Human demyelinating disease and the polyomavirus JCV

2006 ◽  
Vol 12 (2) ◽  
pp. 133-142 ◽  
Author(s):  
K Khalili ◽  
M K White
Keyword(s):  
Demyelinating Disease ◽  
Jc Virus ◽  
Neurological Diseases ◽  
Etiologic Agent ◽  
Cell Mediated Immunity ◽  
Double Stranded Dna ◽  
Tumor Viruses ◽  
Serological Studies ◽  
Immunosuppressed Patients ◽  
The Central Nervous System

Many human neurological diseases involve demyelination of the central and/or peripheral nervous systems. These include the hereditary leukodystrophies -which have a genetic basis; multiple sclerosis (MS) -where the underlying cause of demyelination remains unknown; and progressive multifocal leukoencephalopathy (PML) -where the etiology is well-established as being viral. The human neurotropic polyomavirus -JC virus (JCV) -is the etiologic agent of PML, a fatal demyelinating disease of the central nervous system that occurs mainly in immunosuppressed patients, especially those with HIV/AIDS. JCV belongs to the polyomavirus family of tumor viruses that are characterized by non-enveloped icosahedral capsids containing small, circular, double-stranded DNA genomes. Serological studies have shown that JCV is widespread throughout the human population, but infections are usually restricted by the immune system, particularly cell-mediated immunity, causing the virus to enter a latent phase. An important corollary of this is that situations of severe immunosuppression may permit JCV to replicate and are thus a risk factor for PML.

scholarly journals Oligosaccharides as Receptors for JC Virus

2002 ◽  
Vol 76 (24) ◽  
pp. 12992-13000 ◽  
Author(s):  
Rika Komagome ◽  
Hirofumi Sawa ◽  
Takashi Suzuki ◽  
Yasuo Suzuki ◽  
Shinya Tanaka ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Host Cells ◽  
Hemagglutination Activity ◽  
Dna Viruses ◽  
Double Stranded Dna ◽  
The Central Nervous System ◽  
Capsid Protein Vp1 ◽  
Sugar Chains

ABSTRACT JC virus (JCV) belongs to the polyomavirus family of double-stranded DNA viruses and in humans causes a demyelinating disease of the central nervous system, progressive multifocal leukoencephalopathy. Its hemagglutination activity and entry into host cells have been reported to depend on an N-linked glycoprotein containing sialic acid. In order to identify the receptors of JCV, we generated virus-like particles (VLP) consisting of major viral capsid protein VP1. We then developed an indirect VLP overlay assay to detect VLP binding to glycoproteins and a panel of glycolipids. We found that VLP bound to sialoglycoproteins, including α1-acid glycoprotein, fetuin, and transferrin receptor, and that this binding depended on α2-3-linked sialic acids and N-linked sugar chains. Neoglycoproteins were synthesized by using ovalbumin and conjugation with oligosaccharides containing the terminal α2-3- or α2-6-linked sialic acid or the branched α2-6-linked sialic acid. We show that the neoglycoprotein containing the terminal α2-6-linked sialic acid had the highest affinity for VLP, inhibited the hemagglutination activity of VLP and JCV, and inhibited the attachment of VLP to cells. We also demonstrate that VLP bound to specific glycolipids, such as lactosylceramide, and gangliosides, including GM3, GD2, GD3, GD1b, GT1b, and GQ1b, and that VLP bound weakly to GD1a but did not bind to GM1a, GM2, or galactocerebroside. Furthermore, the neoglycoprotein containing the terminal α2-6-linked sialic acid and the ganglioside GT1b inhibited JCV infection in the susceptible cell line IMR-32. These results suggest that the oligosaccharides of glycoproteins and glycolipids work as JCV receptors and may be feasible as anti-JCV agents.

scholarly journals Progressive Multifocal Leukoencephalopathy

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1424 ◽  
Author(s):  
Laura Adang ◽  
Joseph Berger
Keyword(s):  
Human Immunodeficiency Virus ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Etiologic Agent ◽  
Cell Mediated Immunity ◽  
Significant Morbidity ◽  
Lymphoproliferative Diseases ◽  
System Defect ◽  
Immunodeficiency Virus

Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease with significant morbidity and mortality and no effective, targeted therapies. It is most often observed in association with abnormalities of cell-mediated immunity, in particular human immunodeficiency virus (HIV) infection, but also occurs in association with lymphoproliferative diseases, certain immunosuppressive and immunomodulatory regimens, and other conditions. The etiologic agent of PML is a small, ubiquitous polyomavirus, the JC virus (JCV, also known as JCPyV), for which at least 50% of the adult general population is seropositive. PML results when JCV replicates within cerebral oligodendrocytes and astrocytes, leading to oligodendrocyte death and demyelination. Unfortunately, no treatments have been convincingly demonstrated to be effective, though some have been employed in desperation; treatment otherwise includes attempts to restore any immune system defect, such as the withdrawal of the causative agent if possible, and general supportive care.

scholarly journals Progressive multifocal leukoencephalopathy in an HIV patient was diagnosed by 3 times lumbar punctures and 2 times brain biopsies

2020 ◽  
Vol 26 (6) ◽  
pp. 952-956
Author(s):  
Mengyan Wang ◽  
Zhongdong Zhang ◽  
Jinchuan Shi ◽  
Hong Liu ◽  
Binhai Zhang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Clinical Manifestations ◽  
Brain Biopsy ◽  
Hiv Positive ◽  
Negative Results ◽  
The Central Nervous System ◽  
Rule Out

AbstractProgressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by JC virus (JCV) and is difficult to diagnose. We report on a male HIV-positive patient with PML finally diagnosed by 3 times lumbar punctures and 2 times brain biopsies. Negative results of JCV-PCR in cerebrospinal fluid (CSF) do not rule out the diagnosis of PML when clinical manifestations and neuroimaging features suspected PML. It is necessary to obtain new CSF and make repeat tests and even perform brain biopsy.

scholarly journals Refractory T-Cell Anergy and Rapidly Fatal Progressive Multifocal Leukoencephalopathy After Prolonged CTLA4 Therapy

2017 ◽  
Vol 4 (2) ◽  
Author(s):  
Manon Dekeyser ◽  
Marie-Ghislaine de Goër de Herve ◽  
Houria Hendel-Chavez ◽  
Céline Labeyrie ◽  
David Adams ◽  
...  
Keyword(s):  
T Cell ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Human Polyomavirus ◽  
Therapeutic Approaches ◽  
Cell Responses ◽  
T Cell Anergy ◽  
Immunosuppressed Patients ◽  
Cell Anergy

Abstract Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to central nervous system replication of the human polyomavirus JC virus (JCV) in immunosuppressed patients. The only effective therapeutic approach is to restore anti-JCV T-cell responses. In this study, we describe a case of rapidly fatal PML with JCV T-cell anergy in a renal transplant patient treated with CTLA4-Ig (belatacept, a CD28-B7 costimulation blocker and T-cell anergy inducer). T-cell anergy could not be reversed despite several therapeutic approaches. Progressive multifocal leukoencephalopathy secondary to biotherapy-induced T-cell anergy may thus represent a subset of PML with major resistance to anti-JCV immune recovery.

scholarly journals Detection of JC Virus-Specific Cytotoxic T Lymphocytes in Healthy Individuals

2004 ◽  
Vol 78 (18) ◽  
pp. 10206-10210 ◽  
Author(s):  
R. A. Du Pasquier ◽  
J. E. Schmitz ◽  
J. Jean-Jacques ◽  
Y. Zheng ◽  
J. Gordon ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Mononuclear Cells ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
T Cell Response ◽  
Healthy Individuals ◽  
Peripheral Blood Mononuclear ◽  
Specific Ctls ◽  
The Central Nervous System

ABSTRACT The polyomavirus JC (JCV) infects 85% of healthy individuals, and its reactivation in a limited number of immunosuppressed people causes progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system. We hypothesized that JCV-specific cytotoxic T lymphocytes (CTLs) might control JCV replication in healthy individuals, blocking the evolution of PML. Using 51Cr release and tetramer staining assays, we show that 8 of 11 HLA-A*0201+ healthy subjects (73%) harbor detectable JCV-specific CD8+ CTLs that recognize one or two epitopes of JCV VP1 protein, the HLA-A*0201-restricted VP1p36 and VP1p100 epitopes. We determined that the frequency of JCV VP1 epitope-specific CTLs varied from less than 1/100,000 to 1/2,494 peripheral blood mononuclear cells. More individuals had JCV VP1-specific than cytomegalovirus-specific CTLs (8 of 11 subjects [73%] versus 2 of 10 subjects [20%], respectively). These results show that a CD8+-T-cell response against JCV is commonly found in immunocompetent people and suggest that these cells might protect against the development of PML.

scholarly journals Biomarkers in Rare Demyelinating Disease of the Central Nervous System

2020 ◽  
Vol 21 (21) ◽  
pp. 8409
Author(s):  
Marina Boziki ◽  
Styliani-Aggeliki Sintila ◽  
Panagiotis Ioannidis ◽  
Nikolaos Grigoriadis
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Demyelinating Disease ◽  
Inflammatory Diseases ◽  
Neurological Diseases ◽  
Acute Disseminated Encephalomyelitis ◽  
Demyelinating Diseases ◽  
Organ Specific ◽  
The Central Nervous System ◽  
Biomarker Research

Rare neurological diseases are a heterogeneous group corresponding approximately to 50% of all rare diseases. Neurologists are among the main specialists involved in their diagnostic investigation. At the moment, a consensus guideline on which neurologists may base clinical suspicion is not available. Moreover, neurologists need guidance with respect to screening investigations that may be performed. In this respect, biomarker research has emerged as a particularly active field due to its potential applications in clinical practice. With respect to autoimmune demyelinating diseases of the Central Nervous System (CNS), although these diseases occur in the frame of organ-specific autoimmunity, pathology of the disease itself is orchestrated among several anatomical and functional compartments. The differential diagnosis is broad and includes, but is not limited to, rare neurological diseases. Multiple Sclerosis (MS) needs to be differentially diagnosed from rare MS variants, Acute Disseminated Encephalomyelitis (ADEM), the range of Neuromyelitis Optica Spectrum Disorders (NMOSDs), Myelin Oligodendrocyte Glycoprotein (MOG) antibody disease and other systemic inflammatory diseases. Diagnostic biomarkers may facilitate timely diagnosis and proper disease management, preventing disease exacerbation due to misdiagnosis and false treatment. In this review, we will describe advances in biomarker research with respect to rare neuroinflammatory disease of the CNS.

scholarly journals Replication of JC Virus DNA in the G144 Oligodendrocyte Cell Line Is Dependent Upon Akt

2017 ◽  
Vol 91 (20) ◽  
Author(s):  
Jesse N. Peterson ◽  
Brian Lin ◽  
Jong Shin ◽  
Paul J. Phelan ◽  
Philip Tsichlis ◽  
...  
Keyword(s):  
Dna Replication ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Cell Line ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Specific Inhibitor ◽  
Human Cell Line ◽  
Model System ◽  
Precursor Cell Line ◽  
The Central Nervous System

ABSTRACT Progressive multifocal leukoencephalopathy (PML) is an often-fatal demyelinating disease of the central nervous system. PML results when oligodendrocytes within immunocompromised individuals are infected with the human JC virus (JCV). We have identified an oligodendrocyte precursor cell line, termed G144, that supports robust levels of JCV DNA replication, a central part of the JCV life cycle. In addition, we have determined that JC virus readily infects G144 cells. Furthermore, we have determined that JCV DNA replication in G144 cells is stimulated by myristoylated (i.e., constitutively active) Akt and reduced by the Akt-specific inhibitor MK2206. Thus, this oligodendrocyte-based model system will be useful for a number of purposes, such as studies of JCV infection, establishing key pathways needed for the regulation of JCV DNA replication, and identifying inhibitors of this process. IMPORTANCE The disease progressive multifocal leukoencephalopathy (PML) is caused by the infection of particular brain cells, termed oligodendrocytes, by the JC virus. Studies of PML, however, have been hampered by the lack of an immortalized human cell line derived from oligodendrocytes. Here, we report that the G144 oligodendrocyte cell line supports both infection by JC virus and robust levels of JCV DNA replication. Moreover, we have established that the Akt pathway regulates JCV DNA replication and that JCV DNA replication can be inhibited by MK2206, a compound that is specific for Akt. These and related findings suggest that we have established a powerful oligodendrocyte-based model system for studies of JCV-dependent PML.

scholarly journals JC Virus Agnoprotein Inhibits In Vitro Differentiation of Oligodendrocytes and Promotes Apoptosis

2007 ◽  
Vol 82 (3) ◽  
pp. 1558-1569 ◽  
Author(s):  
Nana Merabova ◽  
Dorota Kaniowska ◽  
Rafal Kaminski ◽  
Satish L. Deshmane ◽  
Martyn K. White ◽  
...  
Keyword(s):  
Demyelinating Disease ◽  
Jc Virus ◽  
Regulatory Protein ◽  
T Antigen ◽  
Productive Infection ◽  
Oligodendrocyte Differentiation ◽  
Virus Life Cycle ◽  
The Central Nervous System ◽  
The Impact

ABSTRACT 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.

scholarly journals NFAT4 Is Required for JC Virus Infection of Glial Cells

2006 ◽  
Vol 80 (24) ◽  
pp. 12079-12085 ◽  
Author(s):  
Kate Manley ◽  
Bethany A. O'Hara ◽  
Gretchen V. Gee ◽  
Carl P. Simkevich ◽  
John M. Sedivy ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Glial Cells ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Human Polyomavirus ◽  
Luciferase Reporter ◽  
Viral Gene ◽  
Activated T Cells ◽  
Immunosuppressed Patients ◽  
Reporter Assays

ABSTRACT The human polyomavirus JC virus (JCV) infects 70% of the population worldwide. In immunosuppressed patients, JCV infection can lead to progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system (CNS). The majority of PML cases occur in the setting of human immunodeficiency virus (HIV) infection, and it has been suggested that the link between HIV and the development of PML is in part related to the production of numerous cytokines in the CNS during HIV infection. To examine the link between the expression of inflammatory cytokines and JCV infection, we tested an anti-inflammatory compound, cyclosporine A (CsA), for its ability to block JCV infection of glial cells. We found that CsA inhibited JCV infection by preventing the activation of the transcription factor nuclear factor of activated T cells 4 (NFAT4). Luciferase reporter assays and chromatin immunoprecipitation assays revealed that NFAT4 directly bound the JCV promoter during infection and was important for the activation of both early and late transcription. In addition, the expression of the JCV early viral gene products increased NFAT activity to further aid viral transcription. The necessity of NFAT for JCV infection suggests that calcium signaling and the activation of NFAT in glial cells are required for JCV infection of the CNS.

scholarly journals JC Polyomavirus (JCV) and Monoclonal Antibodies: Friends or Potential Foes?

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Roberta Antonia Diotti ◽  
Akira Nakanishi ◽  
Nicola Clementi ◽  
Nicasio Mancini ◽  
Elena Criscuolo ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Monoclonal Antibodies ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Jc Polyomavirus ◽  
High Incidence ◽  
Two Factors ◽  
The Central Nervous System

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS), observed in immunodeficient patients and caused by JC virus ((JCV), also called JC polyomavirus (JCPyV)). After the HIV pandemic and the introduction of immunomodulatory therapy, the PML incidence significantly increased. The correlation between the use of natalizumab, a drug used in multiple sclerosis (MS), and the PML development of particular relevance. The high incidence of PML in natalizumab-treated patients has highlighted the importance of two factors: the need of PML risk stratification among natalizumab-treated patients and the need of effective therapeutic options. In this review, we discuss these two needs under the light of the major viral models of PML etiopathogenesis.

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