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Igor J Koralnik - One of the best experts on this subject based on the ideXlab platform.
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JC Virus VP1 capsid protein variants isolated from PML brains.
2018Co-Authors: Spyros Chalkias, Xin Dang, Joshua M. Gorham, Erica Mazaika, Michael Parfenov, Steve Depalma, David Mckean, Christine E. Seidman, Jonathan G. Seidman, Igor J KoralnikAbstract:JC Virus VP1 capsid protein variants isolated from PML brains.
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JC Virus nucleotides 376 396 are critical for vp1 capsid protein expression
Journal of NeuroVirology, 2015Co-Authors: Laura C Ellis, Igor J KoralnikAbstract:JC Virus (JCV) infection of the brain can cause progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy, and JCV encephalopathy (JCVE). JCVCPN, isolated from the brain of a patient with JCVE, is a naturally occurring strain of JCV with a 143-base pair deletion in the agnogene. Cell culture studies of JCVCPN have shown that the loss of these nucleotides in the agnogene results in impaired expression of VP1 and infectious virion production. To better understand the role of this DNA sequence in JCV replication, we generated a series of deletions in the agnogene on the backbone of a Virus which has a mutated agnoprotein start codon preventing agnoprotein expression. We found that deletion of nucleotides 376-396 results in decreased levels of viral DNA replication and a lack of VP1 expression. These results indicate that these nucleotides play a crucial role in JCV replication.
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a fatal case of JC Virus meningitis presenting with hydrocephalus in an hiv seronegative patient
Annals of Neurology, 2014Co-Authors: Shruti P Agnihotri, Christian Wuthrich, Xin Dang, David Nauen, Reza Karimi, Raphael P Viscidi, Evelyn Bord, Stephanie Batson, Juan C Troncoso, Igor J KoralnikAbstract:JC Virus (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy and JCV encephalopathy. Whether JCV can also cause meningitis, has not yet been demonstrated. We report a case of aseptic meningitis resulting in symptomatic hydrocephalus in an HIV-seronegative patient. Brain imaging showed enlargement of ventricles but no parenchymal lesion. She had a very high JC viral load in the CSF and developed progressive cognitive dysfunction despite ventricular drainage. She was diagnosed with pancytopenia and passed away after 5 ½ months. Post-mortem exam revealed productive JCV infection of leptomeningeal and choroid plexus cells, and limited parenchymal involvement. Sequencing of JCV CSF strain showed an archetype-like regulatory region. Further studies of the role of JCV in aseptic meningitis and in idiopathic hydrocephalus are warranted.
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a fatal case of JC Virus meningitis presenting with hydrocephalus in a human immunodeficiency Virus seronegative patient
Annals of Neurology, 2014Co-Authors: Shruti P Agnihotri, Christian Wuthrich, Xin Dang, David Nauen, Reza Karimi, Raphael P Viscidi, Evelyn Bord, Stephanie Batson, Juan C Troncoso, Igor J KoralnikAbstract:JC Virus (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy, and JCV encephalopathy. Whether JCV can also cause meningitis has not yet been demonstrated. We report a case of aseptic meningitis resulting in symptomatic hydrocephalus in a human immunodeficiency Virus–seronegative patient. Brain imaging showed enlargement of ventricles but no parenchymal lesion. She had a very high JC viral load in the cerebrospinal fluid (CSF) and developed progressive cognitive dysfunction despite ventricular drainage. She was diagnosed with pancytopenia and passed away after 5.5 months. Postmortem examination revealed productive JCV infection of leptomeningeal and choroid plexus cells, and limited parenchymal involvement. Sequencing of JCV CSF strain showed an archetype-like regulatory region. Further studies of the role of JCV in aseptic meningitis and in idiopathic hydrocephalus are warranted. Ann Neurol 2014;76:140–147
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a fatal case of JC Virus meningitis presenting with hydrocephalus in a human immunodeficiency Virus seronegative patient
Annals of Neurology, 2014Co-Authors: Shruti P Agnihotri, Christian Wuthrich, Xin Dang, David Nauen, Reza Karimi, Raphael P Viscidi, Evelyn Bord, Stephanie Batson, Juan C Troncoso, Igor J KoralnikAbstract:JC Virus (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy, and JCV encephalopathy. Whether JCV can also cause meningitis has not yet been demonstrated. We report a case of aseptic meningitis resulting in symptomatic hydrocephalus in a human immunodeficiency Virus-seronegative patient. Brain imaging showed enlargement of ventricles but no parenchymal lesion. She had a very high JC viral load in the cerebrospinal fluid (CSF) and developed progressive cognitive dysfunction despite ventricular drainage. She was diagnosed with pancytopenia and passed away after 5.5 months. Postmortem examination revealed productive JCV infection of leptomeningeal and choroid plexus cells, and limited parenchymal involvement. Sequencing of JCV CSF strain showed an archetype-like regulatory region. Further studies of the role of JCV in aseptic meningitis and in idiopathic hydrocephalus are warranted.
Eugene O Major - One of the best experts on this subject based on the ideXlab platform.
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JC Virus quasispecies analysis reveals a complex viral population underlying progressive multifocal leukoencephalopathy and supports viral dissemination via the hematogenous route
Journal of Virology, 2015Co-Authors: Tom Van Loy, Eugene O Major, Ole Lagatie, Luc Tritsmans, Kim Thys, Caroline F Ryschkewitsch, Maria Chiara Monaco, Lieven J StuyverAbstract:Opportunistic infection of oligodendrocytes by human JC polyomaVirus may result in the development of progressive multifocal encephalopathy in immunocompromised individuals. Neurotropic JC Virus generally harbors reorganized noncoding control region (NCCR) DNA interspersed on the viral genome between early and late coding genes. By applying 454 sequencing on NCCR DNA amplified from body fluid samples (urine, plasma, and cerebrospinal fluid [CSF]) from 19 progressive multifocal leukoencephalopathy (PML) patients, we attempted to reveal the composition of the JC polyomaVirus population (the quasispecies, i.e., the whole of the consensus population and minor viral variants) contained in different body compartments and to better understand intrapatient viral dissemination. Our data demonstrate that in the CSF of PML patients, the JC viral population is often a complex mixture composed of multiple viral variants that contribute to the quasispecies. In contrast, urinary JC Virus highly resembled the archetype Virus, and urine most often did not contain minor viral variants. It also appeared that archetype JC Virus could sporadically be identified in PML patient brain, although selection of rearranged JC Virus DNA was favored. Comparison of the quasispecies from different body compartments within a given patient suggested a strong correlation between the viral population in plasma and CSF, whereas the viral population shed in urine appeared to be unrelated. In conclusion, it is shown that the representation of viral DNA in the CSF following the high-level DNA replication in the brain underlying PML has hitherto been much underestimated. Our data also underscore that the hematogenous route might play a pivotal role in viral dissemination from or toward the brain. IMPORTANCE For the first time, the JC polyomaVirus population contained in different body compartments of patients diagnosed with progressive multifocal encephalopathy has been studied by deep sequencing. Two main findings came out of this work. First, it became apparent that the complexity of the viral population associated with PML has been highly underestimated so far, suggestive of a highly dynamic process of reorganization of the noncoding control region of JC polyomaVirus in vivo, mainly in CSF and blood. Second, evidence showing viral dissemination from and/or toward the brain via the hematogenous route was provided, confirming a hypothesis that was recently put forward in the field.
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individuals infected with JC polyomaVirus do not present detectable JC Virus dna in oropharyngeal fluids
Journal of General Virology, 2012Co-Authors: Ana Matos, Vitor Duque, Cristina Luxo, Antonio Melicosilvestre, Eugene O MajorAbstract:JC Virus (JCV) is ubiquitous in the human population. Primary infection normally occurs during childhood and is followed by a lifelong persistent infection. The main mode of transmission remains unknown. Several authors have hypothesized that JCV transmission occurs through the respiratory route, and that respiratory secretions could represent a possible source of viral particles. The present study intended to evaluate oropharyngeal fluids from patients infected with JCV, in order to ascertain if respiratory secretions could indeed constitute a source of exposure to this polyomaVirus. Oropharyngeal washing samples from 25 patients co-infected with JCV and human immunodeficiency Virus type 1 were evaluated for the presence of JCV DNA. Regardless of the titre of antibodies or the presence of viral urinary excretion, JCV genome was not detected in oropharyngeal samples collected from any of the patients infected with JCV included in this study, which may suggest that oropharyngeal fluids are an unlikely source for JCV infection.
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hexadecyloxypropyl cidofovir cmx001 suppresses JC Virus replication in human fetal brain svg cell cultures
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Zhigang Jiang, Jeffrey I Cohen, Leslie J Marshall, Eugene O MajorAbstract:JC Virus (JCV) is a polyomaVirus that infects human oligodendrocytes, leading to development of progressive multifocal leukoencephalopathy (PML), an often fatal demyelinating disease occurring in immunocompromised individuals. Currently there are no effective therapies for the treatment of PML that result in clearance of JCV from the brain. Cidofovir (CDV) is an acyclic nucleoside phosphonate that inhibits DNA polymerases and has been used for the treatment of PML. However, CDV demonstrated little efficacy as a treatment for PML and causes substantial side effects to patients. To improve efficacy and reduce the toxicity of CDV, a lipid-ester derivative, CMX001, was generated by Chimerix and is currently in multicenter phase II clinical trials for the prevention or control of cytomegaloVirus infection in hematopoietic stem cell transplant recipients and of BK Virus in the urine of stem cell or renal allograft recipients. CMX001 caused minimal cytotoxic effects in human fetal brain SVG cells when used at concentrations between 0.01 μM and 0.1 μM. CMX001 resulted in a dose-dependent decrease in the number of JCV-infected cells during initial infection and nearly eliminated JCV-infected cells during an established infection. In addition, CMX001 treatment resulted in a 60% reduction in JCV DNA copy number during initial infection, which suggests that suppression of JCV infection by CMX001 is likely due to inhibition of Virus DNA replication. This study demonstrates that CMX001 suppresses JCV infection at concentrations that have limited toxicity to human brain cells, indicating its potential use to limit JCV replication in infected patients.
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JC Virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab
Annals of Neurology, 2010Co-Authors: Caroline F Ryschkewitsch, Maria Chiara Monaco, Peter N Jensen, Eugene O MajorAbstract: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
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analysis of cerebrospinal fluid and cerebrospinal fluid cells from patients with multiple sclerosis for detection of JC Virus dna
Multiple Sclerosis Journal, 2009Co-Authors: Ellen Iacobaeus, Caroline F Ryschkewitsch, Tomas Olsson, M Gravell, Mohsen Khademi, Erik Wallstrom, Lou Brundin, Eugene O MajorAbstract:Objective 1) To determine whether JC Virus (JCV) DNA was present in the cerebrospinal fluid (CSF) and blood from patients with multiple sclerosis (MS) in comparison with controls and 2) to find out if our clinical material, based on presence of JCV DNA, included any patient at risk for progressive multifocal leukoencephalopathy (PML).
Kamel Khalili - One of the best experts on this subject based on the ideXlab platform.
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Regulation of Human Neurotropic JC Virus Replication by Alternative Splicing Factor SF2/ASF in Glial Cells
2011Co-Authors: Ilker Kudret Sariyer, Kamel KhaliliAbstract:Background: The human neurotropic Virus, JC Virus (JCV), is the etiologic agent of the fatal demyelinating disease of the central nervous system, Progressive Multifocal Leukoencephlopathy (PML) that is seen primarily in immunodeficient individuals. Productive infection of JCV occurs only in glial cells, and this restriction is, to a great extent, due to the activation of the viral promoter that has cell type-specific characteristics. Earlier studies led to the hypothesis that glial-specific activation of the JCV promoter is mediated through positive and negative transcription factors that control reactivation of the JCV genome under normal physiological conditions and suppress its activation in non-glial cells. Methodololgy/Principal Findings: Using a variety of virological and molecular biological approaches, we demonstrate that the alternative splicing factor SF2/ASF has the capacity to exert a negative effect on transcription of the JCV promoter in glial cells through direct association with a specific DNA sequence within the viral enhancer/promoter region. Our results show that down-regulation of SF2/ASF in fetal and adult glial cells increases the level of JCV gene expression and its replication indicating that negative regulation of the JCV promoter by SF2/ASF may control reactivation of JCV replication in brain. Conclusions/Significance: Our results establish a new regulatory role for SF2/ASF in controlling gene expression at th
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JC Virus agnoprotein inhibits in vitro differentiation of oligodendrocytes and promotes apoptosis
Journal of Virology, 2008Co-Authors: Nana Merabova, D. Kaniowska, Armine Darbinyan, Rafal Kaminski, Martyn K. White, Shohreh Amini, Satish L Deshmane, Kamel KhaliliAbstract:Productive infection of oligodendrocytes, which are responsible for the formation of myelin sheath in the central nervous system, with the human neurotropic Virus JC Virus (JCV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). In addition to encoding T antigen and the capsid proteins, which are produced at the early and late phases of the infection cycle, respectively, JCV encodes a small regulatory protein named agnoprotein that is important for successful completion of the Virus life cycle. Here we used bipotential CG-4 cells to examine the impact of agnoprotein on oligodendrocyte differentiation and survival in the absence of JCV lytic infection. We demonstrate that the expression of agnoprotein delayed the formation of complex outgrowth networks of the cells during oligodendrocyte differentiation. These alterations were accompanied by high levels of DNA damage, induction of proapoptotic proteins, and suppression of prosurvival signaling. Accordingly, apoptosis was significantly increased upon the induction of CG-4 cells toward differentiation in cells expressing agnoprotein. These observations provide the first evidence for the possible involvement of agnoprotein, independent from its role in viral replication, in a series of biological events that may contribute to the pathological features seen in PML lesions.
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reactivation of JC Virus and development of pml in patients with multiple sclerosis
Neurology, 2007Co-Authors: Kamel Khalili, Martyn K. White, Pasquale Ferrante, Fred D Lublin, Joseph R BergerAbstract:The attention of researchers and clinicians specializing in both multiple sclerosis (MS) and JC Virus (JCV), the etiologic agent of progressive multifocal leukoencephalopathy (PML), was rekindled by the development of PML in two patients with MS enrolled in a clinical trial of combination therapy with natalizumab (Tysabri) and interferon beta-1A (Avonex) in recent years. PML had not been previously reported with either MS or treatment with interferon beta alone. This occurrence of PML with alpha4beta1-integrin inhibition in MS raised a number of issues in terms both of the scientific understanding of these diseases and for the future of immunomodulatory treatment for MS. In this review, we examine the current status of knowledge of the Virus, its molecular biology, life cycle, and pathogenetic mechanisms, and how this relates to the basic science and clinical perspectives of MS. A better understanding of the specific steps from JCV infection to the development of PML is key to this issue. Other critical issues for further investigation include the role of alpha4beta1-integrin inhibition by natalizumab in the re-expression of JCV from latent sites and in the inhibition of entry into the brain and peripheral sites.
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intracellular approach for blocking JC Virus gene expression by using rna interference during viral infection
Journal of Virology, 2004Co-Authors: Sujatha Radhakrishnan, Luís J. Del Valle, Jennifer Gordon, Jianqi Cui, Kamel KhaliliAbstract:The human polyomaVirus, JC Virus (JCV), encodes two regulatory proteins at the early (T antigen) and the late (agnoprotein) phases of viral infection whose activities are important for the production of the viral capsid proteins and the dysregulation of several host factors and their functions. For this study, we designed and utilized an RNA interference strategy via small interfering RNAs (siRNAs) that targeted the expression of T antigen and agnoprotein in human astrocytic cells. The treatment of cells with specific siRNA oligonucleotides targeting a conserved region of T antigen, nucleotides (nt) 4256 to 4276 (Mad-1 strain), caused a >50% decline in the level of T antigen and in its transcriptional activity upon the viral capsid genes as well as a significant reduction in viral DNA replication in infected cells. Similarly, a single siRNA that aimed at nt 324 to 342 of agnoprotein noticeably reduced early and late viral protein production. A combined treatment of the infected cells with both T-antigen and agnoprotein siRNAs completely abolished viral capsid protein production, indicative of the ability of the siRNAs to effectively halt multiplication of the Virus in infected cells. These observations provide a new avenue for possible treatments of patients with the JCV-induced demyelinating disease progressive multifocal leukoencephalopathy.
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primary central nervous system lymphoma expressing the human neurotropic polyomaVirus JC Virus genome
Journal of Virology, 2004Co-Authors: Luís J. Del Valle, Kamel Khalili, Sahnila Enam, Cesar Lara, Judith Miklossy, Jennifer GordonAbstract:B lymphocytes are known as a potential site for latency and reactivation of the human neurotropic polyomaVirus, JC Virus (JCV). In light of recent studies on the oncogenicity of JCV and the transforming ability of the JCV early protein, T antigen, we investigated the association of JCV with B-cell lymphomas of the central nervous system. Examination of 27 well-characterized clinical specimens by gene amplification and immunohistochemistry revealed the presence of DNA sequences corresponding to the JCV early genome and the late Agnoprotein in 22 samples and the JCV late genome encoding the viral capsid proteins in 8 samples. Expression of T antigen and that of Agnoprotein by immunohistochemistry were each detected in six specimens. No evidence of the production of viral capsid proteins was observed, ruling out productive infection of JCV in the tumor cells. The results from laser capture microdissection verified the presence of JCV T-antigen sequences in tumor cells with positive immunoreactivity to antibodies against the viral proteins T antigen and Agnoprotein. Due to previous reports demonstrating an association of the Epstein-Barr Virus (EBV) with transformation of B lymphocytes, EBV DNA sequences and the EBV transforming protein, latent membrane protein 1 (LMP1), were analyzed in parallel. EBV LMP1 DNA sequences were detected in 16 of 23 samples, and LMP1 expression was detected in 16 samples, 5 of which exhibited positive immunoreactivity to JCV proteins. Double labeling demonstrated coexpression of JCV T antigen and EBV LMP1 in the same cells. The detection of the JCV genome in large numbers of B-cell lymphomas and its coexistence with EBV suggest a potential role for JCV in the pathogenesis of primary CNS lymphoma.
Leonid Gorelik - One of the best experts on this subject based on the ideXlab platform.
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progressive multifocal leukoencephalopathy pml development is associated with mutations in JC Virus capsid protein vp1 that change its receptor specificity
The Journal of Infectious Diseases, 2011Co-Authors: Leonid Gorelik, Margot Brickelmaier, Carl Reid, Manuela Testa, Simona Bossolasco, Annamaria Pazzi, Arabella Bestetti, Paul Carmillo, Ewa Wilson, Michele McauliffeAbstract:Progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease caused by JC Virus (JCV) infection of oligodendrocytes, may develop in patients with immune disorders following reactivation of chronic benign infection. Mutations of JCV capsid viral protein 1 (VP1), the capsid protein involved in binding to sialic acid cell receptors, might favor PML onset. Cerebrospinal fluid sequences from 37/40 PML patients contained one of several JCV VP1 amino acid mutations, which were also present in paired plasma but not urine sequences despite the same viral genetic background. VP1-derived Virus-like particles (VLPs) carrying these mutations lost hemagglutination ability, showed different ganglioside specificity, and abolished binding to different peripheral cell types compared with wild-type VLPs. However, mutants still bound brain-derived cells, and binding was not affected by sialic acid removal by neuraminidase. JCV VP1 substitutions are acquired intrapatient and might favor JCV brain invasion through abrogation of sialic acid binding with peripheral cells, while maintaining sialic acid-independent binding with brain cells.
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anti JC Virus antibodies implications for pml risk stratification
Annals of Neurology, 2010Co-Authors: Leonid Gorelik, Kenneth J Simon, Michaela Lerner, Sarah A Bixler, Mary Crossman, Brian Schlain, Amy Pace, Anne Cheung, Ling Ling Chen, Melissa BermanAbstract: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;68:295–303
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assessment of JC Virus dna in blood and urine from natalizumab treated patients
Annals of Neurology, 2010Co-Authors: Richard A Rudick, Leonid Gorelik, Paul Oconnor, Chris H Polman, Andrew D Goodman, Soma Ray, Nancy M Griffith, Stephanie A Jurgensen, Fiona Forrestal, Alfred SandrockAbstract: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
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identification and characterization of mefloquine efficacy against JC Virus in vitro
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Margot Brickelmaier, Richard J Frisque, Alexey Lugovskoy, Ramya Kartikeyan, Marta M Reviriegomendoza, Norm Allaire, Kenneth J Simon, Leonid GorelikAbstract:Progressive multifocal leukoencephalopathy (PML) is a rare but frequently fatal disease caused by the uncontrolled replication of JC Virus (JCV), a polyomaVirus, in the brains of some immunocompromised individuals. Currently, no effective antiviral treatment for this disease has been identified. As a first step in the identification of such therapy, we screened the Spectrum collection of 2,000 approved drugs and biologically active molecules for their anti-JCV activities in an in vitro infection assay. We identified a number of different drugs and compounds that had significant anti-JCV activities at micromolar concentrations and lacked cellular toxicity. Of the compounds with anti-JCV activities, only mefloquine, an antimalarial agent, has been reported to show sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain. Additional in vitro experiments demonstrated that mefloquine inhibits the viral infection rates of three different JCV isolates, JCV(Mad1), JCV(Mad4), and JCV(M1/SVEΔ), and does so in three different cell types, transformed human glial (SVG-A) cells, primary human fetal glial cells, and primary human astrocytes. Using quantitative PCR to quantify the number of viral copies in cultured cells, we have also shown that mefloquine inhibits viral DNA replication. Finally, we demonstrated that mefloquine does not block viral cell entry; rather, it inhibits viral replication in cells after viral entry. Although no suitable animal model of PML or JCV infection is available for the testing of mefloquine in vivo, our in vitro results, combined with biodistribution data published in the literature, suggest that mefloquine could be an effective therapy for PML.
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adaptive mutations in the JC Virus protein capsid are associated with progressive multifocal leukoencephalopathy pml
PLOS Genetics, 2009Co-Authors: Alexey Lugovskoy, Kenneth J Simon, Shamil R Sunyaev, Leonid GorelikAbstract:PML is a progressive and mostly fatal demyelinating disease caused by JC Virus infection and destruction of infected oligodendrocytes in multiple brain foci of susceptible individuals. While JC Virus is highly prevalent in the human population, PML is a rare disease that exclusively afflicts only a small percentage of immunocompromised individuals including those affected by HIV (AIDS) or immunosuppressive drugs. Viral- and/or host-specific factors, and not simply immune status, must be at play to account for the very large discrepancy between viral prevalence and low disease incidence. Here, we show that several amino acids on the surface of the JC Virus capsid protein VP1 display accelerated evolution in viral sequences isolated from PML patients but not in sequences isolated from healthy subjects. We provide strong evidence that at least some of these mutations are involved in binding of sialic acid, a known receptor for the JC Virus. Using statistical methods of molecular evolution, we performed a comprehensive analysis of JC Virus VP1 sequences isolated from 55 PML patients and 253 sequences isolated from the urine of healthy individuals and found that a subset of amino acids found exclusively among PML VP1 sequences is acquired via adaptive evolution. By modeling of the 3-D structure of the JC Virus capsid, we showed that these residues are located within the sialic acid binding site, a JC Virus receptor for cell infection. Finally, we go on to demonstrate the involvement of some of these sites in receptor binding by demonstrating a profound reduction in hemagglutination properties of viral-like particles made of the VP1 protein carrying these mutations. Collectively, these results suggest that a more virulent PML causing phenotype of JC Virus is acquired via adaptive evolution that changes viral specificity for its cellular receptor(s).
Xin Dang - One of the best experts on this subject based on the ideXlab platform.
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virofind a novel target enrichment deep sequencing platform reveals a complex JC Virus population in the brain of pml patients
PLOS ONE, 2018Co-Authors: Spyros Chalkias, Xin Dang, Joshua M. Gorham, Erica Mazaika, Michael Parfenov, Steve Depalma, David Mckean, Christine E. Seidman, J G SeidmanAbstract:Deep nucleotide sequencing enables the unbiased, broad-spectrum detection of Viruses in clinical samples without requiring an a priori hypothesis for the source of infection. However, its use in clinical research applications is limited by low cost-effectiveness given that most of the sequencing information from clinical samples is related to the human genome, which renders the analysis of viral genomes challenging. To overcome this limitation we developed ViroFind, an in-solution target-enrichment platform for Virus detection and discovery in clinical samples. ViroFind comprises 165,433 viral probes that cover the genomes of 535 selected DNA and RNA Viruses that infect humans or could cause zoonosis. The ViroFind probes are used in a hybridization reaction to enrich viral sequences and therefore enhance the detection of viral genomes via deep sequencing. We used ViroFind to detect and analyze all viral populations in the brain of 5 patients with progressive multifocal leukoencephalopathy (PML) and of 18 control subjects with no known neurological disease. Compared to direct deep sequencing, by using ViroFind we enriched viral sequences present in the clinical samples up to 127-fold. We discovered highly complex polyoma Virus JC populations in the PML brain samples with a remarkable degree of genetic divergence among the JC Virus variants of each PML brain sample. Specifically for the viral capsid protein VP1 gene, we identified 24 single nucleotide substitutions, 12 of which were associated with amino acid changes. The most frequent (4 of 5 samples, 80%) amino acid change was D66H, which is associated with enhanced tissue tropism, and hence likely a viral fitness advantage, compared to other variants. Lastly, we also detected sparse JC Virus sequences in 10 of 18 (55.5%) of control samples and sparse human herpes Virus 6B (HHV6B) sequences in the brain of 11 of 18 (61.1%) control subjects. In sum, ViroFind enabled the in-depth analysis of all viral genomes in PML and control brain samples and allowed us to demonstrate a high degree of JC Virus genetic divergence in vivo that has been previously underappreciated. ViroFind can be used to investigate the structure of the virome with unprecedented depth in health and disease state.
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JC Virus VP1 capsid protein variants isolated from PML brains.
2018Co-Authors: Spyros Chalkias, Xin Dang, Joshua M. Gorham, Erica Mazaika, Michael Parfenov, Steve Depalma, David Mckean, Christine E. Seidman, Jonathan G. Seidman, Igor J KoralnikAbstract:JC Virus VP1 capsid protein variants isolated from PML brains.
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a fatal case of JC Virus meningitis presenting with hydrocephalus in an hiv seronegative patient
Annals of Neurology, 2014Co-Authors: Shruti P Agnihotri, Christian Wuthrich, Xin Dang, David Nauen, Reza Karimi, Raphael P Viscidi, Evelyn Bord, Stephanie Batson, Juan C Troncoso, Igor J KoralnikAbstract:JC Virus (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy and JCV encephalopathy. Whether JCV can also cause meningitis, has not yet been demonstrated. We report a case of aseptic meningitis resulting in symptomatic hydrocephalus in an HIV-seronegative patient. Brain imaging showed enlargement of ventricles but no parenchymal lesion. She had a very high JC viral load in the CSF and developed progressive cognitive dysfunction despite ventricular drainage. She was diagnosed with pancytopenia and passed away after 5 ½ months. Post-mortem exam revealed productive JCV infection of leptomeningeal and choroid plexus cells, and limited parenchymal involvement. Sequencing of JCV CSF strain showed an archetype-like regulatory region. Further studies of the role of JCV in aseptic meningitis and in idiopathic hydrocephalus are warranted.
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a fatal case of JC Virus meningitis presenting with hydrocephalus in a human immunodeficiency Virus seronegative patient
Annals of Neurology, 2014Co-Authors: Shruti P Agnihotri, Christian Wuthrich, Xin Dang, David Nauen, Reza Karimi, Raphael P Viscidi, Evelyn Bord, Stephanie Batson, Juan C Troncoso, Igor J KoralnikAbstract:JC Virus (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy, and JCV encephalopathy. Whether JCV can also cause meningitis has not yet been demonstrated. We report a case of aseptic meningitis resulting in symptomatic hydrocephalus in a human immunodeficiency Virus–seronegative patient. Brain imaging showed enlargement of ventricles but no parenchymal lesion. She had a very high JC viral load in the cerebrospinal fluid (CSF) and developed progressive cognitive dysfunction despite ventricular drainage. She was diagnosed with pancytopenia and passed away after 5.5 months. Postmortem examination revealed productive JCV infection of leptomeningeal and choroid plexus cells, and limited parenchymal involvement. Sequencing of JCV CSF strain showed an archetype-like regulatory region. Further studies of the role of JCV in aseptic meningitis and in idiopathic hydrocephalus are warranted. Ann Neurol 2014;76:140–147
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a fatal case of JC Virus meningitis presenting with hydrocephalus in a human immunodeficiency Virus seronegative patient
Annals of Neurology, 2014Co-Authors: Shruti P Agnihotri, Christian Wuthrich, Xin Dang, David Nauen, Reza Karimi, Raphael P Viscidi, Evelyn Bord, Stephanie Batson, Juan C Troncoso, Igor J KoralnikAbstract:JC Virus (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy, and JCV encephalopathy. Whether JCV can also cause meningitis has not yet been demonstrated. We report a case of aseptic meningitis resulting in symptomatic hydrocephalus in a human immunodeficiency Virus-seronegative patient. Brain imaging showed enlargement of ventricles but no parenchymal lesion. She had a very high JC viral load in the cerebrospinal fluid (CSF) and developed progressive cognitive dysfunction despite ventricular drainage. She was diagnosed with pancytopenia and passed away after 5.5 months. Postmortem examination revealed productive JCV infection of leptomeningeal and choroid plexus cells, and limited parenchymal involvement. Sequencing of JCV CSF strain showed an archetype-like regulatory region. Further studies of the role of JCV in aseptic meningitis and in idiopathic hydrocephalus are warranted.