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JC Virus (jc + virus)
Selected AbstractsInitiation of JC virus DNA replication in vitro by human and mouse DNA polymerase ,-primaseFEBS JOURNAL, Issue 9 2003Richard W. P. Smith Host species specificity of the polyomaviruses simian virus 40 (SV40) and mouse polyomavirus (PyV) has been shown to be determined by the host DNA polymerase ,-primase complex involved in the initiation of both viral and host DNA replication. Here we demonstrate that DNA replication of the related human pathogenic polyomavirus JC virus (JCV) can be supported in vitro by DNA polymerase ,-primase of either human or murine origin indicating that the mechanism of its strict species specificity differs from that of SV40 and PyV. Our results indicate that this may be due to differences in the interaction of JCV and SV40 large T antigens with the DNA replication initiation complex. [source] Investigation on the role of cell transcriptional factor Sp1 and HIV-1 TAT protein in PML onset or developmentJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2005M. Mischitelli JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML), characterized by multiple areas of demyelination and attendant loss of brain function. PML is often associated with immunodepression and it is significantly frequent in AIDS patients. The viral genome is divided into early and late genes, between which lies a non-coding control region (NCCR) that regulates JCV replication and presents a great genetic variability. The NCCR of JCV archetype (CY strain) is divided into six regions: A,F containing binding sites for cell factors involved in viral transcription. Deletions and enhancements of these binding sites characterize JCV variants, which could promote viral gene expression and could be more suitable for the onset or development of PML. Therefore, we evaluated by means of polymerase chain reaction (PCR) the presence of JCV genome in cerebrospinal fluid (CSF) of HIV positive and negative subjects both with PML and after sequencing, we analyzed the viral variants found focusing on Sp1 binding sites (box B and D) and up-TAR sequence (box C). It is known that Sp1 activates JCV early promoter and can contribute in maintaining methylation-free CpG islands in active genes, while up-TAR sequence is important for HIV-1 Tat stimulation of JCV late promoter. Our results showed that in HIV-positive subjects all NCCR structures presented enhancements of up-TAR element, whereas in HIV-negative subjects both Sp1 binding sites were always retained. Therefore, we can support the synergism HIV-1/JCV in CNS and we can hypothesize that both Sp1 binding sites could be important to complete JCV replication cycle in absence of HIV-coinfection. © 2005 Wiley-Liss, Inc. [source] Investigation of pre-diagnostic virological markers for progressive multifocal leukoencephalopathy in human immunodeficiency virus-infected patientsJOURNAL OF MEDICAL VIROLOGY, Issue 7 2009Mary K. Grabowski Abstract Progressive multifocal leukoencephalopathy (PML) is a severe neurological disorder due to JC virus (JCV) infection. Pre-diagnostic biological markers and risk factors for PML are not well understood. We conducted a case,control study nested within the Multicenter AIDS Cohort Study to examine the association between JCV viruria and viremia and serum antibody to JCV capsids, in relation to subsequent PML diagnoses, 5 months to 12 years later. Other demographic and immunologic factors were also examined. The study population included 28 incident cases of PML, 26 matched HIV-positive controls, and 50 HIV-negative controls. Prevalence of JCV viruria was 37% in cases, 42% in HIV-positive controls, and 28% in HIV-negative controls (P,=,0.43). Among persons with JCV viruria, persistent viruria was more common in cases (89%) than in HIV-positive controls (33%) (P,=,0.02). Presence of JCV viruria was not related to the time to PML diagnosis (OR: 1.03, 95% CI: 0.8,1.4); however, the urinary concentration of JCV DNA increased with proximity to the date of PML diagnosis in cases. JCV seropositivity did not differ between cases or controls (P,=,0.42). Four cases tested JCV seronegative, including one case only 5 months prior to diagnosis with PML. JCV DNA was detected in the serum of one HIV-positive control. Smoking was the only demographic variable analyzed associated with an increased risk for PML (MOR: 9.0, 95% CI: 1.2,394.5). The results suggest that persistent JCV viruria and increasing urinary concentration of JCV DNA may be predictive of PML for some patients. J. Med. Virol. 81:1140,1150, 2009. © 2009 Wiley-Liss, Inc. [source] Presence and expression of JCV early gene large T Antigen in the brains of immunocompromised and immunocompetent individualsJOURNAL OF MEDICAL VIROLOGY, Issue 12 2008Serena Delbue Abstract JC virus (JCV) is a polyomavirus that asymptomatically infects up to 80% of the worldwide human population and establishes latency in the kidney. In the case of host immunodeficiency, it can cause progressive multifocal leukoencephalopathy (PML), which is a fatal demyelinating disease of the central nervous system. In an attempt to understand better PML pathogenesis and JCV infection, the presence of the JCV genome and expression of the early viral protein in the brain of deceased individuals, with and without HIV infection, was investigated. Sixty autopsy samples of brain tissues were collected from 15 HIV-positive PML patients, 15 HIV-positive patients with other neurological diseases, 15 HIV-positive patients without neurological disorders, and 15 HIV-negative individuals who died from diseases unrelated to the central nervous system. By means of specific Real Time Polymerase Chain Reaction, the JCV genome was detected in 14 of 15 PML brains, three of 15 HIV-positive brains (with and without neurological diseases), and 1 of 15 HIV-negative brains. JCV genotyping was also performed. Expression of the early JCV protein T Antigen was verified by a specific immunohistochemistry assay, and it was found in the brain tissues from 12 PML cases and one case with other neurological disease. The data obtained demonstrate that infection of the brain with JCV can also be observed in the brains of HIV-negative individuals, without neurological disorders. However, viral protein expression was limited to PML brains and to one brain from a patient with other neurological disease, suggesting that JCV can also be present in the brains of patients without PML. J. Med. Virol. 80:2147,2152, 2008. © 2008 Wiley-Liss, Inc. [source] Genotyping of the JC virus in urine samples of healthy Korean individualsJOURNAL OF MEDICAL VIROLOGY, Issue 2 2004Byung-Hoon Jeong Abstract A human polyomavirus, JC virus (JCV) is ubiquitous in humans and infects children asymptomatically. It persists in renal tissue and is excreted progeny in urine. DNAs from urine samples of 100 healthy Korean individuals were screened for the presence of JCV by polymerase chain reaction (PCR). Twenty of the samples were positive for JCV. JCV DNA was found in one individual (4%) in the 1,19-year group, two individuals (9%) in the 20,39-year group, ten individuals (38%) in the 40,59-year group, seven individuals (28%) in the over 60-year group. The prevalence of JC viral DNA was the highest in the 40,59-year-old Korean population. To investigate genotypes of JCV in Korea, the genotypes were determined by DNA sequence analysis of the regulatory region (333 bp) and the VT-intergenic region (656 bp) of DNA from the 20 JCV isolates. We have identified three distinctive JCV strains in the regulatory region and ten distinctive JCV strains in the VT-intergenic region of DNA from the 20 isolates. Based on restriction fragment length polymorphism (RFLP) analysis and phylogenetic analysis of the VT-intergenic region of JCV, two distinct subtypes, CY and type 2A (MY), were found to be prevalent in this Korean population. CY and type 2A of JCV were identified in 13 individuals (65%) and four individuals (20%), respectively. Interestingly, type 1, which was distributed mostly in Europe, was found in 3 (15%) isolates from healthy Korean individuals. J. Med. Virol. 72:281,289, 2004. © 2004 Wiley-Liss, Inc. [source] Occurrence of the African subgroup (Ia) of BK polyomavirus in younger Japanese childrenMICROBIOLOGY AND IMMUNOLOGY, Issue 6 2009Kaori Tanaka ABSTRACT BK polyomavirus (BKV) is ubiquitous among humans, usually infecting them asymptomatically during childhood. BKV persists in renal tissue of individuals and their progeny are excreted in urine, particularly in immunocompromised patients. JC virus, another human polyomavirus, has been considered to be transmitted from parents to children during prolonged cohabitation. However, BKV has been supposed to be transmitted not only within but also outside the family. In the present study, to clarify this possibility, we analyzed phylogenetically 35 BKV which were excreted in the urine by Japanese children and adults undergoing stem cell transplantation. Subtypes I, III and IV were detected in 15, two and one children and in 15, one and one adults, respectively. Among 15 subtype I isolates from children, three, four and eight belonged to subgroups Ia, Ib-1 and Ic, respectively. All the three children from whom Ia was detected were less than 9 years old. In contrast in the adults, three subtype I belonged to Ib-1 and the other 12 to Ic. These findings may reflect the recent transmission of BKV Ia strains to Japanese children. [source] Anti-JC virus antibodies: Implications for PML Risk StratificationANNALS OF NEUROLOGY, Issue 3 2010Leonid Gorelik PhD Objective A study was undertaken to establish an enzyme-linked immunosorbent assay (ELISA) to detect JC virus (JCV)-specific antibodies in multiple sclerosis (MS) patients, and to evaluate its potential utility for identifying patients at higher or lower risk (ie, risk stratification) of developing progressive multifocal leukoencephalopathy (PML). Methods A 2-step assay for detecting and confirming the presence of anti-JCV antibodies in human serum and plasma was developed and demonstrated to be both sensitive and specific. ELISA cutpoints were statistically established using sera from >800 MS patients from natalizumab clinical studies. Subsequently, this assay was used to determine the presence of anti-JCV antibodies in natalizumab-treated PML patients where serum samples were collected 16-180 months prior to the diagnosis of PML. Results In our evaluation of natalizumab-treated MS patients, 53.6% tested positive for anti-JCV antibodies, with a 95% confidence interval of 49.9 to 57.3%. The false-negative rate of the ELISA was calculated to be approximately 2.5%, with an upper 1-sided confidence limit of 4.4%. Notably, we observed anti-JCV antibodies in all 17 available pre-PML sera samples, which was significantly different from the 53.6% seropositivity observed in the overall MS study population (p < 0.0001). Interpretation This 2-step assay provides a means to classify MS patients as having detectable or not detectable levels of anti-JCV antibodies. The finding that all 17 of the pre-PML samples that were available tested seropositive, and none tested seronegative, warrants further research on the clinical utility of the anti-JCV antibody assay as a potential tool for stratifying MS patients for higher or lower risk of developing PML. Ann Neurol 2010 [source] Assessment of JC virus DNA in blood and urine from natalizumab-treated patientsANNALS OF NEUROLOGY, Issue 3 2010Richard A. Rudick MD Objective Analyses were conducted to determine the clinical utility of measuring JC virus (JCV) DNA in blood or urine of natalizumab-treated multiple sclerosis (MS) patients to predict the risk of progressive multifocal leukoencephalopathy (PML). Methods A total of 12,850 blood and urine samples from nearly 1,400 patients participating in natalizumab clinical trials were tested for JCV DNA using a commercially available quantitative polymerase chain reaction (qPCR) assay. A subset of these samples was also tested using a more sensitive qPCR assay developed at the National Institutes of Health (NIH). Results At the time natalizumab dosing was suspended, JCV DNA was detected in plasma by the commercial assay in 4 of 1,397 (0.3%) patients; the NIH assay confirmed these positive samples and detected JCV DNA in an additional 2 of 205 (1%) patients who tested negative with the commercial assay. None of these 6 JCV DNA positive patients developed PML. In a 48-week study testing the safety of natalizumab redosing, JCV DNA was detected in plasma of 6 of 1,094 (0.3%) patients, none of whom developed PML. Urine at baseline and week 48 was assessed in 224 patients; 58 (26%) were positive at baseline, and 55 (25%) were positive after 48 weeks of natalizumab, treatment. JCV DNA was not detected in peripheral blood mononuclear cells from any of these 1,094 patients before or after natalizumab treatment. In 5 patients who developed PML, JCV DNA was not detected in blood at any time point before symptoms first occurred. Interpretation Measuring JCV DNA in blood or urine with currently available methods is unlikely to be useful for predicting PML risk in natalizumab-treated MS patients. Ann Neurol 2010 [source] JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab,ANNALS OF NEUROLOGY, Issue 3 2010Caroline F. Ryschkewitsch MT JC virus (JCV) DNA in the cerebrospinal fluid (CSF) provides the laboratory confirmatory diagnosis of progressive multifocal leukoencephalopathy (PML) in patients whose clinical symptoms and magnetic resonance imaging findings are consistent with PML. The Laboratory of Molecular Medicine and Neuroscience (LMMN), National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), made the confirmatory laboratory diagnosis in 35 multiple sclerosis (MS) patients treated with natalizumab. Thirteen patients had 3 or more CSF samples taken from weeks to months following PML diagnosis. Seven of the 13 patients demonstrated persistence of JCV DNA in the CSF even though all patients experienced immune reconstitution inflammatory syndrome (IRIS), 11 patients had plasma exchange, and 2 had immunoabsorption. Specific anti-JCV antibody was measured in plasma/sera samples from 25 of the 35 patients. Most of the samples showed moderate to high or rising antibody levels from the time of PML diagnosis. However, plasma from 1 patient at or near the time of PML diagnosis had a titer considered seronegative and 2 other plasma samples from patients had titers considered at baseline for seropositivity. In several PML cases, viral persistence and neurological deficits have continued for several years, indicating that once initiated, JCV infection may not entirely clear, even with IRIS. Ann Neurol 2010;68:384,391 [source] Opportunistic infections and other risks with newer multiple sclerosis therapies,ANNALS OF NEUROLOGY, Issue 4 2009Joseph R. Berger MD The introduction of newer therapies for the treatment of multiple sclerosis has generated considerable optimism. That optimism has been tempered by the potential risks of these therapies, such as the risk for progressive multifocal leukoencephalopathy. A review of the possible causes of reactivation of JC virus in this population has illustrated the need to better understand the untoward effects of monoclonal antibody therapies and other immunomodulatory therapies currently being contemplated for use in multiple sclerosis. These drugs alter the immune response at different sites, and most, if not all, affect more than one aspect of host immunity. Drawing from existing experience with the use of these immunomodulatory therapies in other conditions and that available from the limited experience with multiple sclerosis, we review their potential untoward effects. The latter include a predisposition to opportunistic and community-acquired infections, an altered response to vaccination, the development of cancers, and the appearance of autoimmune diseases. The identification of progressive multifocal leukoencephalopathy as a risk of therapy is relatively straightforward in light of its rarity and high morbidity and mortality, but a relatively slight increased risk for more common and less disabling disorders may be overlooked. Determining the actual risk frequency for many of these complications will likely require careful postmarketing surveillance. Ann Neurol 2009;65:367,377 [source] Detection of JC virus DNA fragments but not proteins in normal brain tissueANNALS OF NEUROLOGY, Issue 4 2008Georgina Perez-Liz MD Objective Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the white matter affecting immunocompromised patients that results from the cytolytic destruction of glial cells by the human neurotropic JC virus (JCV). According to one model, during the course of immunosuppression, JCV departs from its latent state in the kidney and after entering the brain, productively infects and destroys oligodendrocytes. The goal of this study was to test the hypothesis that JCV may reside in a latent state in a specific region of the brains of immunocompetent (non-PML) individuals without any neurological conditions. Methods Gene amplification was performed together with immunohistochemistry to examine the presence of JCV DNA sequences and expression of its genome in five distinct regions of the brain from seven immunocompetent non-PML individuals. Results Although no viral proteins were expressed in any of these cases, fragments of the viral DNA were present in various regions of normal brain. Laser-capture microdissection showed the presence of JCV DNA in oligodendrocytes and astrocytes, but not in neurons. Interpretation The detection of fragments of viral DNA in non-PML brain suggests that JCV has full access to all regions of the brain in immunocompetent individuals. Thus, should the immune system become impaired, the passing and/or the resident virus may gain the opportunity to express its genome and initiate its lytic cycle in oligodendrocytes. The brain as a site of JCV latency is a possibility. Ann Neurol 2008; 64:379,387 [source] Progressive multifocal leukoencephalopathy: A national estimate of frequency in systemic lupus erythematosus and other rheumatic diseasesARTHRITIS & RHEUMATISM, Issue 12 2009Eamonn S. Molloy Objective Progressive multifocal leukoencephalopathy (PML) is a rare, typically fatal, central nervous system demyelinating disease that results from reactivation of the JC virus, which generally occurs in immunosuppressed hosts. The aim of this study was to generate a national estimate of the frequency of PML among patients with rheumatic diseases. Methods Data were obtained from the Nationwide Inpatient Sample database. This is a 20% sample of all hospital discharges, weighted to represent the entire US inpatient population. Data were analyzed for the years 1998,2005 inclusive, representing 297,797,180 hospital discharges. Cases of PML, systemic lupus erythematosus (SLE), and other rheumatic diseases were identified by diagnostic codes from the International Classification of Diseases, Ninth Revision, Clinical Modification. Results A total of 9,675 cases of PML were identified. The majority were associated with human immunodeficiency virus (HIV; 7,934 patients [82.00%]), hematologic cancers (813 patients [8.40%]), and solid cancers (274 patients [2.83%]). Among the rheumatic diseases, 43 cases of PML (0.44%) were associated with SLE, 24 (0.25%) with rheumatoid arthritis (RA), and 25 (0.26%) with other connective tissue diseases (CTDs). When patients with other potential risk factors for PML (HIV, malignancy, bone marrow or other organ transplantation) were excluded, the rates of PML per 100,000 discharges coded for SLE, RA, and other CTDs were 4, 0.4 and 2, respectively, compared with a rate of PML in the background population of 0.2/100,000 discharges. Conclusion This study was confined to hospitalized patients with rheumatic diseases, and it was also limited by the lack of information regarding immunosuppressive therapy. Nevertheless, the findings suggest that, although rare overall, PML occurs more commonly in SLE than in other rheumatic diseases. [source] Progressive multifocal leukoencephalopathy following rituximab treatment in a patient with rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 11 2009R. M. Fleischmann Progressive multifocal leukoencephalopathy (PML) is a rare brain disease caused by reactivation of the JC virus. Herein, a case of PML in association with rituximab treatment in a patient with chronic rheumatoid arthritis (RA) and Sjögren's syndrome is described. The patient received 4 courses of rituximab (2 1,000-mg infusions administered 2 weeks apart) over a period of ,40 months, during a phase III trial and safety extension study. PML was diagnosed ,18 months after the last rituximab course, and the patient died 1 month later. Determination of the cause of PML was confounded by the fact that the patient had developed oropharyngeal cancer, which was treated with chemoradiotherapy, 9 months prior to the development of PML. Although there was no direct evidence that linked rituximab to the development of PML, this case highlights the need to consider a diagnosis of PML in patients with RA who have been treated with rituximab and who subsequently develop new neurologic symptoms. [source] | |||||||||||||