zhu, Hua; Kledal, Thomas N.; Rosenkilde, Mette M.

    2015-01-01

    The use of receptor–ligand interactions to direct toxins to kill diseased cells selectively has shown considerable promise for treatment of a number of cancers and, more recently, autoimmune disease. Here we move the fusion toxin protein (FTP) technology beyond cancer/autoimmune therapeutics to target the human viral pathogen, human cytomegalovirus (HCMV), on the basis of its expression of the 7TM G protein-coupled chemokine receptor US28. The virus origin of US28 provides an exceptional chemokine-binding profile with high selectivity and improved binding for the CX3C chemokine, CX3CL1. Moreover, US28 is constitutively internalizing by nature, providing highly effective FTP delivery. We designed a synthetic CX3CL1 variant engineered to have ultra-high affinity for US28 and greater specificity for US28 than the natural sole receptor for CX3CL1, CX3CR1, and we fused the synthetic variant with the cytotoxic domain of Pseudomonas Exotoxin A. This novel strategy of a rationally designed FTP provided unparalleled anti-HCMV efficacy and potency in vitro and in vivo. PMID:26080445

  14. Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients. The Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.

    PubMed

    Ljungman, P; Deliliers, G L; Platzbecker, U; Matthes-Martin, S; Bacigalupo, A; Einsele, H; Ullmann, J; Musso, M; Trenschel, R; Ribaud, P; Bornhäuser, M; Cesaro, S; Crooks, B; Dekker, A; Gratecos, N; Klingebiel, T; Tagliaferri, E; Ullmann, A J; Wacker, P; Cordonnier, C

    2001-01-15

    A retrospective study was performed to collect information regarding efficacy and toxicity of cidofovir (CDV) in allogeneic stem cell transplant patients. Data were available on 82 patients. The indications for therapy were cytomegalovirus (CMV) disease in 20 patients, primary preemptive therapy in 24 patients, and secondary preemptive therapy in 38 patients. Of the patients, 47 had received previous antiviral therapy with ganciclovir, foscarnet, or both drugs. The dosage of CDV was 1 to 5 mg/kg per week followed by maintenance every other week in some patients. The duration of therapy ranged from 1 to 134 days (median, 22 days). All patients received probenecid and prehydration. Ten of 20 (50%) patients who were treated for CMV disease (9 of 16 with pneumonia) responded to CDV therapy, as did 25 of 38 (66%) patients who had failed or relapsed after previous preemptive therapy and 15 of 24 (62%) patients in whom CDV was used as the primary preemptive therapy. Of the patients, 21 (25.6%) developed renal toxicity that remained after cessation of therapy in 12 patients. Fifteen patients developed other toxicities that were potentially due to CDV or the concomitantly given probenecid. No toxicity was seen in 45 (61.6%) patients. Cidofovir can be considered as second-line therapy in patients with CMV disease failing previous antiviral therapy. However, additional studies are needed before CDV can be recommended for preemptive therapy.

  15. Male genital tract chlamydial infection: implications for pathology and infertility.

    PubMed

    Cunningham, Kelly A; Beagley, Kenneth W

    2008-08-01

    Chlamydia trachomatis infections are prevalent worldwide, but current research, screening, and treatment are focused on females, with the burden of disease and infertility sequelae considered to be a predominantly female problem. The prevalence of chlamydial infection, however, is similar in males and females. Furthermore, a role for this pathogen in the development of male urethritis, epididymitis, and orchitis is widely accepted. The role of Chlamydia in the development of prostatitis is controversial, but we suggest that Chlamydia is an etiological agent, with incidences of up to 39.5% reported in patients with prostatitis. Infection of the testis and prostate is implicated in a deterioration of sperm, possibly affecting fertility. Chlamydia infections also may affect male fertility by directly damaging the sperm, because sperm parameters, proportion of DNA fragmentation, and acrosome reaction capacity are impaired with chlamydial infection. Furthermore, the proportion of male partners of infertile couples with evidence of a Chlamydia infection is greater than that documented in the general population. An effect of male chlamydial infection on the fertility of the female partner also has been reported. Thus, the need for a vaccine to protect both males and females is proposed. The difficulty arises because the male reproductive tract is an immune-privileged site that can be disrupted, potentially affecting spermatogenesis, if inappropriate inflammatory responses are provoked. Examination of responses to infection in humans and in experimental animal models suggest that an immunoglobulin A-inducing vaccine will be able to target the male reproductive tract effectively while avoiding harmful inflammatory responses that may impair fertility.

  16. Intracellular Trafficking of the Human Cytomegalovirus-Encoded 7-trans-Membrane Protein Homologs pUS27 and pUL78 during Viral Infection: A Comparative Analysis

    PubMed Central

    Niemann, Ina; Reichel, Anna; Stamminger, Thomas

    2014-01-01

    Human cytomegalovirus (HCMV) encodes four G protein-coupled receptor (GPCR) homologs, termed pUS27, pUS28, pUL33, and pUL78. In contrast to the extensively characterized vGPCRs pUS28 and pUL33, knowledge concerning pUS27 and pUL78 is limited. Previous studies already demonstrated constitutive internalization of pUS27 and pUL78, as well as an association with the endosomal machinery, however, these results were mainly obtained using transiently transfected cells. To explore the subcellular localization of both receptors during viral infection, we constructed recombinant HCMVs expressing tagged vGPCRs. Colocalization analyses revealed a predominant association of pUS27 or pUL78 with the trans-Golgi network or the endoplasmic reticulum, respectively. Intriguingly, our data emphasize that protein sorting is highly regulated by viral functions as we detected dramatic changes in the colocalization of pUS27 and pUL78 with endosomal markers during progression of HCMV replication. Furthermore, we observed cell type-dependent differences in trafficking of both vGPCRs between fibroblasts and epithelial cells. Most importantly, infection experiments with a recombinant HCMV carrying tagged versions of pUS27 and pUL78 simultaneously, revealed that these two proteins do not colocalize during viral infection. This contrasts to results of transient expression experiments. In conclusion, our results highlight the importance to investigate vGPCR trafficking in a viral context. PMID:24517969

  17. Epstein-Barr and cytomegalovirus DNA salivary shedding correlate with long-term plasma HIV RNA detection in HIV-infected men who have sex with men.

    PubMed

    Scaggiante, Renzo; Andreis, Samantha; Basso, Monica; Franchin, Elisa; Franzetti, Marzia; Del Vecchio, Claudia; Torti, Carlo; Mengoli, Carlo; Cruciani, Mario; Sarmati, Loredana; Palù, Giorgio; Parisi, Saverio Giuseppe

    2016-07-01

    The aim of the study was to evaluate cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNA salivary shedding in HIV-positive men who have sex with men (MSM) and to determine whether viro-immunological parameters and long-term (24 months) plasma HIV RNA (pHIV) detection may predict herpesviruses replication. A total of 193 HIV-positive MSM were consecutively recruited (mean CD4+ cell count 607 cells/mm(3) and mean nadir value 333 cells/mm(3) ); pHIV was analyzed for 24 months prior to saliva sampling: patients were categorized as successfully suppressed (SS) and not suppressed (NS). The EBV viral load was categorized as high viral load (HVL), intermediate (IVL), or low (LVL), CMV DNA as positive or negative. NS patients experienced both herpesviruses detectability more frequently respect to SS patients (P = 0.034); conversely, no salivary shedding was more frequent in SS patients (P = 0.014). HVL EBV was more frequent in NS patients than in SS subjects (P = 0.038 for isolated EBV detection and P = 0.001 when CMV shedding was associated). NS subjects with HVL EBV had a median pHIV of 43,820 copies/ml, significantly higher respect to IVL and LVL patients (P = 0.027 and P = 0.0005, respectively). CMV shedding was mostly associated to EBV shedding. NS patients showed a significantly higher frequency of saliva HVL EBV detection compared to SS patients; moreover, NS patients with HVL EBV had a higher pHIV respect to those with IVL and LVL shedding. Our results suggest that a successful pHIV suppression could reduce the burden of salivary EBV replication and likely the risk of herpesviruses-related cancers.

  18. Characterization of Cytomegalovirus Disease in Solid Organ Transplant Recipients by Markers of Inflammation in Plasma

    PubMed Central

    Rollag, Halvor; Ueland, Thor; Åsberg, Anders; Hartmann, Anders; Jardine, Alan G.; Humar, Atul; Pescovitz, Mark D.; Bignamini, Angelo A.; Aukrust, Pål

    2013-01-01

    Background While several studies have examined the general inflammatory responses in relation to cytomegalovirus infection, the identification of the various inflammatory mediators as well as their relative importance is far from clear. Patients and Methods Solid organ recipients enrolled in an international multicenter trial of cytomegalovirus disease treatment (the VICTOR study) were analyzed (n = 289) (ClinicalTrials.gov NCT00431353). Plasma markers of inflammation and endothelial cell activation were assessed at baseline by enzyme immunoassays. Results The major findings were: (i) Plasma levels of the CXC-chemokine interferon-inducible protein-10 (P<0.001) and C-reactive protein (P = 0.046) were independently associated with the presence of cytomegalovirus DNAemia above lower level of quantification. (ii) High levels of CC-chemokine ligand 21 (P = 0.027) and pentraxin 3 (P = 0.033) were independently associated with tissue invasive cytomegalovirus disease as opposed to cytomegalovirus syndrome. Conclusion Our findings illustrate the complex interaction between cytomegalovirus and the immune system, involving a wide range of inflammatory mediators that could be associated to disease manifestations in cytomegalovirus related disease. PMID:23593305

  19. Acute exercise preferentially redeploys NK-cells with a highly-differentiated phenotype and augments cytotoxicity against lymphoma and multiple myeloma target cells. Part II: impact of latent cytomegalovirus infection and catecholamine sensitivity.

    PubMed

    Bigley, Austin B; Rezvani, Katayoun; Pistillo, Mira; Reed, Justin; Agha, Nadia; Kunz, Hawley; O'Connor, Daniel P; Sekine, Takuya; Bollard, Catherine M; Simpson, Richard J

    2015-10-01

    We showed previously that acute exercise is associated with a preferential redeployment of highly-differentiated NK-cells and increased cytotoxicity against HLA-expressing tumor cell lines during exercise recovery. In this part II study, we retrospectively analyzed these findings in the context of latent cytomegalovirus (CMV) infection and performed additional experiments to explore potential mechanisms underpinning the marked reduction in NK-cell redeployment with exercise in CMV-seropositive individuals. We show here that latent CMV infection impairs NK-cell mobilization with exercise, only when the intensity of the exercise bout exceeds the individual blood lactate threshold (BLT). This impaired mobilization is associated with increased proportions of poorly exercise-responsive NK-cell subsets (NKG2C+/KIR-, NKG2C+/NKG2A-, and NKG2C+/CD57+) and decreased NK-cell β(2)-adrenergic receptor (AR) expression in those with CMV. As a result, NK-cell production of cyclic AMP (cAMP) in response to in vitro isoproterenol (synthetic β-agonist) stimulation was drastically lower in those with CMV (6.0 vs. 20.3pmol/mL, p<0.001) and correlated highly with the proportion of NKG2C+/CD57+ NK-cells (R(2)=0.97). Moreover, NK-cell cytotoxic activity (NKCA) against the K562 (36.6% vs. 22.7%, p<0.05), U266 (23.6% vs. 15.9%, p<0.05), and 221.AEH (41.3% vs. 13.3%, p<0.001) cell lines was increased at baseline in those infected with CMV; however, latent CMV infection abated the post-exercise increase in NKCA as a result of decreased NK-cell mobilization. Additionally, NKCA per cell against the U266 (0.24 vs. 0.12, p<0.01), RPMI-8226 (0.17 vs. 0.11, p<0.05), and 221.AEH (0.18 vs. 0.11, p<0.05) cell lines was increased 1h post-exercise (relative to baseline) in CMV-seronegative subjects, but not in those infected with CMV. Collectively, these data indicate that latent CMV infection may compromise NK-cell mediated immunosurveillance after acute exercise due to an increased proportion of

  20. Upregulation of functionally active vascular endothelial growth factor by human cytomegalovirus.

    PubMed

    Reinhardt, Barbara; Schaarschmidt, Peter; Bossert, Andrea; Lüske, Anke; Finkenzeller, Günter; Mertens, Thomas; Michel, Detlef

    2005-01-01

    Human cytomegalovirus (HCMV) infection is known to modulate host gene expression and has been linked to the pathogenesis of vasculopathies; however, relevant pathomechanisms are still unclear. It was shown that HCMV infection leads to upregulation of vascular endothelial growth factor (VEGF) expression in human foreskin fibroblasts and coronary artery smooth muscle cells (SMC). Activation of VEGF transcription by HCMV infection was confirmed by transient-expression experiments, which revealed that a short promoter fragment, pLuc135 (-85 to +50), is sufficient for activation. Site-directed mutagenesis of Sp1-recognition sites within this fragment abolished the upregulation of transcription. Functional VEGF protein is released into the culture supernatant of infected SMC. Incubation of endothelial cells with supernatants from HCMV-infected SMC cultures induced upregulation of VEGF receptor-2 expression on endothelial cells, as well as a significant upregulation of DNA synthesis, implicating cell proliferation. The mean incline of DNA synthesis at 48 and 72 h post-infection was 148 and 197 %, respectively. Addition of neutralizing antibodies against VEGF completely abolished this effect. Supernatants from SMC cultures incubated with UV-inactivated virus induced a comparable effect. This virus-induced paracrine effect may represent a molecular mechanism for HCMV-induced pathogenesis, such as inflammatory vasculopathies, by inducing a proatherogenic phenotype in SMC.

  1. Cytomegalovirus protease targeted prodrug development.

    PubMed

    Sabit, Hairat; Dahan, Arik; Sun, Jing; Provoda, Chester J; Lee, Kyung-Dall; Hilfinger, John H; Amidon, Gordon L

    2013-04-01

    Human cytomegalovirus (HCMV) is a prevalent virus that infects up to 90% of the population. The goal of this research is to determine if small molecular prodrug substrates can be developed for a specific HCMV encoded protease and thus achieve site-specific activation. HCMV encodes a 256 amino acid serine protease that is responsible for capsid assembly, an essential process for herpes virus production. The esterase activity of the more stable HCMV A143T/A144T protease mutant was evaluated with model p-nitrophenol (ONp) esters, Boc-Xaa-ONp (Ala, Leu, Ile, Val, Gln, Phe at the Xaa position). We demonstrate that the A143T/A144T mutant has esterase activity toward specific small ester compounds, e.g., Boc-L-Ala-ONp. Mono amino acid and dipeptide prodrugs of ganciclovir (GCV) were also synthesized and evaluated for hydrolysis by the A143T/A144T protease mutant in solution. Hydrolysis of these prodrugs was also evaluated in Caco-2 cell homogenates, human liver microsomes (HLMs), and rat and human plasma. For the selectivity potential of the prodrugs, the hydrolysis ratio was evaluated as a percentage of prodrug hydrolyzed by the HCMV protease over the percentages of prodrug hydrolyses by Caco-2 cell homogenates, HLMs, and human/rat plasma. A dipeptide prodrug of ganciclovir, Ac-l-Gln-l-Ala-GCV, emerged as a potential selective prodrug candidate. The results of this research demonstrate that targeting prodrugs for activation by a specific protease encoded by the infectious HCMV pathogen may be achievable.

  2. Hepatitis E virus infection: Epidemiology and treatment implications

    PubMed Central

    Lee, Ga Young; Poovorawan, Kittiyod; Intharasongkroh, Duangnapa; Sa-nguanmoo, Pattaratida; Vongpunsawad, Sompong; Chirathaworn, Chintana; Poovorawan, Yong

    2015-01-01

    Hepatitis E virus (HEV) infection is now established as an emerging enteric viral hepatitis. Standard treatments in acute and chronic hepatitis E remain to be established. This study undertakes a review of the epidemiology, treatment implication and vaccine prevention from published literature. HEV infection is a worldwide public health problem and can cause acute and chronic hepatitis E. HEV genotypes 1 and 2 are primarily found in developing countries due to waterborne transmission, while the zoonotic potential of genotypes 3 and 4 affects mostly industrialized countries. An awareness of HEV transmission through blood donation, especially in the immunocompromised and solid organ transplant patients, merits an effective anti-viral therapy. There are currently no clear indications for the treatment of acute hepatitis E. Despite concerns for side effects, ribavirin monotherapy or in combination with pegylated interferon alpha for at least 3 mo appeared to show significant efficacy in the treatment of chronic hepatitis E. However, there are no available treatment options for specific patient population groups, such as women who are pregnant. Vaccination and screening of HEV in blood donors are currently a global priority in managing infection. New strategies for the treatment and control of hepatitis E are required for both acute and chronic infections, such as prophylactic use of medications, controlling large outbreaks, and finding acceptable antiviral therapy for pregnant women and other patient groups for whom the current options of treatment are not viable. PMID:26568916

  3. Murine cytomegalovirus regulation of NKG2D ligands.

    PubMed

    Lenac, Tihana; Arapović, Jurica; Traven, Luka; Krmpotić, Astrid; Jonjić, Stipan

    2008-06-01

    Human cytomegalovirus (HCMV) is a ubiquitous pathogen that causes morbidity risk in immunologically suppressed and immunodeficient patients including congenital infections. Approaches to curb the consequences of HCMV infections are restricted by a lack of complete understanding of viral pathogenesis. The infection of mice with murine cytomegalovirus (MCMV) as a model of HCMV infection has been particularly useful in elucidating the role of innate and adaptive immune response mechanisms. A large number of cytomegalovirus genes modulate the innate and the adaptive host immune response. The products of several MCMV genes are involved in subverting the natural killer (NK) cell response by down-modulating cellular ligands for the NKG2D receptor expressed on NK cells and CD8(+) T cells. Mutant viruses lacking these immunoevasion genes are attenuated with respect to virus growth in vivo. Given the importance of the NKG2D receptor in controlling both NK- and T cell-mediated immunity, it is of tremendous importance to understand the molecular mechanisms and consequences of viral regulation of the NKG2D ligands.

  4. Cytomegalovirus (For Parents)

    MedlinePlus

    ... poop). It also can be present in blood products and donated organs, causing infection after a blood transfusion or organ transplantation. Diagnosis & Treatment Doctors can diagnose the infection by taking a culture from a person's throat, urine, blood, or other ...

  5. A case report of small bowel perforation secondary to cytomegalovirus related immune reconstitution inflammatory syndrome in an AIDS patient.

    PubMed

    Gutiérrez-Delgado, Eva María; Villanueva-Lozano, Hiram; García Rojas-Acosta, Miguel J; Miranda-Maldonado, Ivett C; Ramos-Jiménez, Javier

    2017-01-01

    Non-traumatic small bowel perforation is rare in adults but carries a high morbidity and mortality. The diagnosis is made on clinical suspicion, and the most common causes in developing countries are infectious diseases, being cytomegalovirus infection in immunocompromised patients the main etiology. We describe a patient with a recently diagnosed advanced stage HIV infection and an intestinal perforation associated with cytomegalovirus immune reconstitution inflammatory syndrome after highly active antiretroviral therapy initiation.

  6. The immune reconstitution after an allogeneic stem cell transplant correlates with the risk of graft-versus-host disease and cytomegalovirus infection.

    PubMed

    Torelli, Giovanni F; Lucarelli, Barbarella; Iori, Anna P; De Propris, Maria S; Capobianchi, Angela; Barberi, Walter; Valle, Veronica; Iannella, Emilia; Natalino, Fiammetta; Mercanti, Caterina; Perrone, Salvatore; Gentile, Giuseppe; Guarini, Anna; Foà, Robin

    2011-08-01

    Aim of the study was to correlate the clinical outcome of eighteen patients who have undergone an allogeneic stem cell transplant (SCT) with the concentration in the peripheral blood (PB) of lymphocyte subpopulations evaluated at 1 year from transplant. The occurrence of acute GVHD and CMV infection correlated with the concentration of Tregs in the PB; CMV infection also correlated with the content of NK cells. The obtained results document that the concentration of Tregs in the PB after an allogeneic SCT may protect from GVHD and from CMV infection; the potential anti-viral role of NK cells is confirmed.

  7. Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

    SciTech Connect

    Dumortier, Jerome; Streblow, Daniel N.; Moses, Ashlee V.; Jacobs, Jon M.; Kreklywich, Craig N.; Camp, David G.; Smith, Richard D.; Orloff, Susan L.; Nelson, Jay

    2008-07-01

    Human cytomegalovirus (HCMV) is implicated in the acceleration of a number of vascular diseases including transplant vascular sclerosis (TVS), the lesion associated with chronic rejection (CR) of solid organ transplants. Although the virus persists in the allograft throughout the course of disease, few cells are directly infected by CMV. This observation is in contrast to the global effects that CMV has on the acceleration of TVS/CR, suggesting that CMV infection indirectly promotes the vascular disease process. Recent transcriptome analysis of CMV-infected heart allografts indicates that the virus induces cytokines and growth factors associated with angiogenesis (AG) and wound healing (WH), suggesting that CMV may accelerate TVS/CR through the induction and secretion of AG/WH factors from infected cells. We analyzed virus-free supernatants from HCMV-infected cells (HCMV secretomes) for growth factors, by mass spectrometry and immunoassays, and found that the HCMV secretome contains over 1,000 cellular proteins, many of which are involved in AG/WH. Importantly, functional assays demonstrated that CMV but not herpes simplex virus secretomes not only induce AG/WH but also promote neovessel stabilization and endothelial cell survival for 2 weeks. These findings suggest that CMV acceleration of TVS occurs through virus-induced growth factors and cytokines in the CMV secretome.

  8. Seronegative occult hepatitis C virus infection: clinical implications.

    PubMed

    Carreño, Vicente

    2014-11-01

    Occult hepatitis C virus infection (OCI) was first described in anti-HCV and serum HCV-RNA negative patients with abnormal values of liver enzymes but who presented HCV-RNA in liver and in peripheral blood mononuclear cells. Up to now, two types of OCI are recognized: seronegative OCI (anti-HCV and serum HCV-RNA negative) and seropositive OCI (anti-HCV positive and serum HCV-RNA negative). The concept of OCI is still a matter of debate, probably because both types of OCI are not considered as different entities. This review focuses on seronegative OCI. The existence of seronegative OCI has been documented all around the world with the implication of different HCV genotypes (1-4). Seronegative OCI is associated with cryptogenic chronic hepatitis and liver cirrhosis and it may be involved in the appearance of hepatocellular carcinoma. Also seronegative OCI may increase the histological liver damage in chronic hepatitis B and in HIV-infected patients. It may have a negative influence in the natural history of hemodialysis patients and in immune-mediated glomerulonephritis. Seronegative OCI has been detected also in patients with haematological diseases, among healthy subjects and in drug users. Other publications indicate the potential infectivity of seronegative OCI in the setting of family members, sexual partners and liver transplantation. In summary, seronegative OCI may play a role in liver diseases and other human pathologies and may be present in healthy people but larger studies are needed to confirm these findings.

  9. Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus

    PubMed Central

    Melendez, Dante P; Razonable, Raymund R

    2015-01-01

    Infection with cytomegalovirus is prevalent in immunosuppressed patients. In solid organ transplant and hematopoietic stem cell transplant recipients, cytomegalovirus infection is associated with high morbidity and preventable mortality. Prevention and treatment of cytomegalovirus with currently approved antiviral drugs is often associated with side effects that sometimes preclude their use. Moreover, cytomegalovirus has developed mutations that confer resistance to standard antiviral drugs. During the last decade, there have been calls to develop novel antiviral drugs that could provide better options for prevention and treatment of cytomegalovirus. Letermovir (AIC246) is a highly specific antiviral drug that is currently undergoing clinical development for the management of cytomegalovirus infection. It acts by inhibiting the viral terminase complex. Letermovir is highly potent in vitro and in vivo against cytomegalovirus. Because of a distinct mechanism of action, it does not exhibit cross-resistance with other antiviral drugs. It is predicted to be active against strains that are resistant to ganciclovir, foscarnet, and cidofovir. To date, early-phase clinical trials suggest a very low incidence of adverse effects. Herein, we present a comprehensive review on letermovir, from its postulated novel mechanism of action to the results of most recent clinical studies. PMID:26345608

  10. Cytomegalovirus Immunoglobulin After Thoracic Transplantation: An Overview.

    PubMed

    Grossi, Paolo; Mohacsi, Paul; Szabolcs, Zoltán; Potena, Luciano

    2016-03-01

    Cytomegalovirus (CMV) is a highly complex pathogen which, despite modern prophylactic regimens, continues to affect a high proportion of thoracic organ transplant recipients. The symptomatic manifestations of CMV infection are compounded by adverse indirect effects induced by the multiple immunomodulatory actions of CMV. These include a higher risk of acute rejection, cardiac allograft vasculopathy after heart transplantation, and potentially bronchiolitis obliterans syndrome in lung transplant recipients, with a greater propensity for opportunistic secondary infections. Prophylaxis for CMV using antiviral agents (typically oral valganciclovir or intravenous ganciclovir) is now almost universal, at least in high-risk transplants (D+/R-). Even with extended prophylactic regimens, however, challenges remain. The CMV events can still occur despite antiviral prophylaxis, including late-onset infection or recurrent disease, and patients with ganciclovir-resistant CMV infection or who are intolerant to antiviral therapy require alternative strategies. The CMV immunoglobulin (CMVIG) and antiviral agents have complementary modes of action. High-titer CMVIG preparations provide passive CMV-specific immunity but also exert complex immunomodulatory properties which augment the antiviral effect of antiviral agents and offer the potential to suppress the indirect effects of CMV infection. This supplement discusses the available data concerning the immunological and clinical effects of CMVIG after heart or lung transplantation.

  11. Specific remodeling of splenic architecture by cytomegalovirus.

    PubMed

    Benedict, Chris A; De Trez, Carl; Schneider, Kirsten; Ha, Sukwon; Patterson, Ginelle; Ware, Carl F

    2006-03-01

    Efficient immune defenses are facilitated by the organized microarchitecture of lymphoid organs, and this organization is regulated by the compartmentalized expression of lymphoid tissue chemokines. Mouse cytomegalovirus (MCMV) infection induces significant remodeling of splenic microarchitecture, including loss of marginal zone macrophage populations and dissolution of T and B cell compartmentalization. MCMV preferentially infected the splenic stroma, targeting endothelial cells (EC) as revealed using MCMV-expressing green fluorescent protein. MCMV infection caused a specific, but transient transcriptional suppression of secondary lymphoid chemokine (CCL21). The loss of CCL21 was associated with the failure of T lymphocytes to locate within the T cell zone, although trafficking to the spleen was unaltered. Expression of CCL21 in lymphotoxin (LT)-alpha-deficient mice is dramatically reduced, however MCMV infection further reduced CCL21 levels, suggesting that viral modulation of CCL21 was independent of LTalpha signaling. Activation of LTbeta-receptor signaling with an agonistic antibody partially restored CCL21 mRNA expression and redirected transferred T cells to the splenic T cell zone in MCMV-infected mice. These results indicate that virus-induced alterations in lymphoid tissues can occur through an LT-independent modulation of chemokine transcription, and targeting of the LT cytokine system can counteract lymphoid tissue remodeling by MCMV.

  12. Clinical evaluation of a chemiluminescence immunoassay for determination of immunoglobulin g avidity to human cytomegalovirus.

    PubMed

    Revello, Maria Grazia; Gorini, Giovanna; Gerna, Giuseppe

    2004-07-01

    Clinical evaluation of a novel fully automated chemiluminescence immunoassay for determination of immunoglobulin G avidity to human cytomegalovirus (HCMV) showed 92.8% sensitivity and 84.7% specificity in detecting a recent (< or =90 days) primary HCMV infection. The assay appears useful for accurately diagnosing recent primary HCMV infections.

  13. Acute Cytomegalovirus Hepatitis in an Immunocompetent Host as a Reason for Upper Right Abdominal Pain

    PubMed Central

    Jensen, Kai Oliver; Angst, Eliane; Hetzer, Franc Heinrich; Gingert, Christian

    2016-01-01

    Cytomegalovirus infections are widely distributed with a seroprevalence of up to 100%. The majority of the cases take a silent course or deal with unspecific clinical symptoms. Complications in immunocompetent patients are rare but may affect the liver and lead up to an acute organ failure. In this case report, we describe a 35-year-old immunocompetent female with an acute cytomegalovirus infection presenting as acute hepatitis with ongoing upper right abdominal pain after cholecystectomy. Upper right abdominal pain is a common symptom with a wide range of differential diagnoses. If common reasons can be excluded, we want to sensitize for cytomegalovirus infection as a minor differential diagnosis even in immunocompetent patients. PMID:27403100

  14. Caprylic acid in the effective treatment of intractable medical problems of frequent urination, incontinence, chronic upper respiratory infection, root canalled tooth infection, ALS, etc., caused by asbestos & mixed infections of Candida albicans, Helicobacter pylori & cytomegalovirus with or without other microorganisms & mercury.

    PubMed

    Omura, Yoshiaki; O'Young, Brian; Jones, Marilyn; Pallos, Andrew; Duvvi, Harsha; Shimotsuura, Yasuhiro

    2011-01-01

    There are many causes of frequent urination. Whenever water or fluids are consumed, the patient has to urinate within 10 or 20 min. Often urinary bladder examinations & blood tests show no significant abnormalities, & treatment by anti-bacterial or anti-viral agents does not improve the symptoms significantly. In intractable frequent urination with difficulty holding urine, as well as other intractable medical problems such as frequent coughing, white pus in gingiva, infection of the apex of a root canalled tooth, slow-healing wounds, & ALS, the authors often found coexisting mixed infections of Candida albicans (C.A.), Helicobacter pylori (H.P.), & Cytomegalovirus (CMV) with or without additional bacterial (Chlamydia trachomatis, etc.) or viral infections & increased Asbestos, with or without Hg deposits. We often found various degrees of mixed infections with C.A., H.P., & CMV in the external sphincters of the urethra & in the Trigone of the urinary bladder which consists of (1) a horizontal, band-like area between the 2 ureter openings & (2) the funnel shaped part of the Trigone at the lower half of the urinary bladder. In the coexistence of significant amounts of C.A., H.P. & CMV, the infection cannot be reduced by otherwise effective medicines for H.P. & CMV. However, one optimal dose of Diflucan, or Caprylic acid taken orally or externally applied, rapidly reduced the symptoms significantly. We found the best treatment is to give a combination of an optimal dose of Caprylic acid orally in the form of "CaprilyCare" or "Caprylic Acid," with a capsule of Omega-3 Fish Oil as an anti-viral agent, Amoxicillin, Substance Z & a Cilantro tablet. We found that an optimal dose of Caprylic acid increases normal cell telomere (NCT) to a desirable 750 ng BDORT units while Diflucan increases NCT by only 25 ng BDORT units, & with Omega-3 fish oil, leads to a mutual cancellation of both drugs. Thus, Caprylic acid is superior to & less expensive than Diflucan, & has potential

  15. Differential effects of Cytomegalovirus carriage on the immune phenotype of middle-aged males and females.

    PubMed

    van der Heiden, Marieke; van Zelm, Menno C; Bartol, Sophinus J W; de Rond, Lia G H; Berbers, Guy A M; Boots, Annemieke M H; Buisman, Anne-Marie

    2016-05-31

    The elderly population is more susceptible to infections as a result of an altered immune response, commonly referred to as immunosenescence. Cytomegalovirus (CMV)-infection associated changes in blood lymphocytes are known to impact this process, but the interaction with gender remains unclear. Therefore, we analysed the effects and interaction of gender and CMV on the absolute numbers of a comprehensive set of naive and memory T- and B-cell subsets in people between 50 and 65 years of age. Enumeration and characterisation of lymphocyte subsets by flow cytometry was performed on fresh whole blood samples from 255 middle-aged persons. CMV-IgG serostatus was determined by ELISA. Gender was a major factor affecting immune cell numbers. CMV infection was mainly associated with an expansion of late-differentiated T-cell subsets. CMV+ males carried lower numbers of total CD4+, CD4+ central memory (CM) and follicular helper T-cells than females and CMV- males. Moreover, CMV+ males had significantly lower numbers of regulatory T (Treg)-cells and memory B-cells than CMV+ females. We here demonstrate an interaction between the effects of CMV infection and gender on T- and B-cells in middle-aged individuals. These differential effects on adaptive immunity between males and females may have implications for vaccination strategies at middle-age.

  16. Differential effects of Cytomegalovirus carriage on the immune phenotype of middle-aged males and females

    PubMed Central

    van der Heiden, Marieke; van Zelm, Menno C.; Bartol, Sophinus J. W.; de Rond, Lia G. H.; Berbers, Guy A. M.; Boots, Annemieke M. H.; Buisman, Anne-Marie

    2016-01-01

    The elderly population is more susceptible to infections as a result of an altered immune response, commonly referred to as immunosenescence. Cytomegalovirus (CMV)-infection associated changes in blood lymphocytes are known to impact this process, but the interaction with gender remains unclear. Therefore, we analysed the effects and interaction of gender and CMV on the absolute numbers of a comprehensive set of naive and memory T- and B-cell subsets in people between 50 and 65 years of age. Enumeration and characterisation of lymphocyte subsets by flow cytometry was performed on fresh whole blood samples from 255 middle-aged persons. CMV-IgG serostatus was determined by ELISA. Gender was a major factor affecting immune cell numbers. CMV infection was mainly associated with an expansion of late-differentiated T-cell subsets. CMV+ males carried lower numbers of total CD4+, CD4+ central memory (CM) and follicular helper T-cells than females and CMV− males. Moreover, CMV+ males had significantly lower numbers of regulatory T (Treg)-cells and memory B-cells than CMV+ females. We here demonstrate an interaction between the effects of CMV infection and gender on T- and B-cells in middle-aged individuals. These differential effects on adaptive immunity between males and females may have implications for vaccination strategies at middle-age. PMID:27243552

  17. Mouse Cytomegalovirus Infection in BALB/c Mice Resembles Virus-Associated Secondary Hemophagocytic Lymphohistiocytosis and Shows a Pathogenesis Distinct from Primary Hemophagocytic Lymphohistiocytosis.

    PubMed

    Brisse, Ellen; Imbrechts, Maya; Put, Karen; Avau, Anneleen; Mitera, Tania; Berghmans, Nele; Rutgeerts, Omer; Waer, Mark; Ninivaggi, Marisa; Kelchtermans, Hilde; Boon, Louis; Snoeck, Robert; Wouters, Carine H; Andrei, Graciela; Matthys, Patrick

    2016-04-01

    Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunological disorder that is characterized by systemic inflammation, widespread organ damage, and hypercytokinemia. Primary HLH is caused by mutations in granule-mediated cytotoxicity, whereas secondary HLH occurs, without a known genetic background, in a context of infections, malignancies, or autoimmune and autoinflammatory disorders. Clinical manifestations of both HLH subtypes are often precipitated by a viral infection, predominantly with Herpesviridae. Exploiting this knowledge, we established an animal model of virus-associated secondary HLH by infecting immunocompetent wild-type mice with the β-herpesvirus murine CMV. C57BL/6 mice developed a mild inflammatory phenotype, whereas BALB/c mice displayed the clinicopathologic features of HLH, as set forth in the Histiocyte Society diagnostic guidelines: fever, cytopenia, hemophagocytosis, hyperferritinemia, and elevated serum levels of soluble CD25. BALB/c mice also developed lymphadenopathy, liver dysfunction, and decreased NK cell numbers. Lymphoid and myeloid cells were in a hyperactivated state. Nonetheless, depletion of CD8(+) T cells could not inhibit or cure the HLH-like syndrome, highlighting a first dissimilarity from mouse models of primary HLH. Immune cell hyperactivation in BALB/c mice was accompanied by a cytokine storm. Notably, plasma levels of IFN-γ, a key pathogenic cytokine in models of primary HLH, were the highest. Nevertheless, murine CMV-infected IFN-γ-deficient mice still developed the aforementioned HLH-like symptoms. In fact, IFN-γ-deficient mice displayed a more complete spectrum of HLH, including splenomegaly, coagulopathy, and decreased NK cell cytotoxicity, indicating a regulatory role for IFN-γ in the pathogenesis of virus-associated secondary HLH as opposed to its central pathogenic role in primary HLH.

  18. Cytomegalovirus (For Parents)

    MedlinePlus

    ... with intravenous (IV) antiviral medication, usually in a hospital. Oral antiviral medicine also might be used at home once the infection is under control and no longer poses a serious risk. Because ...

  19. Microgravity Analogues of Herpes Virus Pathogenicity: Human Cytomegalovirus (hCMV) and Varicella Zoster (VZV) Infectivity in Human Tissue Like Assemblies (TLAs)

    NASA Technical Reports Server (NTRS)

    Goodwin, T. J.; McCarthy, M.; Albrecht, T.; Cohrs, R.

    2009-01-01

    The old adage we are our own worst enemies may perhaps be the most profound statement ever made when applied to man s desire for extraterrestrial exploration and habitation of Space. Consider the immune system protects the integrity of the entire human physiology and is comprised of two basic elements the adaptive or circulating and the innate immune system. Failure of the components of the adaptive system leads to venerability of the innate system from opportunistic microbes; viral, bacteria, and fungal, which surround us, are transported on our skin, and commonly inhabit the human physiology as normal and imunosuppressed parasites. The fine balance which is maintained for the preponderance of our normal lives, save immune disorders and disease, is deregulated in microgravity. Thus analogue systems to study these potential Risks are essential for our progress in conquering Space exploration and habitation. In this study we employed two known physiological target tissues in which the reactivation of hCMV and VZV occurs, human neural and lung systems created for the study and interaction of these herpes viruses independently and simultaneously on the innate immune system. Normal human neural and lung tissue analogues called tissue like assemblies (TLAs) were infected with low MOIs of approximately 2 x 10(exp -5) pfu hCMV or VZV and established active but prolonged low grade infections which spanned .7-1.5 months in length. These infections were characterized by the ability to continuously produce each of the viruses without expiration of the host cultures. Verification and quantification of viral replication was confirmed via RT_PCR, IHC, and confocal spectral analyses of the respective essential viral genomes. All host TLAs maintained the ability to actively proliferate throughout the entire duration of the experiments as is analogous to normal in vivo physiological conditions. These data represent a significant advance in the ability to study the triggering

  20. Acute cervicitis and vulvovaginitis may be associated with Cytomegalovirus

    PubMed Central

    Abou, Magali; Dällenbach, Patrick

    2013-01-01

    Cytomegalovirus (CMV) infection in immunocompetent hosts is generally asymptomatic or may present as a mononucleosic syndrome. Its association with acute cervicitis and vulvovaginitis has rarely been reported. A 24-year-old woman presented with pelvic pain, vulvodynia, abnormal vaginal discharge, burning with urination, fatigue, fever, vomiting and diarrhoea. The vulva and cervix were red with vesicular lesions on the cervix. Genital herpes simplex infection (HSV) was suspected and valacyclovir was given orally. However, serial viral cultures performed 7 weeks apart did not isolate HSV as suspected, but CMV was confirmed by immunofluorescence and early antigen research. Blood tests confirmed an acute CMV infection. Typical inclusions were found at histology. Symptoms resolved slowly with persistence of cervical lesions at 7 weeks from diagnosis. The frequency of CMV genital infection is probably underestimated. The infection is not always asymptomatic and might be confused with genital HSV infection. The clinical course is longer. PMID:23606387

  1. Acute cervicitis and vulvovaginitis may be associated with Cytomegalovirus.

    PubMed

    Abou, Magali; Dällenbach, Patrick

    2013-04-19

    Cytomegalovirus (CMV) infection in immunocompetent hosts is generally asymptomatic or may present as a mononucleosic syndrome. Its association with acute cervicitis and vulvovaginitis has rarely been reported. A 24-year-old woman presented with pelvic pain, vulvodynia, abnormal vaginal discharge, burning with urination, fatigue, fever, vomiting and diarrhoea. The vulva and cervix were red with vesicular lesions on the cervix. Genital herpes simplex infection (HSV) was suspected and valacyclovir was given orally. However, serial viral cultures performed 7 weeks apart did not isolate HSV as suspected, but CMV was confirmed by immunofluorescence and early antigen research. Blood tests confirmed an acute CMV infection. Typical inclusions were found at histology. Symptoms resolved slowly with persistence of cervical lesions at 7 weeks from diagnosis. The frequency of CMV genital infection is probably underestimated. The infection is not always asymptomatic and might be confused with genital HSV infection. The clinical course is longer.

  2. Pneumocystis carinii, Toxoplasma gondii, Cytomegalovirus and the Compromised Host

    PubMed Central

    Ryning, Frank W.; Mills, John

    1979-01-01

    Pneumocystis carinii and Toxoplasma gondii are the two major parasitic protozoan pathogens in the immunocompromised host. Both organisms cause latent infection in humans and many animals. Cats are the definitive hosts for toxoplasmosis; the animal vector for pneumocystis (if any) has not been defined. Toxoplasma is an obligate intracellular parasite, whereas the available evidence suggests that Pneumocystis carinii exists primarily extracellularly. In compromised hosts, pneumocystis infection usually involves only lungs, whereas toxoplasma causes a generalized infection with encephalitis being the principal clinical manifestation. Both types of infection are treated with combinations of folate antagonists (trimethoprim or pyrimethamine with sulfonamide). Both parasites are associated with cytomegalovirus infection in immunosuppressed hosts, an association which may be due to symbiosis between parasites, or to an additive immunosuppressive effect of dual infection on the hosts. ImagesFigure 1.Figure 3.Figure 4.Figure 7.Figure 8.Figure 9. PMID:217182

  3. Occult hepatitis B virus infection: clinical implications in tuberculosis treatment.

    PubMed

    Trigo, C; do Brasil, P E A A; Costa, M J M; de Castro, L

    2016-12-01

    Occult hepatitis B virus infection (OBI) is characterized by the absence of HBsAg and persistence of the virus genome (HBV-DNA) in liver tissue and/or blood. OBI has been reported in several clinical contexts. However, the clinical significance of OBI in tuberculosis (TB) treatment is unknown. We investigated the OBI prevalence and its impact on the risk of drug-induced liver injury (DILI) during TB treatment. This was a prospective cohort study with one hundred patients who were treated for TB from 2008 to 2015. Laboratory, clinical and demographic data of TB patients were extracted from medical records. Based on HBV-DNA testing of serum samples, an OBI prevalence of 12% was established; almost half of these patients had both anti-HBc and anti-HBs serological markers. Low CD4(+) cell counts have been shown to be a risk factor for OBI among TB patients co-infected with HIV (P=.036). High DILI incidence was observed in this study. A multivariable Cox proportional hazard model was conducted and identified OBI (HR 2.98, 95% CI 1.30-6.86) as the strongest predictor for DILI when adjusted to CD4(+) cell count (HR 0.38, 95% CI 0.17-0.90), ALT before TB treatment (HR 1.37, 95% CI 0.81-2.32) and TB extrapulmonary clinical form (HR 2.91, 95% CI 1.75-7.21). The main aim of this study was to highlight DILI as a clinical outcome during treatment of TB patients with OBI. Therefore, HBV-DNA testing should be considered routinely in monitoring DILI, and also in other clinical implications associated with OBI, reduce morbidity and mortality.

  4. Burden of disease associated with human cytomegalovirus and prospects for elimination by universal immunisation.

    PubMed

    Griffiths, Paul D

    2012-10-01

    Cytomegalovirus is the most frequent cause of intrauterine infection and the commonest infectious agent to affect allograft recipients, yet the virus is acknowledged rarely as an occupational hazard for women of childbearing age or as a nosocomial infection. The potential role of cytomegalovirus in hastening the death of patients with AIDS, elderly people, individuals admitted to intensive-care units, and the general population is not emphasised. Development of vaccines against this important human pathogen has been delayed by reluctance to initiate proof-of-concept studies, but after recent trials, protection is a distinct possibility. Cytomegalovirus deserves to be eliminated from selected populations by means of universal immunisation as soon as suitable vaccines become licensed. This action should control disease in neonates and transplant recipients and could provide substantial additional benefits if other disease associations prove to be causal.

  5. Asymptomatic brucellosis infection in humans: implications for diagnosis and prevention.

    PubMed

    Zhen, Q; Lu, Y; Yuan, X; Qiu, Y; Xu, J; Li, W; Ke, Y; Yu, Y; Huang, L; Wang, Y; Chen, Z

    2013-09-01

    Human brucellosis is mainly caused by contact with Brucella-infected animals and their secretions and carcasses. Individuals who are continuously in contact with animals are considered to be at a high risk but only some show symptoms and are diagnosed as cases of brucellosis. Here, we showed that asymptomatic brucellosis infections occur among humans. Asymptomatic infections mainly result from less frequent contact with Brucella and/or contact with low-virulence Brucella. In our study, patients with asymptomatic infection had low antibody titres and different contact patterns. Awareness of asymptomatic infection is important for early diagnosis of brucellosis and prevention of chronic infection.

  6. Cytomegalovirus and the Seemingly Immunocompetent Host: A Case of a Perforating Gastric Ulcer

    PubMed Central

    Shivashankar, Raina; Hansel, Stephanie

    2017-01-01

    Cytomegalovirus (CMV) infection of the gastrointestinal tract has a variety of presentations. We present a case of gastric perforation, which is a relatively infrequent presentation of CMV infection. If the cause of gastric perforation is not readily apparent, testing for CMV should be considered. If CMV workup is positive, an evaluation for immunocompromise is prudent as CMV infections are more common in immunocompromised individuals. PMID:28286792

  7. Cytomegalovirus as an occupational risk in daycare educators

    PubMed Central

    Joseph, Serene A; Béliveau, Claire; Muecke, Cristin J; Rahme, Elham; Soto, Julio C; Flowerdew, Gordon; Johnston, Lynn; Langille, Donald; Gyorkos, Theresa W

    2006-01-01

    BACKGROUND Cytomegalovirus (CMV) infection continues to be an important occupational risk in the daycare setting. A comprehensive update of scientific evidence is timely to inform and promote appropriate preventive measures. METHODS A review of the literature was conducted to examine the evidence for an occupational risk of CMV infection in daycare educators. Sources included Medline, government documents and additional references from published bibliographies. The key words used for searches were ‘child day care centres’ or ‘nurseries’ and ‘cytomegalovirus’ or ‘cytomegalovirus infection’. RESULTS Eight CMV seroprevalence studies on daycare educators in industrialized countries were found: four in the United States, three in Canada and one in Italy. Risk factors for seropositivity were older age, nonwhite race, foreign birth, birth in a low- or middle-income country, diaper changing, having children at home, and a child to educator ratio greater than 6:1 in children 18 to 35 months of age. Risk factors for seroconversion were younger age and working with young children. These studies suggest that daycare centres may be a high-risk setting for CMV infection. DISCUSSION Recommendations to prevent CMV infection in this setting include handwashing, selective serological screening, avoiding work with younger children if pregnant and, in some cases, preventive leave from work. Evaluation and expert opinion of the effectiveness of various preventive options for CMV acquisition are needed to ensure that recommendations are evidence-based. PMID:19030309

  8. Child Care Provider Awareness and Prevention of Cytomegalovirus and Other Infectious Diseases

    ERIC Educational Resources Information Center

    Thackeray, Rosemary; Magnusson, Brianna M.

    2016-01-01

    Background: Child care facilities are prime locations for the transmission of infectious and communicable diseases. Children and child care providers are at high risk for cytomegalovirus (CMV) infection which causes severe birth defects and developmental delays. Objective: The goals of study were: (1) to determine the level of cytomegalovirus…

  9. Herpes Simplex Virus Infection in a University Health Population: Clinical Manifestations, Epidemiology, and Implications

    ERIC Educational Resources Information Center

    Horowitz, Robert; Aierstuck, Sara; Williams, Elizabeth A.; Melby, Bernette

    2010-01-01

    Objective: The authors described clinical presentations of oral and genital herpes simplex virus (HSV) infections in a university health population and implications of these findings. Participants and Methods: Using a standardized data collection tool, 215 records of patients with symptomatic culture-positive HSV infections were reviewed. Results:…

  10. Comparative magnitude and kinetics of human cytomegalovirus-specific CD4⁺ and CD8⁺ T-cell responses in pregnant women with primary versus remote infection and in transmitting versus non-transmitting mothers: Its utility for dating primary infection in pregnancy.

    PubMed

    Fornara, Chiara; Furione, Milena; Arossa, Alessia; Gerna, Giuseppe; Lilleri, Daniele

    2016-07-01

    To discriminate between primary (PI) and remote (RI) human cytomegalovirus (HCMV) infection, several immunological parameters were monitored for a 2-year period in 53 pregnant women with PI, and 33 pregnant women experiencing HCMV PI at least 5 years prior. Cytokine (IFN-γ and IL-2) production by and phenotype (effector/memory CD45RA(+)) of HCMV-specific CD4(+) and CD8(+) T-cells as well as the lymphoproliferative responses (LPR) were evaluated, with special reference to the comparison between a group of women transmitting (T) and a group of non-transmitting (NT) the infection to fetus. While HCMV-specific CD4(+) T-cells reached at 90 days post-infection (p.i.) values comparable to RI, CD8(+) T-cells reached at 60 days p.i. levels significantly higher and persisting throughout the entire follow-up. Instead, IL-2 production and lymphoproliferative responses were lower in PI than RI for the entire follow-up period. Effector memory CD45RA(+) CD4(+) and CD8(+) HCMV-specific T-cells increased until 90 days p.i., reaching and maintaining levels higher than RI. The comparison between T and NT women showed that, at 30 days p.i., in NT women there was a significantly higher IL-2 production by HCMV-specific CD4(+) T-cells, and at 60 days p.i. a significantly higher frequency of both specific CD4(+) and CD8(+) CD45RA(+) T-cells. HCMV T-cell response appears to correlate with virus transmission to fetus and some parameters (CD4(+) lymphoproliferation, and frequency of HCMV-specific CD8(+) IL2(+) T-cells) may help in dating PI during pregnancy.

  11. Temporal profiling of the coding and noncoding murine cytomegalovirus transcriptomes.

    PubMed

    Lacaze, Paul; Forster, Thorsten; Ross, Alan; Kerr, Lorraine E; Salvo-Chirnside, Eliane; Lisnic, Vanda Juranic; López-Campos, Guillermo H; García-Ramírez, José J; Messerle, Martin; Trgovcich, Joanne; Angulo, Ana; Ghazal, Peter

    2011-06-01

    The global transcriptional program of murine cytomegalovirus (MCMV), involving coding, noncoding, and antisense transcription, remains unknown. Here we report an oligonucleotide custom microarray platform capable of measuring both coding and noncoding transcription on a genome-wide scale. By profiling MCMV wild-type and immediate-early mutant strains in fibroblasts, we found rapid activation of the transcriptome by 6.5 h postinfection, with absolute dependency on ie3, but not ie1 or ie2, for genomic programming of viral gene expression. Evidence is also presented to show, for the first time, genome-wide noncoding and bidirectional transcription at late stages of MCMV infection.

  12. Mixed-Strain Mycobacterium tuberculosis Infections and the Implications for Tuberculosis Treatment and Control

    PubMed Central

    van Helden, Paul D.; Wilson, Douglas; Colijn, Caroline; McLaughlin, Megan M.; Abubakar, Ibrahim; Warren, Robin M.

    2012-01-01

    Summary: Numerous studies have reported that individuals can simultaneously harbor multiple distinct strains of Mycobacterium tuberculosis. To date, there has been limited discussion of the consequences for the individual or the epidemiological importance of mixed infections. Here, we review studies that documented mixed infections, highlight challenges associated with the detection of mixed infections, and discuss possible implications of mixed infections for the diagnosis and treatment of patients and for the community impact of tuberculosis control strategies. We conclude by highlighting questions that should be resolved in order to improve our understanding of the importance of mixed-strain M. tuberculosis infections. PMID:23034327

  13. Murine cytomegalovirus resistant to antivirals has genetic correlates with human cytomegalovirus.

    PubMed

    Scott, G M; Ng, H-L; Morton, C J; Parker, M W; Rawlinson, W D

    2005-08-01

    Human cytomegalovirus (HCMV) resistance to antivirals is a significant clinical problem. Murine cytomegalovirus (MCMV) infection of mice is a well-described animal model for in vivo studies of CMV pathogenesis, although the mechanisms of MCMV antiviral susceptibility need elucidation. Mutants resistant to nucleoside analogues aciclovir, adefovir, cidofovir, ganciclovir, penciclovir and valaciclovir, and the pyrophosphate analogue foscarnet were generated by in vitro passage of MCMV (Smith) in increasing concentrations of antiviral. All MCMV antiviral resistant mutants contained DNA polymerase mutations identical or similar to HCMV DNA polymerase mutations known to confer antiviral resistance. Mapping of the mutations onto an MCMV DNA polymerase three-dimensional model generated using the Thermococcus gorgonarius Tgo polymerase crystal structure showed that the DNA polymerase mutations potentially confer resistance through changes in regions surrounding a catalytic aspartate triad. The ganciclovir-, penciclovir- and valaciclovir-resistant isolates also contained mutations within MCMV M97 identical or similar to recognized GCV-resistant mutations of HCMV UL97 protein kinase, and demonstrated cross-resistance to antivirals of the same class. This strongly suggests that MCMV M97 has a similar role to HCMV UL97 in the phosphorylation of nucleoside analogue antivirals. All MCMV mutants demonstrated replication-impaired phenotypes, with the lowest titre and plaque size observed for isolates containing mutations in both DNA polymerase and M97. These findings indicate DNA polymerase and protein kinase regions of potential importance for antiviral susceptibility and replication. The similarities between MCMV and HCMV mutations that arise under antiviral selective pressure increase the utility of MCMV as a model for in vivo studies of CMV antiviral resistance.

  14. Comparative efficacy of handwashing agents against cytomegalovirus.

    PubMed

    Faix, R G

    1987-04-01

    Conscientious handwashing is often recommended as an important method for limiting transmission of cytomegalovirus (CMV) from infected individuals to health, education, and child care professionals. To assess the efficacy of handwashing, fingertips of radiation-sterilized latex gloves were inoculated with 0.2 mL of ten different CMV strains. Virus in each inoculum was quantitated by plaque assay. After five minutes, viral inocula were allowed to remain (control), or were washed away by dropwise application of 10 mL of distilled water (DI), 5 mL of 0.08% soap followed by 5 mL of DI, 5 mL of 0.01% chlorhexidine gluconate followed by 5 mL of DI, or 5 mL of 0.025% povidone-iodine solution followed by 5 mL of DI. Separate glove fingertips were sampled 5, 15, 30, 60, 120 and 240 minutes after washing and cultured in duplicate for CMV. Similar studies were performed using human cadaver skin. Ordinary soap was as effective at preventing CMV recovery as other more expensive agents. For inocula with less than 5 log10 pfu CMV/mL, washing with water alone was as effective as other agents. This was confirmed in similar studies with human hands using five CMV stains. Handwashing is probably an effective method for removing CMV from contaminated hands.

  15. Cytomegalovirus pneumonia in transplant patients: CT findings

    SciTech Connect

    Eun-Young Kang; Patz, E.F. Jr.; Mueller, N.L.

    1996-03-01

    Our goal was to assess the CT findings of cytomegalovirus (CMV) pneumonia in transplant patients. The study included 10 transplant patients who had chest CT scan and pathologically proven isolated pulmonary CMV infection. Five patients had bone marrow transplant and five had solid organ transplant. The CT scans were retrospectively reviewed for pattern and distribution of disease and the CT findings compared with the findings on open lung biopsy (n = 9) and autopsy (n = 1). Nine of 10 patients had parenchymal abnormalities apparent at CT and I had normal CT scans. The findings in the nine patients included small nodules (n = 6), consolidation (n = 4), ground-glass attenuation (n = 4), and irregular lines (n = 1). The nodules had a bilateral and symmetric distribution and involved all lung zones. The consolidation was most marked in the lower lung zones. The CT findings of CMV pneumonia in transplant patients are heterogeneous. The most common patterns include small nodules and areas of consolidation. 13 refs., 4 figs., 1 tab.

  16. Human cytomegalovirus decreases constitutive transcription of MHC class II genes in mature Langerhans cells by reducing CIITA transcript levels.

    PubMed

    Lee, Andrew W; Wang, Nan; Hornell, Tara M C; Harding, James J; Deshpande, Chetan; Hertel, Laura; Lacaille, Vashti; Pashine, Achal; Macaubas, Claudia; Mocarski, Edward S; Mellins, Elizabeth D

    2011-05-01

    Human cytomegalovirus (HCMV) productively infects CD34(+) progenitor-derived, mature Langerhans-type dendritic cells (matLC) and reduces surface expression of MHC class II complexes (MHC II) by increasing intracellular retention of these molecules. To determine whether HCMV also inhibits MHC II expression by other mechanisms, we assessed mRNA levels of the class II transcriptional regulator, CIITA, and several of its target genes in infected matLC. Levels of CIITA, HLA-DRA (DRA) and DRB transcripts, and new DR protein synthesis were compared in mock-infected and HCMV-infected cells by quantitative PCR and pulse-chase immunoprecipitation analyses, respectively. CIITA mRNA levels were significantly lower in HCMV-infected matLC as compared to mock-infected cells. When assessed in the presence of Actinomycin D, the stability of CIITA transcripts was not diminished by HCMV. Analysis of promoter-specific CIITA isoforms revealed that types I, III and IV all were decreased by HCMV, a result that differs from changes after incubation of these cells with lipopolysaccharide (LPS). Exposure to UV-inactivated virus failed to reduce CIITA mRNA levels, implicating de novo viral gene expression in this effect. HCMV-infected matLC also expressed lower levels of DR transcripts and reduced DR protein synthesis rates compared to mock-infected matLC. In summary, we demonstrate that HCMV infection of a human dendritic cell subset inhibits constitutive CIITA expression, most likely at the transcriptional level, resulting in reduced MHC II biosynthesis. We suggest this represents a new mechanism of modulation of mature LC by HCMV.

  17. Stepwise adaptation of murine cytomegalovirus to cells of a foreign host for identification of host range determinants.

    PubMed

    Ostermann, Eleonore; Pawletko, Kerstin; Indenbirken, Daniela; Schumacher, Uwe; Brune, Wolfram

    2015-06-01

    Ever since their first isolation 60 years ago, cytomegaloviruses have been recognized as being highly species specific. They replicate only in cells of their own or a closely related host species, while cells of phylogenetically more distant hosts are usually not permissive for viral replication. For instance, human cytomegalovirus replicates in human and chimpanzee fibroblasts but not in rodent cells, and murine cytomegalovirus (MCMV) replicates in cells of mice and rats but not in primate cells. However, the viral and cellular factors determining the narrow host range of cytomegaloviruses have remained largely unknown. We show that MCMV can be adapted stepwise to replicate in cultured human retinal pigment epithelial (RPE-1) cells and human fibroblasts. The human RPE-1 cells used for the initial adaptation step showed a pronounced contact inhibition and produced very low level of interferon-β transcripts upon cytomegalovirus infection, suggesting that these cells provide a particularly favorable environment for adaptation. By whole genome sequencing of the 230 kbp viral genomes of several adapted mutants, a limited number of mutations were detected. Comparison of several human cell-adapted MCMV clones and introduction of specific mutations into the wild-type MCMV genome by site-directed mutagenesis allows for the identification of viral host range determinants and provides the basis for elucidating the molecular basis of the cytomegalovirus host species specificity.

  18. Experimental rhinovirus infection in COPD: implications for antiviral therapies.

    PubMed

    Gunawardana, Natasha; Finney, Lydia; Johnston, Sebastian L; Mallia, Patrick

    2014-02-01

    Chronic obstructive pulmonary disease (COPD) is a major public health problem and will be one of the leading global causes of mortality over the coming decades. Much of the morbidity, mortality and health care costs of COPD are attributable to acute exacerbations, the commonest causes of which are respiratory infections. Respiratory viruses are frequently detected in COPD exacerbations but direct proof of a causative relationship has been lacking. We have developed a model of COPD exacerbation using experimental rhinovirus infection in COPD patients and this has established a causative relationship between virus infection and exacerbations. In addition it has determined some of the molecular mechanisms linking virus infections to COPD exacerbations and identified potential new therapeutic targets. This new data should stimulate research into the role of antiviral agents as potential treatments for COPD exacerbations. Testing of antiviral agents has been hampered by the lack of a small animal model for rhinovirus infection and experimental rhinovirus infection in healthy volunteers has been used to test treatments for the common cold. Experimental rhinovirus infection in COPD subjects offers the prospect of a model that can be used to evaluate the effects of new treatments for virus-induced COPD exacerbations, and provide essential data that can be used in making decisions regarding large scale clinical trials.

  19. Cytomegalovirus UL103 controls virion and dense body egress.

    PubMed

    Ahlqvist, Jenny; Mocarski, Edward

    2011-05-01

    Human cytomegalovirus UL103 encodes a tegument protein that is conserved across herpesvirus subgroups. Mutant viruses lacking this gene product exhibit dramatically reduced accumulation of cell-free virus progeny and poor cell-to-cell spread. Given that viral proteins and viral DNA accumulate with normal kinetics in cells infected with mutant virus, UL103 appears to function during the late phase of replication, playing a critical role in egress of capsidless dense bodies and virions. Few dense bodies were observed in the extracellular space in mutant virus-infected cells in the presence or absence of the DNA encapsidation inhibitor 2-bromo-5,6-dichloro-1-(β-d-ribofuranosyl)benzimidazole. Upon reversal of encapsidation inhibition, UL103 had a striking impact on accumulation of cell-free virus, but not on accumulation of cell-associated virus. Thus, UL103 plays a novel and important role during maturation, regulating virus particle and dense body egress from infected cells.

  20. The Role of Cytomegalovirus in the Development of ARC-AIDS

    DTIC Science & Technology

    1991-08-30

    sera, taken in chronological order of receipt into the laboratory, from HLV -1- seropositive subjects, for the presence of antibodies to cellular...CI)4 +T-cell numbers in IIIV-1 infected subjects, but CMV infections appear to be important. The drug DHPG (gancyclovir) has been used in suppressing...CMV drugs that can be given orally. The data we have presented in this paper reinforce the recommendation of DiNubile [37] that in cytomegalovirus

  1. Cytomegalovirus

    MedlinePlus

    ... virus, your doctor may suggest a test called amniocentesis. During this test, a needle is inserted into ... familydoctor.org editorial staff Tags: Allergy and Immunologic, Amniocentesis, child, fever, infant, jaundice, newborn, Throat Pain, weakness ...

  2. A review of the clinical implications of anti-infective biomaterials and infection-resistant surfaces.

    PubMed

    Campoccia, Davide; Montanaro, Lucio; Arciola, Carla Renata

    2013-11-01

    Infection is currently regarded as the most severe and devastating complication associated to the use of biomaterials. The important social, clinical and economic impacts of implant-related infections are promoting the efforts to obviate these severe diseases. In this context, the development of anti-infective biomaterials and of infection-resistant surfaces is being regarded as the main strategy to prevent the establishment of implant colonisation and biofilm formation by bacteria. In this review, the attention is focused on the biomaterial-associated infections, from which the need for anti-infective biomaterials originates. Biomaterial-associated infections differ markedly for epidemiology, aetiology and severity, depending mainly on the anatomic site, on the time of biomaterial application, and on the depth of the tissues harbouring the prosthesis. Here, the diversity and complexity of the different scenarios where medical devices are currently utilised are explored, providing an overview of the emblematic applicative fields and of the requirements for anti-infective biomaterials.

  3. Biology of Mouse Thymic Virus, a Herpesvirus of Mice, and the Antigenic Relationship to Mouse Cytomegalovirus

    PubMed Central

    Cross, S. S.; Parker, J. C.; Rowe, W. P.; Robbins, M. L.

    1979-01-01

    Mouse thymic virus (TA) is a herpesvirus which produces extensive necrosis of the thymus of newborn mice 7 to 14 days after infection. Infectious virus can be recovered from the thymus for only 10 days after infection, with highest titers occurring between days 5 and 7. In mice 5 days old or less, TA infects thymus cells and produces massive necrosis. TA also infects the salivary glands and persists as a chronic infection. Newborn mice infected with TA have no detectable humoral immune response. Infected adult mice respond, and humoral antibody is detected 7 days after infection. Titers are maintained for months thereafter. Regardless of the age of the mice inoculated with TA, persistent infection was established in the salivary glands, but no evidence for thymus involvement was observed when adults were infected. TA does not cross-react serologically by immunofluorescent, complement fixation, or virus neutralization tests with mouse cytomegalovirus; however, interestingly, the epidemiology of the two herpesviruses are similar. Both mouse cytomegalovirus and TA were isolated from the same animals in populations of laboratory and wild mice. Evidence of infection with mouse cytomegalovirus and TA were most apparent by virus isolations, since humoral antibody responses are rarely observed. All strains of mice tested were susceptible to TA infection. However, in some strains maximum necrosis occurred at 7 days, compared with 10 to 14 days for other strains. The difference in age susceptibility and the target tissue of thymus in newborn mice suggests that TA is a model herpesvirus for studying the effects of viral infections on humoral and cell-mediated immunological functions. Images PMID:231008

  4. Infection Control and Prevention: A Review of Hospital-Acquired Infections and the Economic Implications

    PubMed Central

    Reed, Deoine; Kemmerly, Sandra A.

    2009-01-01

    The Centers for Disease Control and Prevention estimates that 2 million patients suffer from hospital-acquired infections every year and nearly 100,000 of them die. Most of these medical errors are preventable. Hospital-acquired infections result in up to $4.5 billion in additional healthcare expenses annually. The U.S. government has responded to this financial loss by focusing on healthcare quality report cards and by taking strong action to curb healthcare spending. The Medicare Program has proposed changes to the Hospital Inpatient Prospective Payment System and Fiscal Year Rates: Proposed Rule CMS 1488-P-Healthcare-associated infection. Payment will be linked to performance. Under the new rule, payment will be withheld from hospitals for care associated with treating certain catheter-associated urinary tract infections, vascular catheter-associated infections, and mediastinitis after coronary artery bypass graft surgery. Infection-prevention strategies are essential. In the healthcare setting, the infection control department is categorized as non-revenue-producing. Funds dedicated to resources such as staff, educational programs, and prevention measures are vastly limited. Hospital leaders will need to balance the upfront cost needed to prevent hospital-related infections with the non-reimbursed expense accrued secondary to potentially preventable infections. The purpose of this paper is to present case studies and cost analysis of hospital-acquired infections and present strategies that reduce infections and cost. PMID:21603406

  5. Knowledge and Awareness of Congenital Cytomegalovirus Among Women

    DOE PAGES

    Jeon, Jiyeon; Victor, Marcia; Adler, Stuart P.; ...

    2006-01-01

    Bmore » ackground . Congenital cytomegalovirus (CMV) infection is a leading cause of disabilities in children, yet the general public appears to have little awareness of CMV. Methods . Women were surveyed about newborn infections at 7 different geographic locations. Results . Of the 643 women surveyed, 142 ( 22 % ) had heard of congenital CMV. Awareness increased with increasing levels of education ( P < .0001 ). Women who had worked as a healthcare professional had a higher prevalence of awareness of CMV than had other women ( 56 % versus 16 % , P < .0001 ). Women who were aware of CMV were most likely to have heard about it from a healthcare provider ( 54 % ), but most could not correctly identify modes of CMV transmission or prevention. Among common causes of birth defects and childhood illnesses, women's awareness of CMV ranked last. Conclusion . Despite its large public health burden, few women had heard of congenital CMV, and even fewer were aware of prevention strategies.« less

  6. New paradigms of urinary tract infections: Implications for patient management.

    PubMed

    Horvath, Dennis J; Dabdoub, Shareef M; Li, Birong; Vanderbrink, Brian A; Justice, Sheryl S

    2012-04-01

    Urinary tract infections (UTIs) represent one of the most commonly acquired diseases among the general population as well as hospital in-patients, yet remain difficult to effectively and consistently treat. High rates of recurrence, anatomic abnormalities, and functional disturbances of the urinary tract all contribute to the difficulty in management of these infections. However, recent advances reveal important molecular and genetic factors that contribute to bacterial invasion and persistence in the urinary tract, particularly for the most common causative agent, uropathogenic Escherichia coli. Recent studies using animal models of experimental UTIs have recently provided mechanistic insight into the clinical observations that question the effectiveness of antibiotic therapy in treatment. Ultimately, continuing research will be necessary to identify the best targets for effective treatment of this costly and widespread infectious disease.

  7. Monoclonal Antibodies to Different Components of the Human Cytomegalovirus (HCMV) Pentamer gH/gL/pUL128L and Trimer gH/gL/gO as well as Antibodies Elicited during Primary HCMV Infection Prevent Epithelial Cell Syncytium Formation

    PubMed Central

    Percivalle, Elena; Perez, Laurent; Lanzavecchia, Antonio; Lilleri, Daniele

    2016-01-01

    ABSTRACT Human cytomegalovirus (HCMV) may cause disseminated/end-organ disease in congenitally infected newborns and immunosuppressed transplant recipients. Two glycoprotein complexes, gH/gL/gO and gH/gL/pUL128/pUL130/pUL131 (gH/gL/pUL128L; referred to as the pentamer), are required for HCMV entry into fibroblasts and endothelial/epithelial cells, respectively, in the presence of the viral fusion protein gB. In addition, gH/gL/gO was recently reported to also be required for infection of endothelial/epithelial cells. Virus entry into human fibroblasts involves fusion of the virus envelope with the plasma membrane, whereas entry into endothelial/epithelial cells involves macropinocytosis or endocytosis and low-pH-dependent fusion with endosomes. A large set of neutralizing monoclonal antibodies (MAbs), directed to gH, gB, and multiple components of the pentamer, was developed. In addition, novel anti-gO human monoclonal antibodies were recently isolated. It is known that epithelial cell infection with a wild HCMV strain at a high multiplicity of infection produces a large number of syncytia. Incubation of heavily HCMV VR1814-infected ARPE-19 epithelial cells with neutralizing MAbs to one, two, or three components of the pUL128L portion of the pentamer blocked syncytium formation at an antibody concentration of 10 μg/ml, whereas only a partial inhibitory effect was displayed for MAbs to gO, gH, or gB at the same concentration. A blocking effect was also exhibited by convalescent-phase sera from primary HCMV infections. These findings indicate that the pentamer is required for syncytium formation in epithelial cells. IMPORTANCE Human cytomegalovirus (HCMV) mostly infects epithelial and endothelial cells in vivo. Recently, the pentamer protein complex (gH/gL/pUL128L) was identified as being required for infection of these cells, in association with the other protein complex, gH/gL/gO. In primary infections, HCMV migrates to endothelial cells and then to leukocytes

  8. Cytomegalovirus Reinfections Stimulate CD8 T-Memory Inflation

    PubMed Central

    Trgovcich, Joanne; Kincaid, Michelle; Thomas, Alicia; Griessl, Marion; Zimmerman, Peter; Dwivedi, Varun; Bergdall, Valerie; Klenerman, Paul

    2016-01-01

    Cytomegalovirus (CMV) has been shown to induce large populations of CD8 T-effector memory cells that unlike central memory persist in large quantities following infection, a phenomenon commonly termed “memory inflation”. Although murine models to date have shown very large and persistent CMV-specific T-cell expansions following infection, there is considerable variability in CMV-specific T-memory responses in humans. Historically such memory inflation in humans has been assumed a consequence of reactivation events during the life of the host. Because basic information about CMV infection/re-infection and reactivation in immune competent humans is not available, we used a murine model to test how primary infection, reinfection, and reactivation stimuli influence memory inflation. We show that low titer infections induce “partial” memory inflation of both mCMV specific CD8 T-cells and antibody. We show further that reinfection with different strains can boost partial memory inflation. Finally, we show preliminary results suggesting that a single strong reactivation stimulus does not stimulate memory inflation. Altogether, our results suggest that while high titer primary infections can induce memory inflation, reinfections during the life of a host may be more important than previously appreciated. PMID:27870919

  9. Preventing opportunistic infections in human immunodeficiency virus-infected persons: implications for the developing world.

    PubMed

    Kaplan, J E; Hu, D J; Holmes, K K; Jaffe, H W; Masur, H; De Cock, K M

    1996-07-01

    More than 18 million persons in the world are estimated to have been infected with human immunodeficiency virus (HIV), the cause of the acquired immunodeficiency syndrome (AIDS). As immunodeficiency progresses, these persons become susceptible to a wide variety of opportunistic infections (OIs) The spectrum of OIs varies among regions of the world. Tuberculosis is the most common serious OI in sub-Saharan Africa and is also more common in Latin America and in Asia than in the United States. Bacterial and parasitic infections are prevalent in Africa; protozoal infections such as toxoplasmosis, cryptosporidiosis, and isosporiasis are also common in Latin America. Fungal infections, including cryptococcosis and Penicillium marneffei infection, appear to be prevalent in Southeast Asia. Despite limited health resources in these regions, some measures that are recommended to prevent OIs in the United States may be useful for prolonging and improving the quality of life of HIV-infected persons. These include trimethoprim-sulfamethoxazole to prevent Pneumocystis carinii pneumonia, toxoplasmosis, and bacterial infections; isoniazid to prevent tuberculosis; and 23-valent pneumococcal vaccine to prevent disease due to Streptococcus pneumoniae. Research is needed to determine the spectrum of OIs and the efficacy of various prevention measures in resource-poor nations, and health officials need to determine a minimum standard of care for HIV-infected persons. An increasing problem in the developing world, HIV/AIDS should receive attention comparable to other tropical diseases.

  10. Analysis of the complete DNA sequence of murine cytomegalovirus.

    PubMed Central

    Rawlinson, W D; Farrell, H E; Barrell, B G

    1996-01-01

    The complete DNA sequence of the Smith strain of murine cytomegalovirus (MCMV) was determined from virion DNA by using a whole-genome shotgun approach. The genome has an overall G+C content of 58.7%, consists of 230,278 bp, and is arranged as a single unique sequence with short (31-bp) terminal direct repeats and several short internal repeats. Significant similarity to the genome of the sequenced human cytomegalovirus (HCMV) strain AD169 is evident, particularly for 78 open reading frames encoded by the central part of the genome. There is a very similar distribution of G+C content across the two genomes. Sequences toward the ends of the MCMV genome encode tandem arrays of homologous glycoproteins (gps) arranged as two gene families. The left end encodes 15 gps that represent one family, and the right end encodes a different family of 11 gps. A homolog (m144) of cellular major histocompatibility complex (MHC) class I genes is located at the end of the genome opposite the HCMV MHC class I homolog (UL18). G protein-coupled receptor (GCR) homologs (M33 and M78) occur in positions congruent with two (UL33 and UL78) of the four putative HCMV GCR homologs. Counterparts of all of the known enzyme homologs in HCMV are present in the MCMV genome, including the phosphotransferase gene (M97), whose product phosphorylates ganciclovir in HCMV-infected cells, and the assembly protein (M80). PMID:8971012

  11. Complete Sequence and Genomic Analysis of Rhesus Cytomegalovirus

    PubMed Central

    Hansen, Scott G.; Strelow, Lisa I.; Franchi, David C.; Anders, David G.; Wong, Scott W.

    2003-01-01

    The complete DNA sequence of rhesus cytomegalovirus (RhCMV) strain 68-1 was determined with the whole-genome shotgun approach on virion DNA. The RhCMV genome is 221,459 bp in length and possesses a 49% G+C base composition. The genome contains 230 potential open reading frames (ORFs) of 100 or more codons that are arranged colinearly with counterparts of previously sequenced betaherpesviruses such as human cytomegalovirus (HCMV). Of the 230 RhCMV ORFs, 138 (60%) are homologous to known HCMV proteins. The conserved ORFs include the structural, replicative, and transcriptional regulatory proteins, immune evasion elements, G protein-coupled receptors, and immunoglobulin homologues. Interestingly, the RhCMV genome also contains sequences with homology to cyclooxygenase-2, an enzyme associated with inflammatory processes. Closer examination identified a series of candidate exons with the capacity to encode a full-length cyclooxygenase-2 protein. Counterparts of cyclooxygenase-2 have not been found in other sequenced herpesviruses. The availability of the complete RhCMV sequence along with the ability to grow RhCMV in vitro will facilitate the construction of recombinant viral strains for identifying viral determinants of CMV pathogenicity in the experimentally infected rhesus macaque and to the development of CMV as a vaccine vector. PMID:12767982

  12. Clinical implications of nucleic acid amplification methods for the diagnosis of viral infections of the nervous system.

    PubMed

    Weber, T; Frye, S; Bodemer, M; Otto, M; Lüke, W

    1996-06-01

    Amplification of viral nucleic acids from the cerebrospinal fluid (CSF) has considerably improved the diagnosis of several acute, subacute and chronic viral infections of the nervous system. In herpes simplex virus (HSV) encephalitis (HSE) the polymerase chain reaction (PCR) has become the method of choice for the rapid, non invasive diagnosis. Other herpes virus associated diseases which can now be reliably diagnosed are encephalitis, ventriculoencephalitis, polymyeloradiculitis, myelitis and an inflammatory polyradiculoneuropathy caused by cytomegalovirus (CMV), HSV, varicella-zoster virus (VZV) or Epstein-Barr virus (EBV), EBV associated primary B-cell-lymphoma of the brain, acute aseptic meningitis in young adults allied with VZV, and meningoencephalitis with recurrent seizures due to human herpes virus type 6 (HHV-6). In AIDS patients, PCR has helped to differentiate lesions either due to the human immunodeficiency virus (HIV) itself or to opportunistic infections such as progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) or CMV related complications. HIV can be detected early in the course of infection in the CSF and the amount of proviral DNA in CSF cells seems to be correlated with the severity and/or progression of neurological signs and symptoms. Acute epidemic aseptic meningitis caused by enterovirus infections can now be reliably diagnosed and typed by reverse transcriptase PCR (RT-PCR). Meningitis cases caused by vaccination with the Jeryl Lynn and Urabe vaccine strain of mumps virus have been identified using RT-PCR and sequencing of the amplified products (amplicon).

  13. The molecular mechanism of human resistance to HIV-1 infection in persistently infected individuals--a review, hypothesis and implications.

    PubMed

    Becker, Yechiel

    2005-08-01

    Resistance to HIV-1 infection in Europeans is associated with a mutation in the gene that codes for the CCR5 protein that is present in Th2 cells and serves as a coreceptor for HIV-1 R5 strain. A deletion of 32 amino acids from the cytokine receptor prevents infection. This mutation prevails in Europeans and is absent in Africans. However, duplication of a gene that codes for a chemokine that binds to the CCR5 was discovered in Africans (mean gene copy 6 while in non-Africans the mean gene copy is 3). Higher expression of these genes protects T cells against HIV-1 infection in vitro. It should be noted that resistance to HIV-1 R5 variant does not protect against HIV-1 R4 variant. It was reported that a minority of highly HIV-1 exposed African professional sex workers (APSW) were resistant to the virus infection during a 10 years period. Recently, the analysis of the cytokines in the serum of the persistently infected seronegative women revealed that the latter hypo-expresses the cytokine IL-4. Since the molecular events during HIV-1 infection are associated with a marked increase in the levels of IL-4 and IgE in the sera of the infected individuals, it suggests that AIDS is an allergy. Thus, a very low level of IL-4 production may abrogate the virus infection. Studies on the human IL-4 gene revealed that together with the IL-4 mRNA a spliced variant with a deletion of exon 2 is synthesized. The latter is a natural antagonist of IL-4 and when expressed in an individual at a level higher than IL-4, the person will resist a microbial infection (e.g. Mycobacterium tuberculosis) or asthma. The present hypothesis suggests that the HIV-1 resistant APSWs produce more IL-4 delta 2 molecules than IL-4 molecules. The binding of IL-4 delta 2 to IL-4 receptors on T and B cells prevents their functions and the infection by HIV-1. The implications of these studies are that treatment of HIV-1 infected people with drugs that will block the IL-4 receptors will stop HIV-1 infections

  14. Cytomegalovirus pneumonia as the first manifestation of severe combined immunodeficiency

    PubMed Central

    Jończyk-Potoczna, Katarzyna; Ossowska, Lidia; Bręborowicz, Anna; Bartkowska-Śniatkowska, Alicja; Wachowiak, Jacek

    2014-01-01

    Severe combined immunodeficiency (SCID) is characterized by the absence of functional T lymphocytes and impairment of adaptive immunity. While heterogeneity of the genetic background in SCID leads to the variability of immune phenotypes, most of affected newborns appear healthy but within the first few months they develop life-threatening opportunistic respiratory or gastrointestinal tract infections. The objective of the study was to define the presenting features and etiology of infections in children with SCID. We retrospectively reviewed five children in whom the diagnosis of SCID had been established in our pediatric immunology clinic over the last 10-year period. A viral respiratory tract infection was the first manifestation of SCID in all the children studied. Cytomegalovirus (CMV) pneumonia was recognized in as many as 4 cases and coronavirus pulmonary infection was diagnosed in one case, whereas Pneumocystis jiroveci was identified as a co-pathogen in one CMV-infected patient. Severe combined immunodeficiency is a pediatric emergency condition and given the significant impact of pulmonary CMV infection in SCID children, establishing an accurate etiological diagnosis is of essential importance in instituting the specific treatment and improving the outcome. PMID:26155153

  15. A rare case intractable diarrhea secondary to Clostridium difficile and cytomegalovirus coinfection

    PubMed Central

    John, Santhosh Gheevarghese; Dominguez, Cristian; Chandiramani, Vijay; Vemulappalli, Tejo

    2013-01-01

    Patient: Male, 63 Final Diagnosis: Cytomegalo virus (CMV) infection Symptoms: Diarrhea Medication:— Clinical Procedure:— Specialty: Infectious Diseases Objective: Unusual clinical course Background: Coinfection with cytomegalovirus in a patient with Clostridium difficile persistent diarrhea and colitis can lead to a delay in diagnosis and treatment. Case Report: A 63-year-old man with squamous cell carcinoma of the lower lip, status post surgical resection and currently on chemoradiation presented with intractable diarrhea and abdominal pain. Initial workup showed Clostridium difficile diarrhea with pancolitis. Diarrhea persisted despite being on antibiotics and bacteriological cure for C. difficile. Further noninvasive work up revealed associated cytomegalovirus infection, and patient had a dramatic response to ganciclovir without any relapse. Conclusions: Physicians should be cognizant about other causes of diarrhea and colitis in immunocompromised patient when treatment for primary diagnosis fails to resolve their symptoms. PMID:24298304

  16. Enhancement of Herpes Simplex Virus (HSV) Infection by Seminal Plasma and Semen Amyloids Implicates a New Target for the Prevention of HSV Infection

    PubMed Central

    Torres, Lilith; Ortiz, Tatiana; Tang, Qiyi

    2015-01-01

    Human herpesviruses cause different infectious diseases, resulting in world-wide health problems. Sexual transmission is a major route for the spread of both herpes simplex virus-1 (HSV-1) and -2. Semen plays an important role in carrying the viral particle that invades the vaginal or rectal mucosa and, thereby, initiates viral replication. Previously, we demonstrated that the amyloid fibrils semenogelin (SEM) and semen-derived enhancer of viral infection (SEVI), and seminal plasma (SP) augment cytomegalovirus infection (Tang et al., J. Virol 2013). Whether SEM or SEVI amyloids or SP could also enhance other herpesvirus infections has not been examined. In this study, we found that the two amyloids as well as SP strongly enhance both HSV-1 and -2 infections in cell culture. Along with SP, SEM and SEVI amyloids enhanced viral entry and increased infection rates by more than 10-fold, as assessed by flow cytometry assay and fluorescence microscopy. Viral replication was increased by about 50- to 100-fold. Moreover, viral growth curve assays showed that SEM and SEVI amyloids, as well as SP, sped up the kinetics of HSV replication such that the virus reached its replicative peak more quickly. The interactions of SEM, SEVI, and SP with HSVs are direct. Furthermore, we discovered that the enhancing effects of SP, SEM, and SEVI can be significantly reduced by heparin, a sulfated polysaccharide with an anionic charge. It is probable that heparin abrogates said enhancing effects by interfering with the interaction of the viral particle and the amyloids, which interaction results in the binding of the viral particles and both SEM and SEVI. PMID:25903833

  17. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation.

    PubMed

    Kotton, Camille N; Kumar, Deepali; Caliendo, Angela M; Asberg, Anders; Chou, Sunwen; Snydman, David R; Allen, Upton; Humar, Atul

    2010-04-15

    Cytomegalovirus (CMV) remains one of the most common infections after solid organ transplantation, resulting in significant morbidity, graft loss, and occasional mortality. Management of CMV varies considerably among transplant centers. A panel of experts on CMV and solid organ transplant was convened by The Infectious Diseases Section of The Transplantation Society to develop evidence and expert opinion-based consensus guidelines on CMV management including diagnostics, immunology, prevention, treatment, drug resistance, and pediatric issues.

  18. Human cytomegalovirus function inhibits replication of herpes simplex virus

    SciTech Connect

    Cockley, K.D.; Shiraki, K.; Rapp, F.

    1988-01-01

    Human embryonic lung (HEL) cells infected with human cytomegalovirus (HCMV) restricted the replication of herpes simplex virus type 1 (HSV-1). A delay in HSV replication of 15 h as well as a consistent, almost 3 log inhibition of HSV replication in HCMV-infected cell cultures harvested 24 to 72 h after superinfection were observed compared with controls infected with HSV alone. Treatment of HCMV-infected HEL cells with cycloheximide (100 ..mu..g/ml) for 3 or 24 h was demonstrated effective in blocking HCMV protein synthesis, as shown by immunoprecipitation with HCMV antibody-positive polyvalent serum. Cycloheximide treatment of HCMV-infected HEL cells and removal of the cycloheximide block before superinfection inhibited HSV-1 replication more efficiently than non-drug-treated superinfected controls. HCMV DNA-negative temperature-sensitive mutants restricted HSV as efficiently as wild-type HCMV suggesting that immediate-early and/or early events which occur before viral DNA synthesis are sufficient for inhibition of HSV. Inhibition of HSV-1 in HCMV-infected HEL cells was unaffected by elevated temperature (40.5/sup 0/C). However, prior UV irradiation of HCMV removed the block to HSV replication, demonstrating the requirement for an active HCMV genome. HSV-2 replication was similarly inhibited in HCMV-infected HEL cells. Superinfection of HCMV-infected HEL cells with HSV-1 labeled with (/sup 3/H)thymidine provided evidence that the labeled virus could penetrate to the nucleus of cells after superinfection. Evidence for penetration of superinfecting HSV into HCMV-infected cells was also provided by blot hybridization of HSV DNA synthesized in cells infected with HSV alone versus superinfected cell cultures at 0 and 48 h after superinfection.

  19. Molecular and Culture-Based Bronchoalveolar Lavage Fluid Testing for the Diagnosis of Cytomegalovirus Pneumonitis

    PubMed Central

    Tan, Susanna K.; Burgener, Elizabeth B.; Waggoner, Jesse J.; Gajurel, Kiran; Gonzalez, Sarah; Chen, Sharon F.; Pinsky, Benjamin A.

    2016-01-01

    Background. Cytomegalovirus (CMV) is a major cause of morbidity and mortality in immunocompromised patients, with CMV pneumonitis among the most severe manifestations of infection. Although bronchoalveolar lavage (BAL) samples are frequently tested for CMV, the clinical utility of such testing remains uncertain. Methods. Retrospective analysis of adult patients undergoing BAL testing via CMV polymerase chain reaction (PCR), shell vial culture, and conventional viral culture between August 2008 and May 2011 was performed. Cytomegalovirus diagnostic methods were compared with a comprehensive definition of CMV pneumonitis that takes into account signs and symptoms, underlying host immunodeficiency, radiographic findings, and laboratory results. Results. Seven hundred five patients underwent 1077 bronchoscopy episodes with 1090 BAL specimens sent for CMV testing. Cytomegalovirus-positive patients were more likely to be hematopoietic cell transplant recipients (26% vs 8%, P < .0001) and less likely to have an underlying condition not typically associated with lung disease (3% vs 20%, P < .0001). Histopathology was performed in only 17.3% of CMV-positive bronchoscopy episodes. When CMV diagnostic methods were evaluated against the comprehensive definition, the sensitivity and specificity of PCR, shell vial culture, and conventional culture were 91.3% and 94.6%, 54.4% and 97.4%, and 28.3% and 96.5%, respectively. Compared with culture, PCR provided significantly higher sensitivity and negative predictive value (P ≤ .001), without significantly lower positive predictive value. Cytomegalovirus quantitation did not improve test performance, resulting in a receiver operating characteristic curve with an area under the curve of 0.53. Conclusions. Cytomegalovirus PCR combined with a comprehensive clinical definition provides a pragmatic approach for the diagnosis of CMV pneumonitis. PMID:26885542

  20. Estrogen-related receptor α is required for efficient human cytomegalovirus replication

    PubMed Central

    Hwang, Jesse; Purdy, John G.; Wu, Kai; Rabinowitz, Joshua D.; Shenk, Thomas

    2014-01-01

    An shRNA-mediated screen of the 48 human nuclear receptor genes identified multiple candidates likely to influence the production of human cytomegalovirus in cultured human fibroblasts, including the estrogen-related receptor α (ERRα), an orphan nuclear receptor. The 50-kDa receptor and a 76-kDa variant were induced posttranscriptionally following infection. Genetic and pharmacological suppression of the receptor reduced viral RNA, protein, and DNA accumulation, as well as the yield of infectious progeny. In addition, RNAs encoding multiple metabolic enzymes, including enzymes sponsoring glycolysis (enolase 1, triosephosphate isomerase 1, and hexokinase 2), were reduced when the function of ERRα was inhibited in infected cells. Consistent with the effect on RNAs, a substantial number of metabolites, which are normally induced by infection, were either not increased or were increased to a reduced extent in the absence of normal ERRα activity. We conclude that ERRα is needed for the efficient production of cytomegalovirus progeny, and we propose that the nuclear receptor contributes importantly to the induction of a metabolic environment that supports optimal cytomegalovirus replication. PMID:25512541

  1. Cytomegalovirus immune evasion by perturbation of endosomal trafficking

    PubMed Central

    Lučin, Pero; Mahmutefendić, Hana; Blagojević Zagorac, Gordana; Ilić Tomaš, Maja

    2015-01-01

    Cytomegaloviruses (CMVs), members of the herpesvirus family, have evolved a variety of mechanisms to evade the immune response to survive in infected hosts and to establish latent infection. They effectively hide infected cells from the effector mechanisms of adaptive immunity by eliminating cellular proteins (major histocompatibility Class I and Class II molecules) from the cell surface that display viral antigens to CD8 and CD4 T lymphocytes. CMVs also successfully escape recognition and elimination of infected cells by natural killer (NK) cells, effector cells of innate immunity, either by mimicking NK cell inhibitory ligands or by downregulating NK cell-activating ligands. To accomplish these immunoevasion functions, CMVs encode several proteins that function in the biosynthetic pathway by inhibiting the assembly and trafficking of cellular proteins that participate in immune recognition and thereby, block their appearance at the cell surface. However, elimination of these proteins from the cell surface can also be achieved by perturbation of their endosomal route and subsequent relocation from the cell surface into intracellular compartments. Namely, the physiological route of every cellular protein, including immune recognition molecules, is characterized by specific features that determine its residence time at the cell surface. In this review, we summarize the current understanding of endocytic trafficking of immune recognition molecules and perturbations of the endosomal system during infection with CMVs and other members of the herpesvirus family that contribute to their immune evasion mechanisms. PMID:25263490

  2. Human embryonic stem cell lines model experimental human cytomegalovirus latency.

    PubMed

    Penkert, Rhiannon R; Kalejta, Robert F

    2013-05-28

    Herpesviruses are highly successful pathogens that persist for the lifetime of their hosts primarily because of their ability to establish and maintain latent infections from which the virus is capable of productively reactivating. Human cytomegalovirus (HCMV), a betaherpesvirus, establishes latency in CD34(+) hematopoietic progenitor cells during natural infections in the body. Experimental infection of CD34(+) cells ex vivo has demonstrated that expression of the viral gene products that drive productive infection is silenced by an intrinsic immune defense mediated by Daxx and histone deacetylases through heterochromatinization of the viral genome during the establishment of latency. Additional mechanistic details about the establishment, let alone maintenance and reactivation, of HCMV latency remain scarce. This is partly due to the technical challenges of CD34(+) cell culture, most notably, the difficulty in preventing spontaneous differentiation that drives reactivation and renders them permissive for productive infection. Here we demonstrate that HCMV can establish, maintain, and reactivate in vitro from experimental latency in cultures of human embryonic stem cells (ESCs), for which spurious differentiation can be prevented or controlled. Furthermore, we show that known molecular aspects of HCMV latency are faithfully recapitulated in these cells. In total, we present ESCs as a novel, tractable model for studies of HCMV latency.

  3. Cytomegalovirus and ulcerative colitis: Place of antiviral therapy

    PubMed Central

    Pillet, Sylvie; Pozzetto, Bruno; Roblin, Xavier

    2016-01-01

    The link between cytomegalovirus (CMV) infection and inflammatory bowel diseases remains an important subject of debate. CMV infection is frequent in ulcerative colitis (UC) and has been shown to be potentially harmful. CMV reactivation needs to be diagnosed using methods that include in situ detection of viral markers by immunohistochemistry or by nucleic acid amplification techniques. Determination of the density of infection using quantitative tools (numbers of infected cells or copies of the genome) is particularly important. Although CMV reactivation can be considered as an innocent bystander in active flare-ups of refractory UC, an increasing number of studies suggest a deleterious role of CMV in this situation. The presence of colonic CMV infection is possibly linked to a decreased response to steroids and other immunosuppressive agents. Some treatments, notably steroids and cyclosporine A, have been shown to favor CMV reactivation, which seems not to be the case for therapies using anti-tumor necrosis factor drugs. According to these findings, in flare-ups of refractory UC, it is now recommended to look for the presence of CMV reactivation by using quantitative tools in colonic biopsies and to treat them with ganciclovir in cases of high viral load or severe disease. PMID:26877608

  4. Growth of Murine Cytomegalovirus in Various Cell Lines

    PubMed Central

    Kim, Kwang Soo; Carp, Richard I.

    1971-01-01

    Murine cytomegalovirus (MCMV) was capable of infecting and replicating in both primary and continuous cell lines obtained from various species. In African green monkey kidney (BSC-1) cells, primary rabbit kidney cells, and baby hamster kidney (BHK-21) cells, there were cytopathic effects (CPE) and virus replication upon initial exposure of cells to virus. In primary fetal sheep brain (FSB) cells, L cells, and rabbit kidney (RK-13) cells, it was necessary to subculture the infected cells one or more times before appearance of CPE and replication of virus. In the case of the infected FSB cultures, it was found that the virus effect could be induced if subculturing were accomplished by trypsinization but did not occur if cells were subcultured by scraping. FSB-grown virus replicated better in FSB than in mouse embryo fibroblast (MEF) cells. The CPE produced in all of the above cell lines was similar to that observed in MEF infected with MCMV. The virus grown in different cell lines was completely neutralized when mixed with several reference sera prepared in rabbits or mice. The populations of virions released from infected MEF and FSB cells were compared by isopycnic centrifugation in potassium tartrate, and no differences were revealed in the buoyant densities of the populations. Human embryonic brain cells, human embryonic kidney cells, a human lung fibroblast cell strain (WI-38), HeLa, and Hep-2 were not susceptible to MCMV. PMID:4327583

  5. Controlling cytomegalovirus: helping the immune system take the lead.

    PubMed

    Hanley, Patrick J; Bollard, Catherine M

    2014-05-27

    Cytomegalovirus, of the Herpesviridae family, has evolved alongside humans for thousands of years with an intricate balance of latency, immune evasion, and transmission. While upwards of 70% of humans have evidence of CMV infection, the majority of healthy people show little to no clinical symptoms of primary infection and CMV disease is rarely observed during persistent infection in immunocompetent hosts. Despite the fact that the majority of infected individuals are asymptomatic, immunologically, CMV hijacks the immune system by infecting and remaining latent in antigen-presenting cells that occasionally reactivate subclinically and present antigen to T cells, eventually causing the inflation of CMV-specific T cells until they can compromise up to 10% of the entire T cell repertoire. Because of this impact on the immune system, as well as its importance in fields such as stem cell and organ transplant, the relationship between CMV and the immune response has been studied in depth. Here we provide a review of many of these studies and insights into how CMV-specific T cells are currently being used therapeutically.

  6. Case report: persistent cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation using in vivo alemtuzumab: emergence of resistant CMV due to mutations in the UL97 and UL54 genes.

    PubMed

    Oshima, Kumi; Kanda, Yoshinobu; Kako, Shinichi; Asano-Mori, Yuki; Watanabe, Takuro; Motokura, Toru; Chiba, Shigeru; Shiraki, Kimiyasu; Kurokawa, Mineo

    2008-10-01

    Addition of in vivo alemtuzumab to the conditioning regimen enabled 2- or 3-locus-mismatched hematopoietic stem cell transplantation with an acceptable incidence of graft-versus-host-disease. However, the procedure was associated with a high incidence of cytomegalovirus (CMV) reactivation. Although preemptive therapy with ganciclovir prevented successfully severe CMV diseases and CMV-related mortality, a patient developed persistent positive CMV antigenemia for more than 1 year after transplantation and CMV disease, despite the use of ganciclovir and foscarnet. The in vitro susceptibility assay showed that the clinical isolate was resistant to foscarnet, moderately resistant to ganciclovir, but sensitive to cidofovir. Therefore, cidofovir was administered. CMV antigenemia became negative within 2 weeks and never developed again. Nucleotide sequence of the UL54 and UL97 of the clinical isolate showed 4 amino acid substitutions (V11L, Q578H, S655L, and G874R) in UL54 and 2 mutations (A140V and A594V) in UL97 compared with the Towne and AD169 strains. Ganciclovir resistance was suspected to be caused by both A594V of UL97 and Q578H of UL54, whereas foscarnet resistance was due mainly to Q578H of UL54. In conclusion, the in vitro susceptibility assay as well as nucleotide sequence of clinical isolate is important to choose appropriate antiviral agents for patients who have persistent CMV reactivation after stem cell transplantation.

  7. Human antibody technology and the development of antibodies against cytomegalovirus.

    PubMed

    Ohlin, Mats; Söderberg-Nauclér, Cecilia

    2015-10-01

    Cytomegalovirus (CMV) is a virus that causes chronic infections in a large set of the population. It may cause severe disease in immunocompromised individuals, is linked to immunosenescence and implied to play an important role in the pathogenesis of cardiovascular diseases and cancer. Modulation of the immune system's abilities to manage the virus represent a highly viable therapeutic option and passive immunotherapy with polyclonal antibody preparations is already in clinical use. Defined monoclonal antibodies offer many advantages over polyclonal antibodies purified from serum. Human CMV-specific monoclonal antibodies have consequently been thoroughly investigated with respect to their potential in the treatment of diseases caused by CMV. Recent advances in human antibody technology have substantially expanded the breadth of antibodies for such applications. This review summarizes the fundamental basis for treating CMV disease by use of antibodies, the basic technologies to be used to develop such antibodies, and relevant human antibody specificities available to target this virus.

  8. Cytomegalovirus-targeted immunotherapy and glioblastoma: hype or hope?

    PubMed

    Ferguson, Sherise D; Srinivasan, Visish M; Ghali, Michael Gz; Heimberger, Amy B

    2016-01-01

    Malignant gliomas, including glioblastoma (GBM), are the most common primary brain tumors. Despite extensive research only modest gains have been made in long-term survival. Standard of care involves maximizing safe surgical resection followed by concurrent chemoradiation with temozolomide. Immunotherapy for GBM is an area of intense research in recent years. New immunotherapies, although promising, have not been integrated into standard practice. Human cytomegalovirus (HCMV) is a DNA virus of the family Herpesviridae. Human seroprevalence is approximately 80%, and in most cases, is associated with asymptomatic infection. HCMV may be an important agent in the initiation, promotion and/or progression of tumorigenesis. Regardless of a possible etiologic role in GBM, interest has centered on exploiting this association for development of immunomodulatory therapies.

  9. Properties and mechanisms of immunoglobulins for congenital cytomegalovirus disease.

    PubMed

    Parruti, Giustino; Polilli, Ennio; Ursini, Tamara; Tontodonati, Monica

    2013-12-01

    Immunoglobulins are one major component of adaptive immunity to external and resident microorganisms, evolving very early in phylogenesis. They help eukaryotes in controlling infections, mainly through their neutralizing activity, which quenches both the cytopathic and inflammatory potential of invading microorganisms. Cytomegalovirus (CMV)-related disease is generally blunted in seropositive subjects with conserved specific humoral responses. CMV-seropositive pregnant women, in accordance with such evidence, suffer little or no fetal damage when reexposed to CMV. Several seminal experiences and early experimental models confirmed that repeated infusions of immunoglobulins, either with hyperimmune or standard preparations, may help to reduce maternal-fetal CMV transmission, as well as to quench fetal disease upon transmission. This review focused on experimental evidence supporting the potential role of immunoglobulins as a tool to control fetal CMV-related disease in pregnant women.

  10. Congenital Cytomegalovirus: a "Now" Problem-No Really, Now.

    PubMed

    Bernstein, David I

    2017-01-01

    Despite the clear need, progress toward a vaccine for congenital cytomegalovirus (CMV) has been slow. However, recent events have provided new interest, and several vaccine candidates are either in clinical trials or the trials are close to starting. In this issue of Clinical and Vaccine Immunology, Schleiss and colleagues show that a nonreplicating lymphocytic choriomeningitis virus (rLCMV)-vectored vaccine expressing CMV glycoprotein B (gB) and/or pp65 induces B and T cells and improves pup survival in a guinea pig model of congenital CMV infection (Clin Vaccine Immunol 24:e00300-16, 2017, https://doi.org/10.1128/CVI.00300-16). The combination vaccine appeared to be the most effective.

  11. Fluorescence-Based Laser Capture Microscopy Technology Facilitates Identification of Critical In Vivo Cytomegalovirus Transcriptional Programs

    PubMed Central

    Kreklywich, Craig N.; Smith, Patricia P.; Jones, Carmen Baca; Cornea, Anda; Orloff, Susan L.; Streblow, Daniel N.

    2015-01-01

    Summary Cytomegalovirus gene expression in highly permissive, cultured fibroblasts occurs in three kinetic classes known as immediate early, early and late. Infection of these cells results in a predictable transcriptional program leading to high levels of virus production. Infection of other, so called, “non-permissive cell types” results in a transcriptional program that either fails to produce virus particles or production is substantially reduced compared to fibroblasts. We have found that CMV gene expression profiles in tissues from infected hosts differ greatly from those observed in infected tissue culture cells. The number of viral genes expressed in tissues is much more limited, and the number of highly active genes does not correlate with viral DNA load. Additionally, viral gene expression in vivo is tissue selective with no two tissues expressing the exact same viral gene profile. Thus, in vivo CMV gene expression appears to be governed by mechanisms that are still uncharacterized. Cytomegalovirus remains in a persistent phase for the lifetime of the host. During this phase only a limited number of host cells are infected, and it is very difficult to detect CMV gene expression in whole tissues without sub-fractionating infected vs. uninfected cells. Herein, we describe the development of a fluorescence-based laser capture microscopy technique coupled with small sample size microarray analysis to determine the viral gene expression in 50–100 infected cells isolated from frozen RCMV-infected tissue sections. PMID:24639226

  12. Medical and Legal Implications of Testing for Sexually Transmitted Infections in Children

    PubMed Central

    Hammerschlag, Margaret R.; Guillén, Christina D.

    2010-01-01

    Summary: Testing for sexually transmitted infections (STIs) in children presents a number of problems for the practitioner that are not usually faced when testing adults for the same infections. The identification of an STI in a child can have, in addition to medical implications, serious legal implications. The presence of an STI is often used to support the presence or allegations of sexual abuse, and conversely, the identification of an STI in a child will prompt an investigation of possible abuse. The purpose of this paper is to review the epidemiology of child sexual abuse, including the epidemiology of major STIs including Neisseria gonorrhoeae, Chlamydia trachomatis, syphilis, herpes simplex virus (HSV), Trichomonas vaginalis, and human papillomavirus, and the current recommendations for diagnostic testing in this population. PMID:20610820

  13. Murine Cytomegalovirus Exploits Olfaction To Enter New Hosts

    PubMed Central

    Farrell, Helen E.; Lawler, Clara; Tan, Cindy S. E.; MacDonald, Kate; Bruce, Kimberley; Mach, Michael; Davis-Poynter, Nick

    2016-01-01

    ABSTRACT   Viruses transmit via the environmental and social interactions of their hosts. Herpesviruses have colonized mammals since their earliest origins, suggesting that they exploit ancient, common pathways. Cytomegaloviruses (CMVs) are assumed to enter new hosts orally, but no site has been identified. We show by live imaging that murine CMV (MCMV) infects nasally rather than orally, both after experimental virus uptake and during natural transmission. Replication-deficient virions revealed the primary target as olfactory neurons. Local, nasal replication by wild-type MCMV was not extensive, but there was rapid systemic spread, associated with macrophage infection. A long-term, transmissible infection was then maintained in the salivary glands. The viral m131/m129 chemokine homolog, which influences tropism, promoted salivary gland colonization after nasal entry but was not required for entry per se. The capacity of MCMV to transmit via olfaction, together with previous demonstrations of experimental olfactory infection by murid herpesvirus 4 (MuHV-4) and herpes simplex virus 1 (HSV-1), suggest that this is a common, conserved route of mammalian herpesvirus entry. PMID:27118588

  14. Transmission of viral infections by the water route: implications for developing countries.

    PubMed

    Ramia, S

    1985-01-01

    The "enteric" virus group comprises greater than 100 different viruses. These viruses typically infect the cell lining of the alimentary canal and are discharged in very large numbers in the feces of infected persons. Contamination of water supplies by enteric viruses represents an important source of viral infection. Many communities, particularly in developing countries, depend on sewage-polluted sources for their recreational and drinking water. Because conventional methods of sewage and water treatment have proved inefficient in the removal and inactivation of most enteric viruses, great concern has been raised over the impact of waterborne infection on the health of such communities. Current evidence implicating drinking and recreational water supplies in the transmission of nonbacterial gastroenteritis and hepatitis A virus and adenovirus infections is overwhelming. Water-borne transmission of other enteric viruses is also possible. Effective antiviral drugs are generally unavailable, and current vaccines can control only a limited number of viral infections; therefore, provision of uncontaminated water is a basic requirement in raising the standard of health in affected communities.

  15. Assessing coughing-induced influenza droplet transmission and implications for infection risk control.

    PubMed

    Cheng, Y-H; Wang, C-H; You, S-H; Hsieh, N-H; Chen, W-Y; Chio, C-P; Liao, C-M

    2016-01-01

    Indoor transmission of respiratory droplets bearing influenza within humans poses high risks to respiratory function deterioration and death. Therefore, we aimed to develop a framework for quantifying the influenza infection risk based on the relationships between inhaled/exhaled respiratory droplets and airborne transmission dynamics in a ventilated airspace. An experiment was conducted to measure the size distribution of influenza-containing droplets produced by coughing for a better understanding of potential influenza spread. Here we integrated influenza population transmission dynamics, a human respiratory tract model, and a control measure approach to examine the indoor environment-virus-host interactions. A probabilistic risk model was implemented to assess size-specific infection risk for potentially transmissible influenza droplets indoors. Our results found that there was a 50% probability of the basic reproduction number (R0) exceeding 1 for small-size influenza droplets of 0·3-0·4 µm, implicating a potentially high indoor infection risk to humans. However, a combination of public health interventions with enhanced ventilation could substantially contain indoor influenza infection. Moreover, the present dynamic simulation and control measure assessment provide insights into why indoor transmissible influenza droplet-induced infection is occurring not only in upper lung regions but also in the lower respiratory tract, not normally considered at infection risk.

  16. A review of newly approved antibiotics and antibiotics reserved for resistant infections: Implications for emergency medicine.

    PubMed

    Mazer-Amirshahi, Maryann; Pourmand, Ali; May, Larissa

    2016-10-17

    Millions of patients are evaluated every year in the emergency department (ED) for bacterial infections. Emergency physicians often diagnose and prescribe initial antibiotic therapy for a variety of bacterial infections, ranging from simple urinary tract infections to severe sepsis. In life-threatening infections, inappropriate choice of initial antibiotic has been shown to increase morbidity and mortality. As such, initiation of appropriate antibiotic therapy on the part of the emergency physician is critical. Increasing rates of antibiotic resistance, drug allergies, and antibiotic shortages further complicates the choice of antibiotics. Patients may have a history of prior resistant infections or culture data indicating that common first-line antibiotics used in the ED may be ineffective. In recent years, there have been several new antibiotic approvals as well as renewed interest in second and third line antibiotics because of the aforementioned concerns. In addition, several newly approved antibiotics have the advantage of being administered once weekly or even as a single infusion, which has the potential to decrease hospitalizations and healthcare costs. This article reviews newly approved antibiotics and antibiotics used to treat resistant infections with a focus on implications for emergency medicine.

  17. Outcomes of co-infection by two potyviruses: implications for the evolution of manipulative strategies

    PubMed Central

    Salvaudon, Lucie; De Moraes, Consuelo M.; Mescher, Mark C.

    2013-01-01

    Recent studies have documented effects of plant viruses on host plants that appear to enhance transmission by insect vectors. But, almost no empirical work has explored the implications of such apparent manipulation for interactions among co-infecting pathogens. We examined single and mixed infections of two potyviruses, watermelon mosaic virus (WMV) and zucchini yellow mosaic virus (ZYMV), that frequently co-occur in cucurbitaceae populations and share the same aphid vectors. We found that ZYMV isolates replicated at similar rates in single and mixed infections, whereas WMV strains accumulated to significantly lower levels in the presence of ZYMV. Furthermore, ZYMV induced changes in leaf colour and volatile emissions that enhanced aphid (Aphis gossypii) recruitment to infected plants. By contrast, WMV did not elicit strong effects on plant–aphid interactions. Nevertheless, WMV was still readily transmitted from mixed infections, despite fairing poorly in in-plant competition. These findings suggest that pathogen effects on host–vector interactions may well influence competition among co-infecting pathogens. For example, if non-manipulative pathogens benefit from the increased vector traffic elicited by manipulative competitors, their costs of competition may be mitigated to some extent. Conversely, the benefits of manipulation may be limited by free-rider effects in systems where there is strong competition among pathogens for host resources and/or access to vectors. PMID:23407835

  18. Outcomes of co-infection by two potyviruses: implications for the evolution of manipulative strategies.

    PubMed

    Salvaudon, Lucie; De Moraes, Consuelo M; Mescher, Mark C

    2013-04-07

    Recent studies have documented effects of plant viruses on host plants that appear to enhance transmission by insect vectors. But, almost no empirical work has explored the implications of such apparent manipulation for interactions among co-infecting pathogens. We examined single and mixed infections of two potyviruses, watermelon mosaic virus (WMV) and zucchini yellow mosaic virus (ZYMV), that frequently co-occur in cucurbitaceae populations and share the same aphid vectors. We found that ZYMV isolates replicated at similar rates in single and mixed infections, whereas WMV strains accumulated to significantly lower levels in the presence of ZYMV. Furthermore, ZYMV induced changes in leaf colour and volatile emissions that enhanced aphid (Aphis gossypii) recruitment to infected plants. By contrast, WMV did not elicit strong effects on plant-aphid interactions. Nevertheless, WMV was still readily transmitted from mixed infections, despite fairing poorly in in-plant competition. These findings suggest that pathogen effects on host-vector interactions may well influence competition among co-infecting pathogens. For example, if non-manipulative pathogens benefit from the increased vector traffic elicited by manipulative competitors, their costs of competition may be mitigated to some extent. Conversely, the benefits of manipulation may be limited by free-rider effects in systems where there is strong competition among pathogens for host resources and/or access to vectors.

  19. The Excess Burden of Cytomegalovirus in African American Communities: A Geospatial Analysis

    PubMed Central

    Lantos, Paul M.; Permar, Sallie R.; Hoffman, Kate; Swamy, Geeta K.

    2015-01-01

    Background. Cytomegalovirus (CMV) is a common cause of birth defects and hearing loss in infants and opportunistic infections in the immunocompromised. Previous studies have found higher CMV seroprevalence rates among minorities and among persons with lower socioeconomic status. No studies have investigated the geographic distribution of CMV and its relationship to age, race, and poverty in the community. Methods. We identified patients from 6 North Carolina counties who were tested in the Duke University Health System for CMV immunoglobulin G. We performed spatial statistical analyses to analyze the distributions of seropositive and seronegative individuals. Results. Of 1884 subjects, 90% were either white or African American. Cytomegalovirus seropositivity was significantly more common among African Americans (73% vs 42%; odds ratio, 3.31; 95% confidence interval, 2.7–4.1), and this disparity persisted across the life span. We identified clusters of high and low CMV odds, both of which were largely explained by race. Clusters of high CMV odds were found in communities with high proportions of African Americans. Conclusions. Cytomegalovirus seropositivity is geographically clustered, and its distribution is strongly determined by a community's racial composition. African American communities have high prevalence rates of CMV infection, and there may be a disparate burden of CMV-associated morbidity in these communities. PMID:26716106

  20. Complex Dynamics of Virus Spread from Low Infection Multiplicities: Implications for the Spread of Oncolytic Viruses

    PubMed Central

    Rodriguez-Brenes, Ignacio A.; Hofacre, Andrew; Fan, Hung; Wodarz, Dominik

    2017-01-01

    While virus growth dynamics have been well-characterized in several infections, data are typically collected once the virus population becomes easily detectable. Earlier dynamics, however, remain less understood. We recently reported unusual early dynamics in an experimental system using adenovirus infection of human embryonic kidney (293) cells. Under identical experimental conditions, inoculation at low infection multiplicities resulted in either robust spread, or in limited spread that eventually stalled, with both outcomes occurring with approximately equal frequencies. The reasons underlying these observations have not been understood. Here, we present further experimental data showing that inhibition of interferon-induced antiviral states in cells results in a significant increase in the percentage of robust infections that are observed, implicating a race between virus replication and the spread of the anti-viral state as a central mechanism. Analysis of a variety of computational models, however, reveals that this alone cannot explain the simultaneous occurrence of both viral growth outcomes under identical conditions, and that additional biological mechanisms have to be invoked to explain the data. One such mechanism is the ability of the virus to overcome the antiviral state through multiple infection of cells. If this is included in the model, two outcomes of viral spread are found to be simultaneously stable, depending on initial conditions. In stochastic versions of such models, the system can go by chance to either state from identical initial conditions, with the relative frequency of the outcomes depending on the strength of the interferon-based anti-viral response, consistent with the experiments. This demonstrates considerable complexity during the early phase of the infection that can influence the ability of a virus to become successfully established. Implications for the initial dynamics of oncolytic virus spread through tumors are discussed

  1. Human cytomegalovirus interleukin-10 polarizes monocytes toward a deactivated M2c phenotype to repress host immune responses.

    PubMed

    Avdic, Selmir; Cao, John Z; McSharry, Brian P; Clancy, Leighton E; Brown, Rebecca; Steain, Megan; Gottlieb, David J; Abendroth, Allison; Slobedman, Barry

    2013-09-01

    Several human cytomegalovirus (HCMV) genes encode products that modulate cellular functions in a manner likely to enhance viral pathogenesis. This includes UL111A, which encodes homologs of human interleukin-10 (hIL-10). Depending upon signals received, monocytes and macrophages become polarized to either classically activated (M1 proinflammatory) or alternatively activated (M2 anti-inflammatory) subsets. Skewing of polarization toward an M2 subset may benefit the virus by limiting the proinflammatory responses to infection, and so we determined whether HCMV-encoded viral IL-10 influenced monocyte polarization. Recombinant viral IL-10 protein polarized CD14(+) monocytes toward an anti-inflammatory M2 subset with an M2c phenotype, as demonstrated by high expression of CD163 and CD14 and suppression of major histocompatibility complex (MHC) class II. Significantly, in the context of productive HCMV infection, viral IL-10 produced by infected cells polarized uninfected monocytes toward an M2c phenotype. We also assessed the impact of viral IL-10 on heme oxygenase 1 (HO-1), which is an enzyme linked with suppression of inflammatory responses. Polarization of monocytes by viral IL-10 resulted in upregulation of HO-1, and inhibition of HO-1 function resulted in a loss of capacity of viral IL-10 to suppress tumor necrosis factor alpha (TNF-α) and IL-1β, implicating HO-1 in viral IL-10-induced suppression of proinflammatory cytokines by M2c monocytes. In addition, a functional consequence of monocytes polarized with viral IL-10 was a decreased capacity to activate CD4(+) T cells. This study identifies a novel role for viral IL-10 in driving M2c polarization, which may limit virus clearance by restricting proinflammatory and CD4(+) T cell responses at sites of infection.

  2. Seroprevalence and Seroconversion Rates of Cytomegalovirus pp65 Antigen and Cord Blood Screening of Pregnant Women in Malatya, Turkey

    PubMed Central

    Dogan, Keziban; Kafkasli, Ayse; Kaya, Cihan; Cengiz, Huseyin

    2013-01-01

    Objective: The rates of seropositivity, seroconversion and fetal infection with human cytomegalovirus were analyzed in pregnant women and newborn cord blood in this study. The relationships between maternal age, parity, cytomegalovirus serology and polymerase chain reaction results were evaluated. Materials and Methods: A total of 217 pregnant women attended our pregnancy clinic between April 2004 and October 2005. During each trimester, 5 cc of maternal blood was obtained and 5 cc of cord blood was collected after birth. An enzyme-linked immunosorbent assay (ELISA) was used to assess these samples for the presence of human cytomegalovirus protein pp65 antigen (in leukocytes) and cytomegalovirus DNA (in plasma). Results: The mean age of the pregnant women in our study was 28.1±5.3 years. No seroconversion was observed. Among the pregnant women, 212 (97.7%) were IgG positive, and 29 (13.4%) were IgM positive. Five of the pregnant women were positive for IgM alone (2.3%), whereas 24 (11.3%) were positive for both IgM and IgG. The 29 IgM-positive patients were reevaluated using the polymerase chain reaction, and no seropositivity was found. None of the cord blood samples were IgM positive, whereas 211 (97.3%) were IgG positive. There was no significant correlation between parity and seropositivity (p=0.487). The relationship between human cytomegalovirus seropositivity and maternal age was evaluated by dividing the pregnant women into two groups, with a cut-off age of 35 years. There was a significant difference in seropositivity between these two groups (p=0.045). Conclusion: Clearly, there is no need to screen pregnant women for Human cytomegalovirus (HCMV) in the Malatya region. Confirming serology results using the polymerase chain reaction and antigenemia testing to detect false positive results offers the advantage of avoiding unnecessary invasive interventions. PMID:25610259

  3. Bile Acids Act as Soluble Host Restriction Factors Limiting Cytomegalovirus Replication in Hepatocytes

    PubMed Central

    Schupp, Anna-Kathrin; Trilling, Mirko; Rattay, Stephanie; Le-Trilling, Vu Thuy Khanh; Haselow, Katrin; Stindt, Jan; Zimmermann, Albert; Häussinger, Dieter

    2016-01-01

    ABSTRACT The liver constitutes a prime site of cytomegalovirus (CMV) replication and latency. Hepatocytes produce, secrete, and recycle a chemically diverse set of bile acids, with the result that interactions between bile acids and cytomegalovirus inevitably occur. Here we determined the impact of naturally occurring bile acids on mouse CMV (MCMV) replication. In primary mouse hepatocytes, physiological concentrations of taurochenodeoxycholic acid (TCDC), glycochenodeoxycholic acid, and to a lesser extent taurocholic acid significantly reduced MCMV-induced gene expression and diminished the generation of virus progeny, while several other bile acids did not exert antiviral effects. The anticytomegalovirus activity required active import of bile acids via the sodium-taurocholate-cotransporting polypeptide (NTCP) and was consistently observed in hepatocytes but not in fibroblasts. Under conditions in which alpha interferon (IFN-α) lacks antiviral activity, physiological TCDC concentrations were similarly effective as IFN-γ. A detailed investigation of distinct steps of the viral life cycle revealed that TCDC deregulates viral transcription and diminishes global translation in infected cells. IMPORTANCE Cytomegaloviruses are members of the Betaherpesvirinae subfamily. Primary infection leads to latency, from which cytomegaloviruses can reactivate under immunocompromised conditions and cause severe disease manifestations, including hepatitis. The present study describes an unanticipated antiviral activity of conjugated bile acids on MCMV replication in hepatocytes. Bile acids negatively influence viral transcription and exhibit a global effect on translation. Our data identify bile acids as site-specific soluble host restriction factors against MCMV, which may allow rational design of anticytomegalovirus drugs using bile acids as lead compounds. PMID:27170759

  4. Human cytomegalovirus: propagation, quantification, and storage.

    PubMed

    Britt, William J

    2010-08-01

    Human cytomegalovirus (HCMV) is the largest and perhaps the most structurally complex member of the family of human herpesviruses. It is the prototypic virus of the beta-herpesvirus subfamily. As with other cytomegaloviruses, HCMV is exquisitely species specific and undergoes lytic replication only in cells of human origin. In addition, its replication is limited almost entirely to primary cells and a limited number of transformed cell lines. Together with its prolonged replicative cycle of approximately 48 hr, the propagation and quantification of HCMV can present technical challenges. In this brief set of protocols, the propagation of laboratory strains of HCMV and their quantitation is described. In a third series of protocols, the concentration and gradient purification of HCMV for more specialized downstream applications is described.

  5. Detection of Human Cytomegalovirus and Epstein-Barr Virus in Coronary Atherosclerotic Tissue

    PubMed Central

    Imbronito, Ana Vitória; Marcelino, Silvia Linardi; Grande, Sabrina Rosa; Nunes, Fabio Daumas; Romito, Giuseppe Alexandre

    2010-01-01

    Previous studies indicated that patients with atherosclerosis are predominantly infected by human cytomegalovirus (HCMV), but rarely infected by type 1 Epstein-Barr virus (EBV-1). In this study, atheromas of 30 patients who underwent aortocoronary bypass surgery with coronary endartherectomy were tested for the presence of these two viruses. HCMV occurred in 93.3% of the samples and EBV-1 was present in 50% of them. Concurrent presence of both pathogens was detected in 43.3% of the samples. PMID:24031529

  6. HIV infection in the native and allograft kidney: implications for management, diagnosis, and transplantation.

    PubMed

    Avettand-Fenoël, Véronique; Rouzioux, Christine; Legendre, Christophe; Canaud, Guillaume

    2017-02-11

    The native kidney is a reservoir for HIV-1 and a site of viral replication, similar to lymphoid tissue, gut-associated lymphoid tissue or semen. The ability of the virus to persist may result from either a true latency or sequestration in an anatomic site that is not effectively exposed to antiretroviral therapy. The presence of HIV in kidney epithelial cells will lead progressively to end-stage renal disease. For decades, HIV-infected patients were excluded from consideration for kidney transplantation. Hemodialysis and peritoneal dialysis were the only forms of treatment available to these patients. The introduction of combined antiretroviral therapy has changed the overall prognosis of these patients and allowed them to benefit from kidney transplantation without an increased risk of opportunistic infections or cancer. However, we recently established that HIV-1 can infect kidney transplant epithelial cells in the absence of detectable viremia. The presence of HIV in kidney cells can manifest itself in multiple ways, ranging from indolent nephropathy and inflammation to proteinuria with glomerular abnormalities. Because the tools that are available to diagnose the presence of HIV in kidney cells are complex, the rate of infection is certainly underestimated. This finding will certainly have implications in the management of patients, particularly for HIV-positive donors. The purpose of this review is to highlight recent evidence that the allograft kidney can be infected by the virus after transplantation as well as the associated consequences.

  7. Human Cytomegalovirus UL97 Phosphorylates the Viral Nuclear Egress Complex

    PubMed Central

    Sharma, Mayuri; Bender, Brian J.; Kamil, Jeremy P.; Lye, Ming F.; Pesola, Jean M.; Reim, Natalia I.; Hogle, James M.

    2014-01-01

    ABSTRACT Herpesvirus nucleocapsids exit the host cell nucleus in an unusual process known as nuclear egress. The human cytomegalovirus (HCMV) UL97 protein kinase is required for efficient nuclear egress, which can be explained by its phosphorylation of the nuclear lamina component lamin A/C, which disrupts the nuclear lamina. We found that a dominant negative lamin A/C mutant complemented the replication defect of a virus lacking UL97 in dividing cells, validating this explanation. However, as complementation was incomplete, we investigated whether the HCMV nuclear egress complex (NEC) subunits UL50 and UL53, which are required for nuclear egress and recruit UL97 to the nuclear rim, are UL97 substrates. Using mass spectrometry, we detected UL97-dependent phosphorylation of UL50 residue S216 (UL50-S216) and UL53-S19 in infected cells. Moreover, UL53-S19 was specifically phosphorylated by UL97 in vitro. Notably, treatment of infected cells with the UL97 inhibitor maribavir or infection with a UL97 mutant led to a punctate rather than a continuous distribution of the NEC at the nuclear rim. Alanine substitutions in both UL50-S216 and UL53-S19 resulted in a punctate distribution of the NEC in infected cells and also decreased virus production and nuclear egress in the absence of maribavir. These results indicate that UL97 phosphorylates the NEC and suggest that this phosphorylation modulates nuclear egress. Thus, the UL97-NEC interaction appears to recruit UL97 to the nuclear rim both for disruption of the nuclear lamina and phosphorylation of the NEC. IMPORTANCE Human cytomegalovirus (HCMV) causes birth defects and it can cause life-threatening diseases in immunocompromised patients. HCMV assembles in the nucleus and then translocates to the cytoplasm in an unusual process termed nuclear egress, an attractive target for antiviral therapy. A viral enzyme, UL97, is important for nuclear egress. It has been proposed that this is due to its role in disruption of the

  8. Positive Expression of Human Cytomegalovirus Phosphoprotein 65 in Atherosclerosis

    PubMed Central

    Wang, Zhe; Cai, Jun; Zhang, Mingming; Wang, Xiaojing; Chi, Hongjie; Feng, Haijun

    2016-01-01

    Previous studies showed that human cytomegalovirus (HCMV) is associated with atherosclerosis. However, local vascular atherosclerosis related HCMV infection and protein expression remain unclear. This study aimed to assess the relationship between HCMV infection and atherosclerosis. Formalin-fixed, paraffin-embedded peripheral artery specimens were obtained from 15 patients with atherosclerosis undergoing vascular surgery from 2008 to 2010 at Zhongnan Hospital, Wuhan University. Pathological analyses were carried out after hematoxylin and eosin (H&E) and Masson trichrome staining. In situ hybridization and immunohistochemistry with two different monoclonal antibodies were employed to detect HCMV nucleic acids and proteins, respectively. H&E and Masson trichrome staining showed homogeneous extracellular matrix in femoral artery, while smooth muscle fibers were interlaced with collagen fibers; in carotid artery, inflammatory cell infiltration, foam cell vascular change, cholesterol crystals, and layered collagen fibers were observed. In situ hybridization showed no expression of HCMV nucleic acids in all 15 cases. Immunohistochemical staining for protein immediate-early protein (IE1 72) was negative in all cases, while phosphoprotein 65 (pp65) expression was detected in 14 cases. A high rate of positive pp65 signals was found in patients with atherosclerosis, suggesting that local HCMV infection may be associated with the pathogenesis of atherosclerosis. Further studies on this relationship are warranted. PMID:27990427

  9. Limits and patterns of cytomegalovirus genomic diversity in humans

    PubMed Central

    Renzette, Nicholas; Pokalyuk, Cornelia; Gibson, Laura; Bhattacharjee, Bornali; Schleiss, Mark R.; Hamprecht, Klaus; Yamamoto, Aparecida Y.; Mussi-Pinhata, Marisa M.; Britt, William J.; Jensen, Jeffrey D.; Kowalik, Timothy F.

    2015-01-01

    Human cytomegalovirus (HCMV) exhibits surprisingly high genomic diversity during natural infection although little is known about the limits or patterns of HCMV diversity among humans. To address this deficiency, we analyzed genomic diversity among congenitally infected infants. We show that there is an upper limit to HCMV genomic diversity in these patient samples, with ∼25% of the genome being devoid of polymorphisms. These low diversity regions were distributed across 26 loci that were preferentially located in DNA-processing genes. Furthermore, by developing, to our knowledge, the first genome-wide mutation and recombination rate maps for HCMV, we show that genomic diversity is positively correlated with these two rates. In contrast, median levels of viral genomic diversity did not vary between putatively single or mixed strain infections. We also provide evidence that HCMV populations isolated from vascular compartments of hosts from different continents are genetically similar and that polymorphisms in glycoproteins and regulatory proteins are enriched in these viral populations. This analysis provides the most highly detailed map of HCMV genomic diversity in human hosts to date and informs our understanding of the distribution of HCMV genomic diversity within human hosts. PMID:26150505

  10. Childhood environments and cytomegalovirus serostatus and reactivation in adults.

    PubMed

    Janicki-Deverts, Denise; Cohen, Sheldon; Doyle, William J; Marsland, Anna L; Bosch, Jos

    2014-08-01

    Childhood adversity, defined in terms of material hardship or physical or emotional maltreatment has been associated with risk for infection with cytomegalovirus (CMV) among children and adolescents, and with CMV reactivation in children and adults. The present study examined whether different dimensions of childhood experience-those pertaining to socioeconomic status (SES), physical environment, or family relationships-relate differentially to CMV serostatus and reactivation during adulthood. Participants were 140 healthy adults, aged 18-55years (41% female; 64% white). Childhood environments were assessed retrospectively and included family SES (parental housing tenure); childhood neighborhood environment (urban residence; physical conditions; safety; and social atmosphere); residential exposures (parental smoking and physical condition of home); and family relationships (parental divorce; warmth; harmony; dysfunction; parental bonding). Approximately 39% (n=53) of participants were CMV+. In individual analyses controlling for age, sex, race, body mass, current adult SES and smoking status, fewer years of parental home ownership, having a parent who smoked, and living in a poorly maintained or unsafe neighborhood each were associated with greater odds of infection with CMV. By comparison, in individual analyses limited to CMV+ participants, less family warmth, less harmony, greater dysfunction, and suboptimal parental bonding each were related to higher antibody levels, independent of the aforementioned covariates. Findings were not attributable to current adult perceptions of psychological stress or relative levels of emotional stability. These results suggest that different types of childhood adversity may be associated with differential effects on CMV infection and latency.

  11. γδ T Cells Confer Protection against Murine Cytomegalovirus (MCMV)

    PubMed Central

    Villacreces, Arnaud; Juzan, Marina; Rousseau, Benoît; Dulanto, Sara; Giese, Alban; Costet, Pierre; Praloran, Vincent; Moreau, Jean-François; Dubus, Pierre; Vermijlen, David

    2015-01-01

    Cytomegalovirus (CMV) is a leading infectious cause of morbidity in immune-compromised patients. γδ T cells have been involved in the response to CMV but their role in protection has not been firmly established and their dependency on other lymphocytes has not been addressed. Using C57BL/6 αβ and/or γδ T cell-deficient mice, we here show that γδ T cells are as competent as αβ T cells to protect mice from CMV-induced death. γδ T cell-mediated protection involved control of viral load and prevented organ damage. γδ T cell recovery by bone marrow transplant or adoptive transfer experiments rescued CD3ε−/− mice from CMV-induced death confirming the protective antiviral role of γδ T cells. As observed in humans, different γδ T cell subsets were induced upon CMV challenge, which differentiated into effector memory cells. This response was observed in the liver and lungs and implicated both CD27+ and CD27− γδ T cells. NK cells were the largely preponderant producers of IFNγ and cytotoxic granules throughout the infection, suggesting that the protective role of γδ T cells did not principally rely on either of these two functions. Finally, γδ T cells were strikingly sufficient to fully protect Rag−/−γc−/− mice from death, demonstrating that they can act in the absence of B and NK cells. Altogether our results uncover an autonomous protective antiviral function of γδ T cells, and open new perspectives for the characterization of a non classical mode of action which should foster the design of new γδ T cell based therapies, especially useful in αβ T cell compromised patients. PMID:25747674

  12. Development of breeding populations of rhesus macaques (Macaca mulatta) that are specific pathogen-free for rhesus cytomegalovirus.

    PubMed

    Barry, Peter A; Strelow, Lisa

    2008-02-01

    Development of breeding colonies of rhesus macaques (Macaca mulatta) that are specific pathogen-free (SPF) for rhesus cytomegalovirus (RhCMV) is relatively straightforward and requires few modifications from current SPF programs. Infants separated from the dam at or within a few days of birth and cohoused with similarly treated animals remain RhCMV seronegative indefinitely, provided they are never directly or indirectly exposed to a RhCMV-infected monkey. By systematically cohousing seronegative animals into larger social cohorts, breeding populations of animals SPF for RhCMV can be established. The additional costs involved in expanding the current definition of SPF status to include RhCMV are incremental compared with the money already being spent on existing SPF efforts. Moreover, the large increase in research opportunities available for RhCMV-free animals arguably would far exceed the development costs. Potential new areas of research and further expansion of existing research efforts involving these newly defined SPF animals would have direct implications for improvements in human health.

  13. Detection of human cytomegalovirus in normal and neoplastic breast epithelium

    PubMed Central

    2010-01-01

    Introduction Human cytomegalovirus (HCMV) establishes a persistent life-long infection, and can cause severe pathology in the fetus and the immunocompromised host[1]. Breast milk is the primary route of transmission in humans worldwide, and breast epithelium is thus a likely site of persistent infection and/or reactivation, though this phenomenon has not previously been demonstrated. Increasing evidence indicates HCMV infection can modulate signaling pathways associated with oncogenesis. We hypothesized that persistent HCMV infection occurs in normal adult breast epithelium and that persistent viral expression might be associated with normal and neoplastic ductal epithelium. Methods Surgical biopsy specimens of normal breast (n = 38) breast carcinoma (n = 39) and paired normal breast from breast cancer patients (n = 21) were obtained. Specimens were evaluated by immunohistochemistry, in situ hybridization, PCR and DNA sequencing for evidence of HCMV antigens and nucleic acids. Results We detected HCMV expression specifically in glandular epithelium in 17/27 (63%) of normal adult breast cases evaluated. In contrast, HCMV expression was evident in the neoplastic epithelium of 31/32 (97%) patients with ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC) cases evaluated (p = 0.0009). Conclusions These findings are the first to demonstrate that persistent HCMV infection occurs in breast epithelium in a significant percentage of normal adult females. HCMV expression was also evident in neoplastic breast epithelium in a high percentage of normal and neoplastic breast tissues obtained from breast cancer patients, raising the possibility that viral infection may be involved in the neoplastic process. PMID:21429243

  14. Severe Cytomegalovirus Gastritis During Natalizumab-Mediated Immunosuppression

    PubMed Central

    Hassan, Adil; Hassan, Anjum; Hassan, Tariq

    2017-01-01

    We report a 35-year-old female receiving natalizumab as monotherapy for multiple sclerosis who subsequently developed severe cytomegalovirus gastritis. As cytomegalovirus gastritis has not been previously described during natalizumab treatment, we discuss the biological plausibility of this potential association and avenues for further study. PMID:28331881

  15. Host cellular annexin II is associated with cytomegalovirus particles isolated from cultured human fibroblasts.

    PubMed Central

    Wright, J F; Kurosky, A; Pryzdial, E L; Wasi, S

    1995-01-01

    A significant amount of host cellular annexin II was found to be associated with human cytomegalovirus isolated from cultured human fibroblasts (approximately 1,160 molecules per virion). This composition was established by four different analytical approaches that included (i) Western blot (immunoblot) analysis of gradient-purified virions with a monoclonal antibody specific for annexin II, (ii) peptide mapping and sequence analysis of virus-associated proteins and proteins dissociated from virus following EDTA treatment, (iii) electron microscopic immunocytochemistry of gradient-purified virions, and (iv) labeling of virus-associated proteins by lactoperoxidase-catalyzed radioiodination. These results indicated that annexin II was primarily localized to the viral surface, where it bound in a divalent cation-dependent manner. In functional experiments, a rabbit antiserum raised against annexin II inhibited cytomegalovirus plaque formation in human foreskin fibroblast monolayers in a concentration-dependent manner. Cumulatively, these studies demonstrate an association of host annexin II with cytomegalovirus particles and provide evidence for the involvement of this cellular protein in virus infectivity. PMID:7609045

  16. Implications of co-infection of Leptomonas in visceral leishmaniasis in India.

    PubMed

    Selvapandiyan, Angamuthu; Ahuja, Kavita; Puri, Niti; Krishnan, Anuja

    2015-12-01

    Protozoan parasites Leishmania donovani (family: Trypanosomatidae) cause fatal visceral leishmaniasis (VL) and the infection relapses in apparently cured population as post kala-azar dermal leishmaniasis (PKDL) in the Indian subcontinent. In recent years co-infection of another Trypanosomatid parasite Leptomonas with L. donovani during VL/PKDL in this region has become prominent. The observation of clinically lesser-known insect parasite, Leptomonas in leishmaniasis is intriguing to researchers. The presence of Leishmania look alike Leptomonas in the cultures of clinical isolates of Leishmania has been worrisome to those, who prefer to work with pure Leishmania cultures for drug and vaccine development or immune response studies. The exact implications of such a co-habitation, which might lead to a delay in the diagnostics of VL and elevate mortality, need a thorough investigation. Also whether Leptomonas is involved in leishmaniasis manifestation needs to be ascertained. Thus we are currently witnessing a new paradigm of a parasitic co-infection in VL/PKDL cases in India and this review outlines various opportunities for further research in understanding such emerging co-infection.

  17. Implications of apathy for everyday functioning outcomes in persons living with HIV infection.

    PubMed

    Kamat, Rujvi; Woods, Steven Paul; Marcotte, Thomas D; Ellis, Ronald J; Grant, Igor

    2012-08-01

    Apathy is a relatively common clinical feature of HIV-Associated Neurocognitive Disorders, but little is known about its implications for everyday functioning outcomes. In the present study, we examined the associations between apathy and self-reported instrumental activities of daily living (IADL) and neurocognitive complaints in 75 participants with HIV infection and 52 demographically comparable seronegative comparison subjects. All volunteers completed the apathy subscale of the Frontal Systems Behavioral Scale as part of a comprehensive neuromedical, psychiatric, and neurocognitive research evaluation. When compared with the seronegative comparison participants, the HIV+ group reported significantly higher current levels of apathy, but did not differ in self-report of prior (i.e., pre-seroconversion) apathy. Higher current apathy self-ratings were associated with greater severity of IADL declines and more numerous cognitive complaints in the HIV+ sample, even after adjusting for potential psychiatric (e.g., depression), medical (e.g., hepatitis C co-infection), and neurocognitive predictors. Cognitive complaints, but not IADLs, were also uniquely associated with ratings of executive dysfunction and disinhibition. All told, these findings suggest that apathy may make a unique contribution to important everyday functioning outcomes among persons living with HIV infection. The clinical detection of apathy may help identify HIV-infected individuals at particular risk for functional impairments who may require additional support to maintain independence.

  18. Species distribution in human immunodeficiency virus-related mycobacterial infections: implications for selection of initial treatment.

    PubMed

    Montessori, V; Phillips, P; Montaner, J; Haley, L; Craib, K; Bessuille, E; Black, W

    1996-06-01

    Management of mycobacterial infection is species specific; however, treatment is prompted by positive smears or cultures, often several weeks before species identification. The objective of this study was to determine the species distribution of mycobacterial isolates from various body sites in patients infected with human immunodeficiency virus (HIV). All mycobacterial isolates recovered at St. Paul's Hospital (Vancouver, British Columbia, Canada) from April 1989 to March 1993 were reviewed. Among 357 HIV-positive patients with mycobacterial infections, 64% (96) of the sputum isolates were Mycobacterium avium complex (MAC), 18% were Mycobacterium tuberculosis, and 17% were Mycobacterium kansasii. Lymph node involvement (25 patients) was due to either MAC (72%) or M. tuberculosis (24%). Two hundred ninety-eight episodes of mycobacteremia were due to MAC (98%), M. tuberculosis (1%), and M. kansasii (1%). Similarly, cultures of 84 bone marrow biopsy specimens (99%), 19 intestinal biopsy specimens (100%), and 30 stool specimens (97%) yielded predominantly MAC. These results have implications for initial therapy, particularly in areas where rapid methods for species identification are not readily available. Because of considerable geographic variation, development of guidelines for selection of initial therapy depends on regional determination of species distribution in HIV-related mycobacterial infections.

  19. Receptor expression and responsiveness of human peripheral blood mononuclear cells to a human cytomegalovirus encoded CC chemokine.

    PubMed

    Zheng, Qi; Xu, Jun; Gao, Huihui; Tao, Ran; Li, Wei; Shang, Shiqiang; Gu, Weizhong

    2015-01-01

    Human cytomegalovirus is a ubiquitous pathogen that infects the majority of the world's population. After long period of time co-evolving with human being, this pathogen has developed several strategies to evade host immune surveillance. One of the major trick is encoding homologous to those of the host organism or stealing host cellular genes that have significant functions in immune system. To date, we have found several viral immune analogous which include G protein coupled receptor, class I major histocompatibility complex and chemokine. Chemokine is a small group of molecules which is defined by the presence of four cysteines in highly conserved region. The four kinds of chemokines (C, CC, CXC, and CX3C) are classified based on the arrangement of 1 or 2 N-terminal cysteine residues. UL128 protein is one of the analogous that encoded by human cytomegalovirus that has similar amino acid sequences to the human CC chemokine. It has been proved to be one of the essential particles that involved in human cytomegalovirus entry into epithelial/endothelial cells as well as macrophages. It is also the target of potent neutralizing antibodies in human cytomegalovirus-seropositive individuals. We had demonstrated the chemotactic trait of UL128 protein in our previous study. Recombinant UL128 in vitro has the ability to attract monocytes to the infection region and enhances peripheral blood mononuclear cell proliferation by activating the MAPK/ERK signaling pathway. However, the way that this viral encoded chemokine interacting with peripheral blood mononuclear cells and the detailed mechanism that involving the virus entry into host cells keeps unknown. Here we performed in vitro investigation into the effects of UL128 protein on peripheral blood mononuclear cell's activation and receptor binding, which may help us further understand the immunomodulatory function of UL128 protein as well as human cytomegalovirus diffusion mechanism.

  20. Seropositivity of cytomegalovirus in patients with recurrent pregnancy loss

    PubMed Central

    Sherkat, Roya; Meidani, Mohsen; Zarabian, Hossein; Rezaei, Abbas; Gholamrezaei, Ali

    2014-01-01

    Background: Some evidence has shown a relationship between human cytomegalovirus (CMV) infection and pregnancy loss. However, whether recurrent or latent CMV infection or altered immune response to CMV is related to recurrent pregnancy loss (RPL) is unclear. We evaluated CMV infection and avidity of antibodies to CMV in women with RPL. Materials and Methods: This case-control study was conducted on 43 women with RPL referred to a clinical immunology out-patient clinic in Isfahan (Iran), and 43 age-matched multiparous women without history of abortion as control subjects. Patients and controls were evaluated for anti-CMV IgG and IgM antibodies and IgG avidity index (AI) using the enzyme linked immunosorbent assay method. Student's t-test and Chi-square test were used to analyze the data. Results: One case (2.3%) of positive anti-CMV IgM was detected in each group. Anti-CMV IgG positivity was more frequent in patients than in controls (90.6% vs. 69.8%, P = 0.014), but there was no difference between the two groups in anti-CMV IgG AI (79.4 ± 11.4 vs. 80.1 ± 10.2, P = 0.781). IgG titer was significantly higher in seropositive cases with RPL than seropositive controls (5.18 ± 1.99 vs. 2.00 ± 0.81, P < 0.001). Conclusion: We found that previous exposure to CMV was significantly higher in patients with RPL than the control group. However, no association was found between IgG AI and RPL. Further investigations are needed to find whether latent CMV infection starts an indirect process of autoimmune etiology in RPL or women with RPL have recurrent or reactivation of CMV infection. PMID:25002889

  1. Cytomegalovirus Hyper Immunoglobulin for CMV Prophylaxis in Thoracic Transplantation.

    PubMed

    Rea, Federico; Potena, Luciano; Yonan, Nizar; Wagner, Florian; Calabrese, Fiorella

    2016-03-01

    Cytomegalovirus (CMV) infection negatively influences both short- and long-term outcomes after cardiothoracic transplantation. In heart transplantation, registry analyses have shown that CMV immunoglobulin (CMVIG) with or without virostatic prophylaxis is associated with a significant reduction in mortality and graft loss versus no prophylaxis, particularly in high-risk donor (D)+/recipient (R)- transplants. Randomized comparative trials are lacking but retrospective data suggest that addition of CMVIG to antiviral prophylaxis may reduce rates of CMV-related events after heart transplantation, including the incidence of acute rejection or chronic allograft vasculopathy. However, available data consistently indicate that when CMVIG is used, it should be administered with concomitant antiviral therapy, and that evidence concerning preemptive management with CMVIG is limited, but promising. In lung transplantation, CMVIG should again only be used with concomitant antiviral therapy. Retrospective studies have shown convincing evidence that addition of CMVIG to antiviral prophylaxis lowers CMV endpoints and mortality. The current balance of evidence suggests that CMVIG prophylaxis reduces the risk of bronchiolitis obliterans syndrome, but a controlled trial is awaited. Overall, the relatively limited current data set suggests that prophylaxis with CMVIG in combination with antiviral therapy appears effective in D+/R- heart transplant patients, whereas in lung transplantation, addition of CMVIG in recipients of a CMV-positive graft may offer an advantage in terms of CMV infection and disease.

  2. New cell-signaling pathways for controlling cytomegalovirus replication.

    PubMed

    Roy, S; Arav-Boger, R

    2014-06-01

    Cytomegalovirus (CMV) is increasingly recognized as an accomplished modulator of cell-signaling pathways, both directly via interaction between viral and cellular proteins, and indirectly by activating metabolic/energy states of infected cells. Viral genes, as well as captured cellular genes, enable CMV to modify these pathways upon binding to cellular receptors, up until generation of virus progeny. Deregulation of cell-signaling pathways appears to be a well-developed tightly balanced virus strategy to achieve the desired consequences in each infected cell type. Importantly and perhaps surprisingly, identification of new signaling pathways in cancer cells positioned CMV as a sophisticated user and abuser of many such pathways, creating opportunities to develop novel therapeutic strategies for inhibiting CMV replication (in addition to standard of care CMV DNA polymerase inhibitors). Advances in genomics and proteomics allow the identification of CMV products interacting with the cellular machinery. Ultimately, clinical implementation of candidate drugs capable of disrupting the delicate balance between CMV and cell-signaling will depend on the specificity and selectivity index of newly identified targets.

  3. Use of indium 111-labeled white blood cell scan in the diagnosis of cytomegalovirus pneumonia in a renal transplant recipient with a normal chest roentgenogram

    SciTech Connect

    Chinsky, K.; Goodenberger, D.M. )

    1991-03-01

    Opportunistic infections are common in patients after renal transplantation. This report describes a case of cytomegalovirus pneumonia in a renal transplant recipient with a normal chest roentgenogram and normal arterial oxygenation. An abnormal 111In-white blood cell scan led to the discovery of a pulmonary source of his recurrent fevers.

  4. Cytomegalovirus immediate early proteins promote stemness properties in glioblastoma

    PubMed Central

    Soroceanu, Liliana; Matlaf, Lisa; Khan, Sabeena; Akhavan, Armin; Singer, Eric; Bezrookove, Vladimir; Decker, Stacy; Ghanny, Saleena; Hadaczek, Piotr; Bengtsson, Henrik; Ohlfest, John; Luciani-Torres, Maria-Gloria; Harkins, Lualhati; Perry, Arie; Guo, Hong; Soteropoulos, Patricia; Cobbs, Charles S

    2015-01-01

    Glioblastoma (GBM) is the most common and aggressive human brain tumor. Human cytomegalovirus (HCMV) immediate early (IE) proteins that are endogenously expressed in GBM cells are strong viral transactivators with onconcogenic properties. Here, we show how HCMV IE are preferentially expressed in glioma stem-like cells (GSC), where they co-localize with the other GBM stemness markers, CD133, Nestin, and Sox2. In patient-derived GSC that are endogenously infected with HCMV, attenuating IE expression by an RNA-i-based strategy, was sufficient to inhibit tumorsphere formation, Sox2 expression, cell cycle progression, and cell survival. Conversely, HCMV infection of HMCV-negative GSC elicited robust self-renewal and proliferation of cells that could be partially reversed by IE attenuation. In HCMV-positive GSC, IE attenuation induced a molecular program characterized by enhanced expression of mesenchymal markers and pro-inflammatory cytokines, resembling the therapeutically-resistant GBM phenotype. Mechanistically, HCMV/IE regulation of Sox2 occurred via inhibition of miRNA-145, a negative regulator of Sox2 protein expression. In a spontaneous mouse model of glioma, ectopic expression of the IE1 gene (UL123) specifically increased Sox2 and Nestin levels in the IE1-positive tumors, upregulating stemness and proliferation markers in vivo. Similarly, human GSC infected with the HCMV strain Towne but not the IE1-deficient strain CR208 showed enhanced growth as tumorspheres and intracranial tumor xenografts, compared to mock-infected human GSC. Overall, our findings offer new mechanistic insights into how HCMV/IE control stemness properties in glioblastoma cells. PMID:26239477

  5. Anti-cytomegalovirus activity of the anthraquinone atanyl blue PRL.

    PubMed

    Alam, Zohaib; Al-Mahdi, Zainab; Zhu, Yali; McKee, Zachary; Parris, Deborah S; Parikh, Hardik I; Kellogg, Glen E; Kuchta, Alison; McVoy, Michael A

    2015-02-01

    Human cytomegalovirus (CMV) causes significant disease in immunocompromised patients and serious birth defects if acquired in utero. Available CMV antivirals target the viral DNA polymerase, have significant toxicities, and suffer from resistance. New drugs targeting different pathways would be beneficial. The anthraquinone emodin is proposed to inhibit herpes simplex virus by blocking the viral nuclease. Emodin and related anthraquinones are also reported to inhibit CMV. In the present study, emodin reduced CMV infectious yield with an EC50 of 4.9μM but was cytotoxic at concentrations only twofold higher. Related anthraquinones acid blue 40 and alizarin violet R inhibited CMV at only high concentrations (238-265μM) that were also cytotoxic. However, atanyl blue PRL inhibited infectious yield of CMV with an EC50 of 6.3μM, significantly below its 50% cytotoxic concentration of 216μM. Atanyl blue PRL reduced CMV infectivity and inhibited spread. When added up to 1h after infection, it dramatically reduced CMV immediate early protein expression and blocked viral DNA synthesis. However, it had no antiviral activity when added 24h after infection. Interestingly, atanyl blue PRL inhibited nuclease activities of purified CMV UL98 protein with IC50 of 4.5 and 9.3μM. These results indicate that atanyl blue PRL targets very early post-entry events in CMV replication and suggest it may act through inhibition of UL98, making it a novel CMV inhibitor. This compound may provide valuable insights into molecular events that occur at the earliest times post-infection and serve as a lead structure for antiviral development.

  6. Intricacies of cardiac damage in coxsackievirus B3 infection: Implications for therapy

    PubMed Central

    Reddy, Jay

    2015-01-01

    Heart disease is the leading cause of death in humans, and myocarditis is one predominant cause of heart failure in young adults. Patients affected with myocarditis can develop dilated cardiomyopathy (DCM), a common reason for heart transplantation, which to date is the only viable option for combatting DCM. Myocarditis/DCM patients show antibodies to coxsackievirus B (CVB)3 and cardiac antigens, suggesting a role for CVB-mediated autoimmunity in the disease pathogenesis; however, a direct causal link remains to be determined clinically. Experimentally, myocarditis can be induced in susceptible strains of mice using the human isolates of CVB3, and the disease pathogenesis of postinfectious myocarditis resembles that of human disease, making the observations made in animals relevant to humans. In this review, we discuss the complex nature of CVB3-induced myocarditis as it relates to the damage caused by both the virus and the host's response to infection. Based on recent data we obtained in the mouse model of CVB3 infection, we provide evidence to suggest that CVB3 infection accompanies the generation of cardiac myosin-specific CD4 T cells that can transfer the disease to naïve recipients. The therapeutic implications of these observations are also discussed. PMID:25449464

  7. Cytomegalovirus pp65 limits dissemination but is dispensable for persistence

    SciTech Connect

    Malouli, Daniel; Hansen, Scott G.; Nakayasu, Ernesto S.; Marshall, Emily E.; Hughes, Colette M.; Ventura, Abigail B.; Gilbride, Roxanne M.; Lewis, Matthew S.; Xu, Guangwu; Kreklywich, Craig; Whizin, Nathan; Fischer, Miranda; Legasse, Alfred W.; Viswanathan, Kasinath; Siess, Don; Camp, David G.; Axthelm, Michael K.; Kahl, Christoph; DeFilippis, Victor R.; Smith, Richard D.; Streblow, Daniel N.; Picker, Louis J.; Früh, Klaus

    2014-04-01

    The tegument phosphoprotein pp65 (UL83) is the most abundant virion protein in human cytomegalovirus (HCMV). Since pp65 is immunodominant in persistently infected individuals, subunit vaccines against HCMV often include pp65 as T cell stimulatory component. Although HCMV pp65 is non-essential for viral growth in vitro it is thought to have an important role in primary and persistent infection since pp65 displays multiple immunomodulatory functions. To determine whether pp65 is required for infection and to evaluate its role in natural and vaccination-induced immunity we generated a rhesus CMV lacking both homologues, pp65a (Rh111) and pp65b (Rh112). Lack of pp65 resulted in a slight growth defect in vitro and an increase of defective particle formation. However, most pp65-deleted virions in the supernatant were phenotypically normal and proteomics analysis revealed that the ratios of the remaining viral proteins were largely unchanged. RhCMV Δpp65ab was able to persistently infect CMV-negative rhesus macaques (RM) and to super-infect RM previously infected with CMV. To determine whether T cells against pp65 are essential for protection against CMV, we challenged Δpp65ab-infected animals with RhCMV ΔUS2-11, a viral recombinant that lacks inhibitors of MHC-I antigen presentation and is thus unable to overcome CMV-specific T cell immunity. Despite a complete lack of pp65-specific T cells, Δpp65ab protected against ΔUS2-11 challenge suggesting that pp65-specific T cells are not essential for T cell immunity against CMV. Using the same approach we further demonstrate that pp65b-specific T cells, induced by heterologous prime/boost vaccination, are not sufficient to protect against ΔUS2-11 challenge. Our data provides a new approach to test the efficacy of subunit vaccine candidates and suggest that pp65 vaccines are insufficient to induce a T cell response that recapitulates the protective effect of natural infection.

  8. Report from the second cytomegalovirus and immunosenescence workshop.

    PubMed

    Wills, Mark; Akbar, Arne; Beswick, Mark; Bosch, Jos A; Caruso, Calogero; Colonna-Romano, Giuseppina; Dutta, Ambarish; Franceschi, Claudio; Fulop, Tamas; Gkrania-Klotsas, Effrossyni; Goronzy, Joerg; Griffiths, Stephen J; Henson, Sian; Herndler-Brandstetter, Dietmar; Hill, Ann; Kern, Florian; Klenerman, Paul; Macallan, Derek; Macualay, Richard; Maier, Andrea B; Mason, Gavin; Melzer, David; Morgan, Matthew; Moss, Paul; Nikolich-Zugich, Janko; Pachnio, Annette; Riddell, Natalie; Roberts, Ryan; Sansoni, Paolo; Sauce, Delphine; Sinclair, John; Solana, Rafael; Strindhall, Jan; Trzonkowski, Piotr; van Lier, Rene; Vescovini, Rosanna; Wang, George; Westendorp, Rudi; Pawelec, Graham

    2011-10-28

    The Second International Workshop on CMV & Immunosenescence was held in Cambridge, UK, 2-4th December, 2010. The presentations covered four separate sessions: cytomegalovirus and T cell phenotypes; T cell memory frequency, inflation and immunosenescence; cytomegalovirus in aging, mortality and disease states; and the immunobiology of cytomegalovirus-specific T cells and effects of the virus on vaccination. This commentary summarizes the major findings of these presentations and references subsequently published work from the presenter laboratory where appropriate and draws together major themes that were subsequently discussed along with new areas of interest that were highlighted by this discussion.

  9. Intractable diarrhoea caused by cytomegalovirus enterocolitis in an immunocompetent term neonate.

    PubMed

    Gupta, Amit Kumar; Maria, Arti; Goyal, Deepak; Verma, Arushi

    2013-12-01

    Symptomatic cytomegalovirus (CMV) infection mainly affects preterm and immunocompromised infants and usually manifest as rash, pneumonia, hepatospleenomegaly or encephalitis. To our knowledge intractable diarrhoea at two weeks of age caused by postnatally acquired CMV in immunocompetent term neonate is not reported. An unusual case of postnatally acquired CMV enterocolitis manifesting as protracted diarrhoea in an immunocompetent baby in neonatal period is reported. We conclude that CMV should be considered in the differential diagnosis of intractable diarrhoea in neonatal period and treatment with intravenous ganciclovir for CMV enterocolitis is not only indicated but is therapeutic.

  10. Canadian society of transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report.

    PubMed

    Preiksaitis, Jutta K; Brennan, Daniel C; Fishman, Jay; Allen, Upton

    2005-02-01

    The Canadian Society of Transplantation sponsored a Cytomegalovirus (CMV) Consensus Working Group that met on March 19, 2003. The objectives of this group were to determine the current burden of CMV-associated disease in the setting of solid organ transplantation in Canada, make recommendations regarding optimal strategies for the diagnosis, treatment and prevention of CMV infection and disease, highlight gaps in knowledge and outline priorities for research and other initiatives that might further reduce the burden of CMV-associated effects in this setting. This report summarizes the recommendations of the working group including ratings of the strength of evidence supporting the recommendations.

  11. Clinical and biologic aspects of human cytomegalovirus resistance to antiviral drugs.

    PubMed

    Baldanti, Fausto; Lurain, Nell; Gerna, Giuseppe

    2004-05-01

    The emergence of human cytomegalovirus (HCMV) drug resistant strains is a life-threatening condition in immunocompromised individuals with active HCMV infection. HCMV drug resistance represented a major problem in patients with acquired immunodeficiency syndrome until the recent introduction of highly active antiretroviral combination therapy, which dramatically decreased the incidence in this clinical setting. However, HCMV resistance to antiviral drugs is now an emerging problem in the transplantation setting. The molecular mechanisms of HCMV drug resistance have been elucidated and rely on the selection during treatment of HCMV strains harboring mutations in two key viral genes: UL97 coding for a viral phosphotransferase and UL54 coding for the viral DNA polymerase.

  12. Human cytomegalovirus resistance to antiviral drugs: diagnosis, monitoring and clinical impact.

    PubMed

    Baldanti, Fausto; Gerna, Giuseppe

    2003-09-01

    The incidence of human cytomegalovirus (HCMV) disease in AIDS patients decreased dramatically after the introduction, a few years ago, of highly active antiretroviral combination therapy. As a consequence, the emergence of drug-resistant HCMV strains is no longer a major problem in HIV-infected individuals. However, HCMV resistance to antiviral drugs is presently recognized as an emerging problem in transplantation settings. The mechanisms of HCMV drug resistance will be analysed along with the clinical features relevant to the emergence of drug-resistant HCMV strains during antiviral treatment of patients receiving either solid organ or haematopoietic stem cell transplantation.

  13. Pseudoneoplastic appearance of cytomegalovirus-associated colitis in nonimmunocompromised patients: report of 2 cases.

    PubMed

    Maiorana, Antonio; Torricelli, Pietro; Giusti, Federica; Bellini, Nicola

    2003-09-01

    Two cases of human cytomegalovirus (HCMV) colitis with pseudoneoplastic appearance are described. Patients presented with abdominal pain, fever, and diarrhea. Colonoscopy revealed a stenosing lesion in one patient and a broad-based, vegetant mass in the other patient, and histopathological examination of colectomy specimens revealed exuberant inflammatory masses with infiltration of mononuclear cells and ulcers with granulation tissue. Typical intranuclear HCMV inclusions were numerous. Peculiar to both patients was the lack of any apparent causes of immunodeficiency, such as human immunodeficiency virus infection or previous organ transplantation.

  14. Case of cytomegalovirus-associated direct anti-globulin test-negative autoimmune hemolytic anemia.

    PubMed

    Kaneko, Saeko; Sato, Masanori; Sasaki, Goro; Eguchi, Hiroyuki; Oishi, Tsutomu; Kamesaki, Toyomi; Kawaguchi, Hiroyuki

    2013-12-01

    A 1-year-old boy developed autoimmune hemolytic anemia after a negative direct anti-globulin test. The concentration of erythrocyte membrane-associated immunoglobulin G, determined using an immunoradiometric assay, correlated with disease activity. He was positive for cytomegalovirus (CMV) both serologically and by quantitative real-time polymerase chain reaction, indicating that his autoimmune hemolytic anemia was directly caused by CMV infection. Since anti-CMV immunoglobulin G was not absorbed by the patient's erythrocytes, cross-reaction between erythrocyte antigens and CMV was not likely a causative factor for hemolysis.

  15. Announcement: Guidance for U.S. Laboratory Testing for Zika Virus Infection: Implications for Health Care Providers.

    PubMed

    2016-11-25

    CDC has released updated guidance online for U.S. laboratory testing for Zika virus infection. The guidance is available at https://www.cdc.gov/zika/laboratories/lab-guidance.html. Frequently asked questions are addressed at https://www.cdc.gov/zika/laboratories/lab-guidance-faq.html. This guidance updates recommendations for testing of specimens by U.S. laboratories for possible Zika virus infection. Major updates to the guidance with clinical implications for health care providers include the following.

  16. Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry.

    PubMed

    Wu, Yiquan; Prager, Adrian; Boos, Simone; Resch, Moritz; Brizic, Ilija; Mach, Michael; Wildner, Sabrina; Scrivano, Laura; Adler, Barbara

    2017-04-01

    Herpesvirus gH/gL envelope glycoprotein complexes are key players in virus entry as ligands for host cell receptors and by promoting fusion of viral envelopes with cellular membranes. Human cytomegalovirus (HCMV) has two alternative gH/gL complexes, gH/gL/gO and gH/gL/UL128,130,131A which both shape the HCMV tropism. By studying binding of HCMV particles to fibroblasts, we could for the first time show that virion gH/gL/gO binds to platelet-derived growth factor-α (PDGFR-α) on the surface of fibroblasts and that gH/gL/gO either directly or indirectly recruits gB to this complex. PDGFR-α functions as an entry receptor for HCMV expressing gH/gL/gO, but not for HCMV mutants lacking the gH/gL/gO complex. PDGFR-α-dependent entry is not dependent on activation of PDGFR-α. We could also show that the gH/gL/gO-PDGFR-α interaction starts the predominant entry pathway for infection of fibroblasts with free virus. Cell-associated virus spread is either driven by gH/gL/gO interacting with PDGFR-α or by the gH/gL/UL128,130,131A complex. PDGFR-α-positive cells may thus be preferred first target cells for infections with free virus which might have implications for the design of future HCMV vaccines or anti-HCMV drugs.

  17. Human cytomegalovirus latent gene expression in granulocyte-macrophage progenitors in culture and in seropositive individuals.

    PubMed Central

    Kondo, K; Xu, J; Mocarski, E S

    1996-01-01

    Following infection with cytomegalovirus, human granulocyte-macrophage progenitors carry the viral genome but fail to support productive replication. Viral transcripts arise from a region encompassing the major regulatory gene locus; however, their structure differs significantly from productive phase transcripts. One class, sense transcripts, is encoded in the same direction as productive phase transcripts but uses two novel start sites in the ie1/ie2 promoter/enhancer region. These transcripts have the potential to encode a novel 94 aa protein. The other class, antisense transcript, is unspliced and complimentary to ie1 exons 2-4, and has the potential to encode novel 154 and 152 aa proteins. Consistent with a role in latency, these transcripts are present in bone marrow aspirates from naturally infected, healthy seropositive donors but are not present in seronegative controls. Sense latent transcripts are present in a majority of seropositive individuals. Consistent with the expression of latent transcripts, antibody to the 94 aa and 152 aa proteins is detectable in the serum of seropositive individuals. Thus, latent infection by cytomegalovirus is accompanied by the presence of latency-associated transcripts and expression of immunogenic proteins. Overall, these results suggest that bone marrow-derived myeloid progenitors are an important natural site of viral latency. Images Fig. 1 Fig. 2 Fig. 3 PMID:8855322

  18. The immunological underpinnings of vaccinations to prevent cytomegalovirus disease

    PubMed Central

    Louise McCormick, A.; Mocarski, Edward S.

    2015-01-01

    A universal cytomegalovirus (CMV) vaccination promises to reduce the burden of the developmental damage that afflicts up to 0.5% of live births worldwide. An effective vaccination that prevents transplacental transmission would reduce CMV congenital disease and CMV-associated still births and leave populations less susceptible to opportunistic CMV disease. Thus, a vaccination against this virus has long been recognized for the potential of enormous health-care savings because congenital damage is life-long and existing anti-viral options are limited. Vaccine researchers, industry leaders, and regulatory representatives have discussed the challenges posed by clinical efficacy trials that would lead to a universal CMV vaccine, reviewing the links between infection and disease, and identifying settings where disrupting viral transmission might provide a surrogate endpoint for disease prevention. Reducing the complexity of such trials would facilitate vaccine development. Children and adolescents are the targets for universal vaccination, with the expectation of protecting the offspring of immunized women. Given that a majority of females worldwide experience CMV infection during childhood, a universal vaccine must boost natural immunity and reduce transmission due to reactivation and re-infection as well as primary infection during pregnancy. Although current vaccine strategies recognize the value of humoral and cellular immunity, the precise mechanisms that act at the placental interface remain elusive. Immunity resulting from natural infection appears to limit rather than prevent reactivation of latent viruses and susceptibility to re-infection, leaving a challenge for universal vaccination to improve upon natural immunity levels. Despite these hurdles, early phase clinical trials have achieved primary end points in CMV seronegative subjects. Efficacy studies must be expanded to mixed populations of CMV-naive and naturally infected subjects to understand the overall

  19. Differential susceptibility of RAE-1 isoforms to mouse cytomegalovirus.

    PubMed

    Arapovic, Jurica; Lenac, Tihana; Antulov, Ronald; Polic, Bojan; Ruzsics, Zsolt; Carayannopoulos, Leonidas N; Koszinowski, Ulrich H; Krmpotic, Astrid; Jonjic, Stipan

    2009-08-01

    The NKG2D receptor is one of the most potent activating natural killer cell receptors involved in antiviral responses. The mouse NKG2D ligands MULT-1, RAE-1, and H60 are regulated by murine cytomegalovirus (MCMV) proteins m145, m152, and m155, respectively. In addition, the m138 protein interferes with the expression of both MULT-1 and H60. We show here that one of five RAE-1 isoforms, RAE-1delta, is resistant to downregulation by MCMV and that this escape has functional importance in vivo. Although m152 retained newly synthesized RAE-1delta and RAE-1gamma in the endoplasmic reticulum, no viral regulator was able to affect the mature RAE-1delta form which remains expressed on the surfaces of infected cells. This differential susceptibility to downregulation by MCMV is not a consequence of faster maturation of RAE-1delta compared to RAE-1gamma but rather an intrinsic property of the mature surface-resident protein. This difference can be attributed to the absence of a PLWY motif from RAE-1delta. Altogether, these findings provide evidence for a novel mechanism of host escape from viral immunoevasion of NKG2D-dependent control.

  20. Resistance to antivirals in human cytomegalovirus: mechanisms and clinical significance.

    PubMed

    Pérez, J L

    1997-09-01

    Long term therapies needed for managing human cytomegalovirus (HCMV) infections in immunosupressed patients provided the background for the emergence of the resistance to antivirals active against HCMV. In addition, laboratory selected mutants have also been readily achieved. Both clinical and laboratory resistant strains share the same determinants of resistance. Ganciclovir resistance may be due to a few mutations in the HCMV UL97 gene and/or viral DNA pol gene, the former being responsible for about 70% of clinical resistant isolates. Among them, V464, V594, S595 and F595 are the most frequent mutations. Because of their less extensive clinical use, much less is known about resistance to foscarnet and cidofovir (formerly, HPMPC) but in both cases, it has been associated to mutations in the DNA pol. Ganciclovir resistant strains showing DNA pol mutations are cross-resistant to cidofovir and their corresponding IC50 are normally higher than those from strains harboring only mutations at the UL97 gene. To date, foscarnet resistance seems to be independent of both ganciclovir and cidofovir resistance.

  1. Developmental analysis of the cytomegalovirus enhancer in transgenic animals.

    PubMed

    Baskar, J F; Smith, P P; Ciment, G S; Hoffmann, S; Tucker, C; Tenney, D J; Colberg-Poley, A M; Nelson, J A; Ghazal, P

    1996-05-01

    The major immediate-early promoter (MIEP) of human, cytomegalovirus (HCMV) constitutes a primary genetic switch for viral activation. In this study, regulation of the enhancer-containing segment (nucleotides -670 to +54) of the HCMV MIEP attached to the 1acZ reporter gene was examined in the developing embryos of transgenic mice to identify temporal and tissue-specific expression. We find that the transgene reporter is first detected as a dorsal stripe of expression in the neural folds of embryos at day 8.5 postcoitum (p.c.). A broad expression pattern is exhibited in embryos at day 9.5 p.c. This pattern becomes more restricted by day 10.5 p.c. as organogenesis progresses. By day 14.5 p.c., prominent expression is observed in a subpopulation of central nervous system cells and spinal ganglia, endothelial cells, muscle, skin, thyroid, parathyroid, kidney, lung, liver, and gut cells, and the pancreas and submandibular and pituitary glands. This distribution pattern is discussed in relation to human congenital HCMV infection. These results suggest that the transcriptional activity of the HCMV MIEP may determine in part, the ability of the virus to specifically target developing fetal tissues in utero.

  2. Behavioral Convergence: Implications for Mathematical Models of Sexually Transmitted Infection Transmission

    PubMed Central

    Aral, Sevgi O.; Ward, Helen

    2014-01-01

    Recent trends in the behaviors of some groups with high sexual activity and of the general population in some countries suggest that sexual behavior profiles of high and low sexual activity categories may be converging and may call into question the assumptions around sexual mixing that are built into theoretical models of sexually transmitted infections (STIs)/human immunodeficiency virus (HIV) transmission dynamics. One category of high sexual activity, sex work, has been undergoing modification in many societies, becoming more acceptable, more dispersed, and larger in volume in some societies and shrinking in others. Concurrent with changes in the characteristics of sex work, the accumulating data on the sexual behaviors of the general population suggest a shift toward those of sex workers, including large numbers of sex partners and short-duration partnerships. The closing of the gap between behaviors associated with high and low sexual activity may have important implications for theories of sexual structure and models of transmission dynamics for STIs, including HIV infection. PMID:25381381

  3. Cryptosporidium infection in Brazil: implications for veterinary medicine and public health.

    PubMed

    Meireles, Marcelo Vasconcelos

    2010-01-01

    The aim of this review paper is to report the results of cryptosporidiosis research in Brazil, mainly its occurrence in animals and implications for veterinary medicine and public health. An increasing number of papers related to Cryptosporidium spp. infection in Brazil are available at national and international literature. The main focus described in these papers is the occurrence of Cryptosporidium spp. in food, environmental samples, in humans and several animal species, particularly birds, cattle, dogs and cats. Using molecular biology techniques, most Cryptosporidium species and genotypes identified in other countries have been described in Brazil. In mammals, there are descriptions of infection by C. bovis, C. canis, C. felis, C. meleagridis, C. parvum, and the cervine genotype; in birds, the following species and genotypes have been described: C. baileyi, C. galli, C. meleagridis, C. parvum and the avian genotypes I, II and III. Several species have been described in humans, such as C. parvum, C. hominis, and some species adapted to animal hosts such as C. canis, C. felis and C. meleagridis.

  4. Cell and molecular biology of simian virus 40: implications for human infections and disease

    NASA Technical Reports Server (NTRS)

    Butel, J. S.; Lednicky, J. A.

    1999-01-01

    Simian virus 40 (SV40), a polyomavirus of rhesus macaque origin, was discovered in 1960 as a contaminant of polio vaccines that were distributed to millions of people from 1955 through early 1963. SV40 is a potent DNA tumor virus that induces tumors in rodents and transforms many types of cells in culture, including those of human origin. This virus has been a favored laboratory model for mechanistic studies of molecular processes in eukaryotic cells and of cellular transformation. The viral replication protein, named large T antigen (T-ag), is also the viral oncoprotein. There is a single serotype of SV40, but multiple strains of virus exist that are distinguishable by nucleotide differences in the regulatory region of the viral genome and in the part of the T-ag gene that encodes the protein's carboxyl terminus. Natural infections in monkeys by SV40 are usually benign but may become pathogenic in immunocompromised animals, and multiple tissues can be infected. SV40 can replicate in certain types of simian and human cells. SV40-neutralizing antibodies have been detected in individuals not exposed to contaminated polio vaccines. SV40 DNA has been identified in some normal human tissues, and there are accumulating reports of detection of SV40 DNA and/or T-ag in a variety of human tumors. This review presents aspects of replication and cell transformation by SV40 and considers their implications for human infections and disease pathogenesis by the virus. Critical assessment of virologic and epidemiologic data suggests a probable causative role for SV40 in certain human cancers, but additional studies are necessary to prove etiology.

  5. Cytomegalovirus retinitis in Good syndrome: case report and review of literature

    PubMed Central

    Popiela, Magdalena; Varikkara, Mohan; Koshy, Zachariah

    2009-01-01

    This report describes the case of a 59-year-old woman diagnosed with cytomegalovirus (CMV) retinitis. The diagnosis was suggested by a typical fundus appearance, and confirmed by a positive PCR for CMV of both serum and vitreous biopsy. HIV status was negative. The patient’s medical history included thymoma followed by a thymectomy, recent multiple oral thrush infections, lower respiratory tract infections, urinary tract infections and severe weight loss. She had previously been treated for toxoplasma chorioretinitis and had vitrectomies for retinal detachment in the right eye. Immunological investigations revealed low T cells, almost absent B cells with reduced immunoglobulins consistent with the diagnosis of Good syndrome. The patient received treatment with intravenous ganciclovir, followed by maintenance valganciclovir, resulting in resolution of the ocular pathology. Immunoglobulin replacement therapy to boost the humoral immunity has been commenced. PMID:21691402

  6. The history of vaccination against cytomegalovirus.

    PubMed

    Plotkin, Stanley

    2015-06-01

    Cytomegalovirus vaccine development started in the 1970s with attenuated strains. In the 1980s, one of the strains was shown to be safe and effective in renal transplant patients. Then, attention switched to glycoprotein gB, which was shown to give moderate but transient protection against acquisition of the virus by women. The identification of the pp65 tegument protein as the principal target of cellular immune responses resulted in new approaches, particularly DNA, plasmids to protect hematogenous stem cell recipients. The subsequent discovery of the pentameric protein complex that generates most neutralizing antibodies led to efforts to incorporate that complex into vaccines. At this point, there are many candidate CMV vaccines, including live recombinants, replication-defective virus, DNA plasmids, soluble pentameric proteins, peptides, virus-like particles and vectored envelope proteins.

  7. [Infections after organ transplantation].

    PubMed

    Kern, W V; Wagner, D; Hirsch, H H

    2005-06-01

    Early postoperative infections after transplantation vary according to the transplanted organ. During the subsequent course opportunistic infections such as cytomegalovirus reactivation, Pneumocystis jiroveci pneumonia, invasive pneumococcal infection and mould infections predominate. Reactivated tuberculous infection appears to become more prevalent. Some of the opportunistic infections are preventable by chemoprophylaxis; others can be managed very effectively by monitoring and early preemptive therapy. Physicians caring for patients after organ transplantation need to early consider in the differential diagnosis rare pathogens which are often overlooked with standard diagnostic procedures.

  8. The Canonical Immediate Early 3 Gene Product pIE611 of Mouse Cytomegalovirus Is Dispensable for Viral Replication but Mediates Transcriptional and Posttranscriptional Regulation of Viral Gene Products

    PubMed Central

    Rattay, Stephanie; Trilling, Mirko; Megger, Dominik A.; Sitek, Barbara; Meyer, Helmut E.; Hengel, Hartmut

    2015-01-01

    ABSTRACT Transcription of mouse cytomegalovirus (MCMV) immediate early ie1 and ie3 is controlled by the major immediate early promoter/enhancer (MIEP) and requires differential splicing. Based on complete loss of genome replication of an MCMV mutant carrying a deletion of the ie3-specific exon 5, the multifunctional IE3 protein (611 amino acids; pIE611) is considered essential for viral replication. Our analysis of ie3 transcription resulted in the identification of novel ie3 isoforms derived from alternatively spliced ie3 transcripts. Construction of an IE3-hemagglutinin (IE3-HA) virus by insertion of an in-frame HA epitope sequence allowed detection of the IE3 isoforms in infected cells, verifying that the newly identified transcripts code for proteins. This prompted the construction of an MCMV mutant lacking ie611 but retaining the coding capacity for the newly identified isoforms ie453 and ie310. Using Δie611 MCMV, we demonstrated the dispensability of the canonical ie3 gene product pIE611 for viral replication. To determine the role of pIE611 for viral gene expression during MCMV infection in an unbiased global approach, we used label-free quantitative mass spectrometry to delineate pIE611-dependent changes of the MCMV proteome. Interestingly, further analysis revealed transcriptional as well as posttranscriptional regulation of MCMV gene products by pIE611. IMPORTANCE Cytomegaloviruses are pathogenic betaherpesviruses persisting in a lifelong latency from which reactivation can occur under conditions of immunosuppression, immunoimmaturity, or inflammation. The switch from latency to reactivation requires expression of immediate early genes. Therefore, understanding of immediate early gene regulation might add insights into viral pathogenesis. The mouse cytomegalovirus (MCMV) immediate early 3 protein (611 amino acids; pIE611) is considered essential for viral replication. The identification of novel protein isoforms derived from alternatively spliced ie3

  9. Quantitation of Cytomegalovirus: Methodologic Aspects and Clinical Applications

    PubMed Central

    Boeckh, Michael; Boivin, Guy

    1998-01-01

    Cytomegalovirus (CMV) is an important pathogen in transplant recipients and human immunodeficiency virus (HIV)-infected individuals. Major progress has been made in developing quantitative detection methods for CMV in recent years. Due to their high sensitivity, these assays can detect CMV early, and quantitation may be useful in predicting the patient’s risk for disease and in monitoring the effect of antiviral therapy. This review discusses methodological aspects of currently used quantitative assays for CMV (i.e., viral culture techniques, antigen detection assays, DNA detection assays including PCR, branched-DNA assay, and the DNA hybrid capture assay) and addresses the correlation of systemic and site-specific CMV load and CMV disease in different populations of immunosuppressed patients as well as the response to antiviral treatment. To date, direct antigen detection and molecular techniques have largely replaced traditional culture-based techniques for CMV quantitation. In general, a high systemic CMV load is correlated with CMV disease. This correlation is strong in the HIV-infected population and in solid-organ transplant recipients but less clear in allogeneic marrow transplant recipients. Measuring the viral load at specific anatomic sites may be an alternative way to assess disease activity in situations where the systemic viral load correlates poorly with disease activity. A reduction of the systemic CMV load also correlates with a response to antiviral treatment, but more research is needed to evaluate the role of viral load as a surrogate marker for drug resistance. Due to the widespread use of quantitative CMV detection techniques to direct and monitor antiviral treatment, there is a great need for an assessment of the reproducibility of test results and better standardization of the assays. PMID:9665982

  10. Type 1 Interferons and NK Cells Limit Murine Cytomegalovirus Escape from the Lymph Node Subcapsular Sinus

    PubMed Central

    Bruce, Kimberley; Lawler, Clara; Cardin, Rhonda D.

    2016-01-01

    Cytomegaloviruses (CMVs) establish chronic, systemic infections. Peripheral infection spreads via lymph nodes, which are also a focus of host defence. Thus, this is a point at which systemic infection spread might be restricted. Subcapsular sinus macrophages (SSM) captured murine CMV (MCMV) from the afferent lymph and poorly supported its replication. Blocking the type I interferon (IFN-I) receptor (IFNAR) increased MCMV infection of SSM and of the fibroblastic reticular cells (FRC) lining the subcapsular sinus, and accelerated viral spread to the spleen. Little splenic virus derived from SSM, arguing that they mainly induce an anti-viral state in the otherwise susceptible FRC. NK cells also limited infection, killing infected FRC and causing tissue damage. They acted independently of IFN-I, as IFNAR blockade increased NK cell recruitment, and NK cell depletion increased infection in IFNAR-blocked mice. Thus SSM restricted MCMV infection primarily though IFN-I, with NK cells providing a second line of defence. The capacity of innate immunity to restrict MCMV escape from the subcapsular sinus suggested that enhancing its recruitment might improve infection control. PMID:27926941

  11. Rising Stakes for Healthcare-Associated Infection Prevention: Implications for the Clinical Microbiology Laboratory (REVISED).

    PubMed

    Diekema, Daniel J

    2017-01-25

    Healthcare associated infection (HAI) rates are subject to public reporting, and are linked to hospital reimbursement from the Centers for Medicare and Medicaid Services (CMS). The increasing pressure to lower HAI rates comes at a time when advances in the clinical microbiology laboratory (CML) provide more precise and sensitive tests, altering HAI detection in ways that may increase reported HAI rates. I review how changing CML practices can impact HAI rates, and how the financial implications of HAI metrics may produce pressure to change diagnostic testing practices. Finally, I provide suggestions for how to respond to this rapidly changing environment. SCENARIO 1: During an investigation of rising rates of central-line associated bloodstream infection (CLABSI), the infection prevention program (IPP) notes that some CLABSIs were due to organisms that grew in only one of several blood cultures, and which prior to the institution of matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) for organism identification would have been classified as contaminants. An example included a CLABSI attributed to an unusual species of Actinomyces that previously would have been categorized as a "diphtheroid". Your hospital leadership requests that you either revert to former identification methods or change your reporting in a way that prevents these events from being classified as CLABSIs. SCENARIO 2: Since you changed to a nucleic acid amplification test (NAAT) for Clostridium difficile detection, your positivity rate has increased by over 100%. The rate of hospital-onset C. difficile infection (HO-CDI) has increased similarly. During an investigation of the increase in CDI, you find that many samples positive by NAAT are toxin negative by enzyme immunoassay (EIA), and that many patients with low pretest probability of disease are being tested. However, after an initiative to improve testing practices, your hospital-onset CDI Lab ID-event rate remains high

  12. Antibody responses of cervids (Cervus elaphus) following experimental Mycobacterium bovis infection and the implications for immunodiagnosis.

    PubMed

    Harrington, Noel P; Surujballi, Om P; Prescott, John F; Duncan, J Robert; Waters, W Ray; Lyashchenko, Konstantin; Greenwald, Rena

    2008-11-01

    Captive and free-ranging wildlife animals are implicated in the maintenance and transmission of bovine tuberculosis and therefore pose a significant obstacle to eradication of the disease from domestic livestock. The current antemortem diagnostic method, the intradermal tuberculin skin test, is impractical for routine use with many wild animals. Antibody-based assays are particularly attractive because the animals are handled only once and immediate processing of the sample is not required. This report characterizes the antibody responses of red deer-elk hybrids (Cervus elaphus) against Mycobacterium bovis and subsequently evaluates the diagnostic performance of select antigens in a rapid-test format. Sequential serum samples were collected from 10 animals experimentally infected with M. bovis and 5 noninfected animals over a 7-month period postinfection (p.i.). Samples were evaluated by enzyme-linked immunosorbent assays, immunoblot analyses, and multiantigen print immunoassays for seroreactivity to mycobacterial antigens. Although all infected animals produced antibodies to M. bovis protein antigens, there was significant animal-to-animal variation in the kinetics and magnitudes of responses and the antigens recognized. The most frequently recognized antigens included MPB83, ESAT-6, CFP10, and MPB70. Responses to some antigens, such as MPB83, were consistently detected as early as 4 weeks after inoculation, whereas other antigens were detected only much later (>140 days p.i.). Antibody responses were boosted by injection of tuberculin for intradermal tuberculin skin testing. Comparison of single-antigen (fluorescence polarization assay) with multiantigen (CervidTB STAT-PAK) rapid tests demonstrated that a highly sensitive and specific serodiagnostic test for tuberculosis in cervids will require multiple and carefully selected seroreactive antigens covering a broad spectrum of antibody specificities.

  13. HPV Infection in Cervical and Other Cancers in Saudi Arabia: Implication for Prevention and Vaccination

    PubMed Central

    Alsbeih, Ghazi

    2014-01-01

    Human papillomavirus (HPV) is closely associated with cervical cancer that the incidence of this tumor is regarded as a surrogate marker for HPV infection in countries lacking epidemiological studies. HPV is also implicated in subsets of anogenital and oropharyngeal cancers. Although cervical cancer is the third most common cancer in women worldwide, its reported incidence is low in Saudi Arabia, ranking number 12 between all cancers in females and accounts only for 2.4% of all new cases, despite the lack of national screening programs. However, the limited available studies from Saudi Arabia indicate that HPV prevalence and genotypes’ distribution in invasive cervical cancer show similar pattern as in the world. Cytology screening (Pap smear) and HPV vaccinations are the two preventive measures against cervical cancer. The two available vaccines are effective against the two most common HPV genotypes (HPV-16 and -18). Since 92% of cervical tumors in the Kingdom are infected with HPV of which 78% are HPV-16 and -18 genotypes, vaccination is expected to protect against more than two-third of cervical cancers in Saudi Arabia. Nevertheless, due to its low incidence (2.1/100,000 women), a proper cost-effectiveness analysis is required to justify the implementation of a costly vaccine bearing in mind that HPV could potentially be associated with about 3% of all cancers. However, further studies are needed to ascertain the real prevalence of HPV at the population level at large, its association with various types of cancers, and also the impact of local tradition and emerging behavioral trends that could affect HPV transmission and consequently the effectiveness of applying national vaccination program. PMID:24744990

  14. Incidence and clinical implication of nosocomial infections associated with implantable biomaterials - catheters, ventilator-associated pneumonia, urinary tract infections.

    PubMed

    Guggenbichler, Josef Peter; Assadian, Ojan; Boeswald, Michael; Kramer, Axel

    2011-01-01

    Health care associated infections, the fourth leading cause of disease in industrialised countries, are a major health issue. One part of this condition is based on the increasing insertion and implantation of prosthetic medical devices, since presence of a foreign body significantly reduces the number of bacteria required to produce infection. The most significant hospital-acquired infections, based on frequency and potential severity, are those related to procedures e.g. surgical site infections and medical devices, including urinary tract infection in catheterized patients, pneumonia in patients intubated on a ventilator and bacteraemia related to intravascular catheter use. At least half of all cases of nosocomial infections are associated with medical devices.Modern medical and surgical practices have increasingly utilized implantable medical devices of various kinds. Such devices may be utilized only short-time or intermittently, for months, years or permanently. They improve the therapeutic outcome, save human lives and greatly enhance the quality of life of these patients. However, plastic devices are easily colonized with bacteria and fungi, able to be colonized by microorganisms at a rate of 0.5 cm per hour. A thick biofilm is formed within 24 hours on the entire surface of these plastic devices once inoculated even with a small initial number of bacteria.The aim of the present work is to review the current literature on causes, frequency and preventive measures against infections associated with intravascular devices, catheter-related urinary tract infection, ventilator-associated infection, and infections of other implantable medical devices. Raising awareness for infection associated with implanted medical devices, teaching and training skills of staff, and establishment of surveillance systems monitoring device-related infection seem to be the principal strategies used to achieve reduction and prevention of such infections. The intelligent use of

  15. Incidence and clinical implication of nosocomial infections associated with implantable biomaterials – catheters, ventilator-associated pneumonia, urinary tract infections

    PubMed Central

    Guggenbichler, Josef Peter; Assadian, Ojan; Boeswald, Michael; Kramer, Axel

    2012-01-01

    Health care associated infections, the fourth leading cause of disease in industrialised countries, are a major health issue. One part of this condition is based on the increasing insertion and implantation of prosthetic medical devices, since presence of a foreign body significantly reduces the number of bacteria required to produce infection. The most significant hospital-acquired infections, based on frequency and potential severity, are those related to procedures e.g. surgical site infections and medical devices, including urinary tract infection in catheterized patients, pneumonia in patients intubated on a ventilator and bacteraemia related to intravascular catheter use. At least half of all cases of nosocomial infections are associated with medical devices. Modern medical and surgical practices have increasingly utilized implantable medical devices of various kinds. Such devices may be utilized only short-time or intermittently, for months, years or permanently. They improve the therapeutic outcome, save human lives and greatly enhance the quality of life of these patients. However, plastic devices are easily colonized with bacteria and fungi, able to be colonized by microorganisms at a rate of up to 0.5 cm per hour. A thick biofilm is formed within 24 hours on the entire surface of these plastic devices once inoculated even with a small initial number of bacteria. The aim of the present work is to review the current literature on causes, frequency and preventive measures against infections associated with intravascular devices, catheter-related urinary tract infection, ventilator-associated infection, and infections of other implantable medical devices. Raising awareness for infection associated with implanted medical devices, teaching and training skills of staff, and establishment of surveillance systems monitoring device-related infection seem to be the principal strategies used to achieve reduction and prevention of such infections. The intelligent use

  16. Cytomegalovirus enterocolitis in a patient with diffuse large B-cell lymphoma after chemotherapy with rituximab.

    PubMed

    Seewoodhary, Jason

    2006-12-07

    Rituximab has been associated with the development of cytomegalovirus enterocolitis in immunosuppressed patients. A 51-year-old patient with diffuse large B-cell lymphoma who received a conditioning chemotherapy regimen (RCVP and RICE) consisting of rituximab before bone marrow transplantation went on to develop cytomegalovirus enterocolitis. This supports evidence from previously described cases that rituximab may be associated with cytomegalovirus enterocolitis.

  17. High-Throughput Analysis of Human Cytomegalovirus Genome Diversity Highlights the Widespread Occurrence of Gene-Disrupting Mutations and Pervasive Recombination

    PubMed Central

    Thys, Kim; Mbong Ngwese, Mirabeau; Van Damme, Ellen; Dvorak, Jan; Van Loock, Marnix; Li, Guangdi; Tachezy, Ruth; Busson, Laurent; Aerssens, Jeroen; Van Ranst, Marc

    2015-01-01

    ABSTRACT Human cytomegalovirus is a widespread pathogen of major medical importance. It causes significant morbidity and mortality in immunocompromised individuals, and congenital infections can result in severe disabilities or stillbirth. Development of a vaccine is prioritized, but no candidate is close to release. Although correlations of viral genetic variability with pathogenicity are suspected, knowledge about the strain diversity of the 235-kb genome is still limited. In this study, 96 full-length human cytomegalovirus genomes from clinical isolates were characterized, quadrupling the amount of information available for full-genome analysis. These data provide the first high-resolution map of human cytomegalovirus interhost diversity and evolution. We show that cytomegalovirus is significantly more divergent than all other human herpesviruses and highlight hot spots of diversity in the genome. Importantly, 75% of strains are not genetically intact but contain disruptive mutations in a diverse set of 26 genes, including the immunomodulatory genes UL40 and UL111A. These mutants are independent of culture passage artifacts and circulate in natural populations. Pervasive recombination, which is linked to the widespread occurrence of multiple infections, was found throughout the genome. The recombination density was significantly higher than those of other human herpesviruses and correlated with strain diversity. While the overall effects of strong purifying selection on virus evolution are apparent, evidence of diversifying selection was found in several genes encoding proteins that interact with the host immune system, including UL18, UL40, UL142, and UL147. These residues may present phylogenetic signatures of past and ongoing virus-host interactions. IMPORTANCE Human cytomegalovirus has the largest genome of all viruses that infect humans. Currently, there is a great interest in establishing associations between genetic variants and strain pathogenicity of

  18. Abattoir condemnation due to parasitic infections and its economic implications in the region of Trikala, Greece.

    PubMed

    Theodoropoulos, G; Theodoropoulou, E; Petrakos, G; Kantzoura, V; Kostopoulos, J

    2002-08-01

    The prevalence of parasitic infections responsible for the condemnation of carcasses and viscera during meat inspection, and their economic implication, was estimated in a year long abattoir survey of 10 277 slaughtered farm animals in the region of Trikala, Greece. The organs examined for the presence of parasitic lesions during meat inspection were: liver and lungs of all animals, rumen of cattle, small intestine of lambs and kids, and muscles of cattle and swine. The parasitic lesions observed in the lungs of cattle, sheep and goats were caused only by hydatid cysts. No hydatid cysts were observed in the lungs of swine. The parasitic lesions observed in the liver of cattle, sheep and goats were as a result of hydatid cysts and flukes of Fasciola hepatica and Dicrocoelium dendriticum, while those of swine were due to milk spots only. Moniezia sp. proglottids were found in the small intestine of lambs only. The prevalence of parasites responsible for the condemnation of marketable organs was low (0.26%). Parasites were responsible for 22% of the total of condemned organs, and their annual cost was 99, 00 GDR (approximately 292 Euros). The parasites most contributing to marketable organ condemnation were hydatid cysts (26%) and D. dendriticum flukes (26%).

  19. Microbial Etiology and Antimicrobial Susceptibility of Bactria Implicated in Urinary Tract Infection in Tehran, Iran

    PubMed Central

    Nozarian, Zohreh; Abdollahi, Alireza

    2015-01-01

    Background and Objectives: Urinary tract infections (UTI) are one of the most common infectious diseases with different microbial agent and antimicrobial resistant pattern in hospitalized patients and outpatients. In order to assess the adequacy of therapy, knowledge of prevalence and resistance pattern of the bacteria is necessary. The main aim of this study was to evaluate the prevalence and the antimicrobial resistance pattern of main bacterial responsible for UTI in order to establish an appropriate empirical therapy. Methods: All urine samples were referred to Imam Hospital Laboratory, Tehran, Iran during 2011-2012, urine culture isolated and bacteria were identified and the profile of antibiotic susceptibility was characterized. Result: From 1851 urine cultures, UTI was more frequent in woman (68%) E. coli was as usual the most common pathogen implicated in UTI. Most susceptibility was to imipenem (98.9%). nitroforantoin (96%) and amikacin (94.1%) and increased resistance to penicillin (66.6%), nalidixic acid (62.1%) ampicilin (60.1%) and cotrimoxazole 54.3%. Discussion: The most common isolated pathogen was E. coli . According to antibiogram susceptibility, the recommended antimicrobial drugs are nitroforantoin and imipenem. nalidixic acid and cotrimoxazole are not recommended because drug resistance is high. PMID:26516326

  20. Parainfluenza virus infection in adult lung transplant recipients: an emergent clinical syndrome with implications on allograft function.

    PubMed

    Vilchez, Regis A; Dauber, James; McCurry, Kenneth; Iacono, Aldo; Kusne, Shimon

    2003-02-01

    Parainfluenza virus is a common cause of seasonal upper respiratory tract infections in children and adults. Studies indicate that parainfluenza virus may play an important role in the etiology of respiratory tract infections in lung transplant recipients with an estimated incidence of 5.3 per 100 patients. Parainfluenza virus type 3 is the most frequent serotype in lung transplant patients. The rate of lower respiratory tract infections with parainfluenza virus among lung transplant recipients is between 10 and 66% of cases. In addition, trans-bronchial biopsy at the time of parainfluenza infection shows signs of acute allograft rejection. Subsequently, 32% of patients have been found to have active bronchiolitis obliterans at a median time of 6 months (range 1-14) postviral infection. These findings indicate that parainfluenza virus infections may have long-term implications for lung transplant recipients. Further studies are required to identify the mechanisms of immunomodulation of parainfluenza virus among these patients. In addition, controlled studies are needed to evaluate the efficacy of aerosolized ribavarin in the treatment of parainfluenza virus infection and to determine whether vaccines may be effective in these high-risk patients.

  1. Human Papillomavirus Infection in HIV-1 Infected Women in Catalonia (Spain): Implications for Prevention of Cervical Cancer

    PubMed Central

    Stuardo, Valeria; Agustí, Cristina; Godinez, José Manuel; Montoliu, Alexandra; Torné, Aureli; Tarrats, Antoni; Alcalde, Carmen; Martín, Dolores; Fernández-Montoli, Eulalia; Vanrell, Cristina; Solé, Josefa; Canet, Yolanda; Marqueta, José Manuel; Mohamed, Jadiyettu; Cuenca, Isabel; Lonca, Montserrat; Sirera, Guillem; Ferrer, Elena; Domingo, Pere; Lloveras, Belen; Miro, Josep María; De Sanjosé, Silvia; Casabona, Jordi

    2012-01-01

    Background High-risk human Papillomavirus infection is a necessary factor for cervical squamous intraepithelial lesions and invasive cervical cancer. In HIV-1-infected women, HPV infection is more prevalent and a higher risk of cervical cancer has been identified. We aimed to calculate the prevalence of infection by HR-HPV, determine the factors associated with this infection and abnormal cytology findings and to describe the history of cervical cancer screening in HIV-1-infected women. Methods We enrolled 479 HIV-1–infected women from the PISCIS cohort. Each patient underwent a gynecological check-up, PAP smear, HPV AND Hybrid capture, HPV genotyping, and colposcopy and biopsy, if necessary. We applied questionnaires to obtain information on sociodemographic, behavioral, clinical, and cervical screening variables. We present a cross-sectional analysis. Results Median age was 42 years. The prevalence of HR-HPV infection was 33.2% and that of high-grade squamous intraepithelial lesions (HSIL) was 3.8%. The most common genotypes were 16(23%), 53(20.3%), and 52(16.2%). The factor associated with HR-HPV infection was age <30 years (odds ratio[OR],2.5; 95%confidence interval[CI],1.1–5.6). The factors associated with the presence of HSIL or low-grade squamous intraepithelial lesions (LSIL) were CD4T-lymphocyte count <200cells/mm3 versus >500cells/mm3 (OR,8.4; 95%CI,3.7–19.2), HIV-1 viral load >10,000copies/mL versus <400copies/mL (OR,2.1; 95%CI,1.0–4.4), and use of oral contraceptives (OR,2.0; 95%CI,1.0–3.9). Sixty percent of HIV-1–infected women had had one Pap smear within the last 2 years. Conclusions The high prevalence of HPV infection and cervical lesions in the HIV-1–infected population in Catalonia, as well as the low coverage and frequency of screening in this group, means that better preventive efforts are necessary and should include vaccination against HPV, better accessibility to screening programs, training of health care professionals, and

  2. Esophageal ulcer caused by cytomegalovirus: resolution during combination antiretroviral therapy for acquired immunodeficiency syndrome.

    PubMed

    Mönkemüller, K E; Wilcox, C M

    2000-08-01

    A 36-year-old man with a 5-year history of untreated human immunodeficiency virus (HIV) infection had odynophagia for 14 days. Fifteen days earlier, he had begun taking trimethoprim-sulphamethoxazole and combination antiretroviral therapy that included lamivudine, zidovudine, and nelfinavir. He had no history of opportunistic infection. The CD4 lymphocyte count was 67/microL and HIV-RNA level was 359,396 copies/mL. Esophagogastroduodenoscopy revealed a large, well-circumscribed esophageal ulceration 31 cm from the incisors. Histopathologic examination of esophageal biopsy specimens showed cytopathic changes diagnostic of cytomegalovirus (CMV). In situ DNA hybridization was positive for CMV. While combination antiretroviral therapy was continued, the esophageal symptoms resolved within 4 days of endoscopy without specific therapy for CMV. Follow-up endoscopy 4 weeks later revealed a normal-appearing esophagus, and the patient has remained symptom-free for 10 months.

  3. In Vitro Anti-Cytomegalovirus Activity of Kampo (Japanese Herbal) Medicine

    PubMed Central

    2004-01-01

    We examined the effect of three types of Kampo medicines on human cytomegalovirus (CMV) replication in the human embryonic fibroblast cell line, MRC-5. Treatment of cells with at least 0.01 μg/ml of Kampo medicines inhibited the cytopathic effects of CMV-infected MRC-5 cells. Moreover, Kampo medicine decreased the replication of CMV without affecting the inhibition of host cells, with a concomitant decrease in CMV DNA levels. However, Kampo medicine demonstrated no virocidal effect on cell-free CMV. Furthermore, western blotting analysis demonstrated that the Kampo medicine decreased the amount of 65 kDa late antigen expression in the infected cells. These results suggest that Kampo medicine may be sufficient to inhibit viral DNA replication and late protein synthesis, resulting in anti-CMV effects. Therefore, these three Kampo medicines have the potential of being a source of new powerful anti-CMV compounds. PMID:15841262

  4. Rapid detection and quantitation of ganciclovir resistance in cytomegalovirus quasispecies.

    PubMed

    Ruiz-Carrascoso, Guillermo; Romero-Gómez, María Pilar; Plaza, Diego; Mingorance, Jesús

    2013-07-01

    Human cytomegalovirus (HCMV) may cause severe or fatal disease among immunocompromised patients. The first line prophylaxis and systemic HCMV disease therapy is ganciclovir (GCV). The presence of GCV-resistant virus has been linked to fatal HCMV disease. The implementation of rapid and sensitive techniques for the early detection and monitoring of GCV-resistance may be helpful to support antiviral therapy management. A pyrosequencing assay for the detection and quantitation of the most frequent mutations conferring moderate- and high-grade GCV resistance was implemented. The pyrosequencing achieved an analytical sensitivity for adequate interpretation of ≥10(3)  copies/ml. The assay was validated with 18 whole blood samples taken over a 6-month period from an umbilical cord blood recipient infected persistently with HCMV and allowed the detection and monitoring of the M460I and A594V GCV-resistant mutations. The percentage of resistant quasispecies ranged from 7.9% to 55.2% for the M460I mutation and from 19.8% to 43% for the A594V mutation. Clearance of the M460I mutation occurred in parallel with a decrease in the HCMV viremia, while the A594V mutation persisted. The pyrosequencing method for detection of GCV is sensitive enough to be used directly on clinical samples for the early identification of resistance mutations and allows the quantitation of resistant and wild type virus quasispecies within hours. The quantitation of minor resistant variants is an important issue to understand their relationship with viral load modification, and potentially anticipate treatment adjustment.

  5. Pregnancy, Labor, and Delivery after Ebola Virus Disease and Implications for Infection Control in Obstetric Services, United States.

    PubMed

    Kamali, Amanda; Jamieson, Denise J; Kpaduwa, Julius; Schrier, Sarah; Kim, Moon; Green, Nicole M; Ströher, Ute; Muehlenbachs, Atis; Bell, Michael; Rollin, Pierre E; Mascola, Laurene

    2016-07-01

    Many of the survivors of the 2014-2015 epidemic of Ebola virus disease (EVD) in western Africa were women of childbearing age. Limited clinical and laboratory data exist that describe these women's pregnancies and outcomes. We report the case of an EVD survivor who became pregnant and delivered her child in the United States, and we discuss implications of this case for infection control practices in obstetric services. Hospitals in the United States must be prepared to care for EVD survivors.

  6. Outbreaks where food workers have been implicated in the spread of foodborne disease. Part 4. Infective doses and pathogen carriage.

    PubMed

    Todd, Ewen C D; Greig, Judy D; Bartleson, Charles A; Michaels, Barry S

    2008-11-01

    In this article, the fourth in a series reviewing the role of food workers in foodborne outbreaks, background information on the presence of enteric pathogens in the community, the numbers of organisms required to initiate an infection, and the length of carriage are presented. Although workers have been implicated in outbreaks, they were not always aware of their infections, either because they were in the prodromic phase before symptoms began or because they were asymptomatic carriers. Pathogens of fecal, nose or throat, and skin origin are most likely to be transmitted by the hands, highlighting the need for effective hand hygiene and other barriers to pathogen contamination, such as no bare hand contact with ready-to-eat food. The pathogens most likely to be transmitted by food workers are norovirus, hepatitis A virus, Salmonella, Shigella, and Staphylococcus aureus. However, other pathogens have been implicated in worker-associated outbreaks or have the potential to be implicated. In this study, the likelihood of pathogen involvement in foodborne outbreaks where infected workers have been implicated was examined, based on infectious dose, carriage rate in the community, duration of illness, and length of pathogen excretion. Infectious dose estimates are based on volunteer studies (mostly early experiments) or data from outbreaks. Although there is considerable uncertainty associated with these data, some pathogens appear to be able to infect at doses as low as 1 to 100 units, including viruses, parasites, and some bacteria. Lengthy postsymptomatic shedding periods and excretion by asymptomatic individuals of many enteric pathogens is an important issue for the hygienic management of food workers.

  7. Examination of brains of AIDS cases for human immunodeficiency virus and human cytomegalovirus nucleic acids.

    PubMed Central

    Walker, D G; Itagaki, S; Berry, K; McGeer, P L

    1989-01-01

    The role of direct virus infection as a determining factor in acquired immunodeficiency syndrome (AIDS) dementia was investigated using in situ hybridisation for human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV). Four of the five AIDS dementia patients in this series demonstrated HIV infected cells distributed in widely different parts of the brain, but only one case showed HCMV infected cells. The greater abundance of HIV was in subcortical white matter in nodular areas consisting of monocyte/macrophage infiltrates. The cells were occasionally arranged as a multinucleated syncitium. In two cases, a few large cells with the appearance of neurons were positive for HIV hybridisation. By appropriate treatment with ribonuclease, it was shown that hybridisation was primarily to HIV RNA. HCMV infected cells were observed in small numbers in only one of the positive cases, suggesting that HCMV is not a determining factor in AIDS dementia. HCMV positive cells were located in the grey matter, with an appearance suggestive of neurons. Cells expressing the MHC-class II antigen HLA-DR, a marker of reactive microglia and macrophages, were observed to be extensive in affected brain sections in the one case examined. These cells were present in greater number than HIV infected cells. In this case, extensive numbers of HIV infected cells were noticed along the peripheral margin of the substantia innominata. This could indicate infection in this case of a critical brain region from the cerebrospinal fluid. Images PMID:2543795

  8. Leflunomide for cytomegalovirus: bench to bedside.

    PubMed

    Chacko, B; John, G T

    2012-04-01

    Cytomegalovirus (CMV) remains a major cause of morbidity and mortality among transplant recipients, frequently engaging the clinician in a struggle to balance graft preservation with control of CMV disease. Leflunomide has been shown to have immunosuppressive activity in experimental allograft models together with antiviral activity inhibiting CMV both in vitro and in vivo. Data are emerging about its potential role in ganciclovir-sensitive and -resistant CMV, primarily by virtue of a unique mechanism inhibiting virion assembly, as opposed to inhibition of viral DNA synthesis by current agents. This review aims to put in perspective, the knowledge acquired in the last decade or so on leflunomide for CMV. Evidence suggests that it might have activity against human CMV with good oral bioavailability and, more importantly in the resource-poor setting, is economical. Although the data presented here are not from randomized trials, several relevant observations have been made that could influence future, more structured assessments of the drug. An immune suppressive compound with antiviral features and experimental activity in chronic rejection is an attractive combination for organ transplantation, and it appears that leflunomide may just fit that niche.

  9. Evaluation of T Cell Immunity against Human Cytomegalovirus: Impact on Patient Management and Risk Assessment of Vertical Transmission

    PubMed Central

    Quaranta, Paola; Pistello, Mauro

    2016-01-01

    Cytomegalovirus (CMV) is one of the most common infectious agents, infecting the general population at an early age without causing morbidity most of the time. However, on particular occasions, it may represent a serious risk, as active infection is associated with rejection and disease after solid organ transplantation or fetal transmission during pregnancy. Several methods for CMV diagnosis are available on the market, but because infection is so common, careful selection is needed to discriminate primary infection from reactivation. This review focuses on methods based on CMV-specific T cell reactivity to help monitor the consequences of CMV infection/reactivation in specific categories of patients. This review makes an attempt at discussing the pros and cons of the methods available. PMID:28044143

  10. A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions.

    PubMed

    Chen, Han; Coseno, Molly; Ficarro, Scott B; Mansueto, My Sam; Komazin-Meredith, Gloria; Boissel, Sandrine; Filman, David J; Marto, Jarrod A; Hogle, James M; Coen, Donald M

    2017-02-10

    Human cytomegalovirus DNA polymerase comprises a catalytic subunit, UL54, and an accessory subunit, UL44, the interaction of which may serve as a target for the development of new antiviral drugs. Using a high-throughput screen, we identified a small molecule, (5-((dimethylamino)methylene-3-(methylthio)-6,7-dihydrobenzo[c]thiophen-4(5H)-one), that selectively inhibits the interaction of UL44 with a UL54-derived peptide in a time-dependent manner, full-length UL54, and UL44-dependent long-chain DNA synthesis. A crystal structure of the compound bound to UL44 revealed a covalent reaction with lysine residue 60 and additional noncovalent interactions that cause steric conflicts that would prevent the UL44 connector loop from interacting with UL54. Analyses of the reaction of the compound with model substrates supported a resonance-stabilized conjugation mechanism, and substitution of the lysine reduced the ability of the compound to inhibit UL44-UL54 peptide interactions. This novel covalent inhibitor of polymerase subunit interactions may serve as a starting point for new, needed drugs to treat human cytomegalovirus infections.

  11. Cytomegalovirus survival and transferability and the effectiveness of common hand-washing agents against cytomegalovirus on live human hands.

    PubMed

    Stowell, Jennifer D; Forlin-Passoni, Daniela; Radford, Kay; Bate, Sheri L; Dollard, Sheila C; Bialek, Stephanie R; Cannon, Michael J; Schmid, D Scott

    2014-01-01

    Congenital cytomegalovirus (CMV) transmission can occur when women acquire CMV while pregnant. Infection control guidelines may reduce risk for transmission. We studied the duration of CMV survival after application of bacteria to the hands and after transfer from the hands to surfaces and the effectiveness of cleansing with water, regular and antibacterial soaps, sanitizer, and diaper wipes. Experiments used CMV AD169 in saliva at initial titers of 1 × 10(5) infectious particles/ml. Samples from hands or surfaces (points between 0 and 15 min) were placed in culture and observed for at least 2 weeks. Samples were also tested using CMV real-time PCR. After application of bacteria to the hands, viable CMV was recovered from 17/20 swabs at 0 min, 18/20 swabs at 1 min, 5/20 swabs at 5 min, and 4/20 swabs at 15 min. After transfer, duration of survival was at least 15 min on plastic (1/2 swabs), 5 min on crackers and glass (3/4 swabs), and 1 min or less on metal and cloth (3/4 swabs); no viable virus was collected from wood, rubber, or hands. After cleansing, no viable virus was recovered using water (0/22), plain soap (0/20), antibacterial soap (0/20), or sanitizer (0/22). Viable CMV was recovered from 4/20 hands 10 min after diaper wipe cleansing. CMV remains viable on hands for sufficient times to allow transmission. CMV may be transferred to surfaces with reduced viability. Hand-cleansing methods were effective at eliminating viable CMV from hands.

  12. Cytomegalovirus Survival and Transferability and the Effectiveness of Common Hand-Washing Agents against Cytomegalovirus on Live Human Hands

    PubMed Central

    Stowell, Jennifer D.; Forlin-Passoni, Daniela; Radford, Kay; Bate, Sheri L.; Dollard, Sheila C.; Bialek, Stephanie R.; Cannon, Michael J.

    2014-01-01

    Congenital cytomegalovirus (CMV) transmission can occur when women acquire CMV while pregnant. Infection control guidelines may reduce risk for transmission. We studied the duration of CMV survival after application of bacteria to the hands and after transfer from the hands to surfaces and the effectiveness of cleansing with water, regular and antibacterial soaps, sanitizer, and diaper wipes. Experiments used CMV AD169 in saliva at initial titers of 1 × 105 infectious particles/ml. Samples from hands or surfaces (points between 0 and 15 min) were placed in culture and observed for at least 2 weeks. Samples were also tested using CMV real-time PCR. After application of bacteria to the hands, viable CMV was recovered from 17/20 swabs at 0 min, 18/20 swabs at 1 min, 5/20 swabs at 5 min, and 4/20 swabs at 15 min. After transfer, duration of survival was at least 15 min on plastic (1/2 swabs), 5 min on crackers and glass (3/4 swabs), and 1 min or less on metal and cloth (3/4 swabs); no viable virus was collected from wood, rubber, or hands. After cleansing, no viable virus was recovered using water (0/22), plain soap (0/20), antibacterial soap (0/20), or sanitizer (0/22). Viable CMV was recovered from 4/20 hands 10 min after diaper wipe cleansing. CMV remains viable on hands for sufficient times to allow transmission. CMV may be transferred to surfaces with reduced viability. Hand-cleansing methods were effective at eliminating viable CMV from hands. PMID:24185855

  13. Duration of SHIV production by infected cells is not exponentially distributed: Implications for estimates of infection parameters and antiviral efficacy

    PubMed Central

    Beauchemin, Catherine A. A.; Miura, Tomoyuki; Iwami, Shingo

    2017-01-01

    The duration of the eclipse phase, from cell infection to the production and release of the first virion progeny, immediately followed by the virus-production phase, from the first to the last virion progeny, are important steps in a viral infection, by setting the pace of infection progression and modulating the response to antiviral therapy. Using a mathematical model (MM) and data for the infection of HSC-F cells with SHIV in vitro, we reconfirm our earlier finding that the eclipse phase duration follows a fat-tailed distribution, lasting 19 h (18–20 h). Most importantly, for the first time, we show that the virus-producing phase duration, which lasts 11 h (9.8–12 h), follows a normal-like distribution, and not an exponential distribution as is typically assumed. We explore the significance of this finding and its impact on analysis of plasma viral load decays in HIV patients under antiviral therapy. We find that incorrect assumptions about the eclipse and virus-producing phase distributions can lead to an overestimation of antiviral efficacy. Additionally, our predictions for the rate of plasma HIV decay under integrase inhibitor therapy offer an opportunity to confirm whether HIV production duration in vivo also follows a normal distribution, as demonstrated here for SHIV infections in vitro. PMID:28202942

  14. Duration of SHIV production by infected cells is not exponentially distributed: Implications for estimates of infection parameters and antiviral efficacy

    NASA Astrophysics Data System (ADS)

    Beauchemin, Catherine A. A.; Miura, Tomoyuki; Iwami, Shingo

    2017-02-01

    The duration of the eclipse phase, from cell infection to the production and release of the first virion progeny, immediately followed by the virus-production phase, from the first to the last virion progeny, are important steps in a viral infection, by setting the pace of infection progression and modulating the response to antiviral therapy. Using a mathematical model (MM) and data for the infection of HSC-F cells with SHIV in vitro, we reconfirm our earlier finding that the eclipse phase duration follows a fat-tailed distribution, lasting 19 h (18–20 h). Most importantly, for the first time, we show that the virus-producing phase duration, which lasts 11 h (9.8–12 h), follows a normal-like distribution, and not an exponential distribution as is typically assumed. We explore the significance of this finding and its impact on analysis of plasma viral load decays in HIV patients under antiviral therapy. We find that incorrect assumptions about the eclipse and virus-producing phase distributions can lead to an overestimation of antiviral efficacy. Additionally, our predictions for the rate of plasma HIV decay under integrase inhibitor therapy offer an opportunity to confirm whether HIV production duration in vivo also follows a normal distribution, as demonstrated here for SHIV infections in vitro.

  15. Current controversies in diagnosis, management, and prevention of congenital cytomegalovirus: updates for the pediatric practitioner.

    PubMed

    Harrison, Gail J

    2015-05-01

    Congenital cytomegalovirus (CMV) infection has been called "the elephant in our living room" because it is a major public health problem that for decades has been unrecognized and unaddressed. Congenital CMV infection is a common cause of sensorineural hearing loss, vision loss, neurodevelopment disabilities, liver disease, and growth failure. Diagnostic tests are now widely available to identify newborns with congenital CMV infection, congenitally infected newborns now can be easily assessed for evidence of organ involvement, and there are now antiviral treatments and other interventions available to improve the outcome in children with congenital CMV disease. A licensed vaccine to prevent CMV infection is not yet available; however, a "CMV knowledge vaccine," composed of "an ounce of CMV awareness and three simple precautions" and that is endorsed by the Centers for Disease Control and Prevention is available for pregnant women who wish to reduce their contact with potentially CMV-infected secretions and therefore reduce their risk of acquiring CMV during pregnancy. Medical experts in the field of congenital CMV have been called upon for a consensus statement for diagnosis and treatment, and nonprofit organizations of families affected by congenital CMV from around the world have formed a collaborative coalition to facilitate the spread of CMV knowledge and awareness.

  16. Cytomegalovirus related fatal duodenal diverticular bleeding: Case report and literature review

    PubMed Central

    Makker, Jasbir; Bajantri, Bharat; Sakam, Sailaja; Chilimuri, Sridhar

    2016-01-01

    Involvement of gastrointestinal tract by cytomegalovirus (CMV) is common. CMV infections mainly run their course without any clinical signs in immunocompetent hosts. In contrast, CMV can cause severe infections with serious consequences in a immunocompromised state typically associated with organ transplants, highly immunosuppressive cancer chemotherapy, advanced HIV infection or treatment with corticosteroids. The incidence and severity of these manifestations of CMV is directly proportional with the degree of cellular immune dysfunction, i.e., CD8+ Cytotoxic T-cell response. Cli