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 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 Regulation of Human Polyomavirus JC Virus Gene Transcription by AP-1 in Glial Cells

2003 ◽  
Vol 77 (1) ◽  
pp. 665-672 ◽  
Author(s):  
Beata Sadowska ◽  
Robert Barrucco ◽  
Kamel Khalili ◽  
Mahmut Safak
Keyword(s):  
Glial Cells ◽  
Gene Transcription ◽  
Dna Sequences ◽  
Jc Virus ◽  
Family Members ◽  
Ectopic Expression ◽  
Human Polyomavirus ◽  
Viral Gene ◽  
Infection Cycle ◽  
Binding Studies

ABSTRACT The activating transcription factor 1 (AP-1) family of proteins consists of a large number of inducible factors that are implicated in many biological processes, including cellular and viral gene expression, cell proliferation, differentiation, and tumorigenesis. Here, we investigated the role of the AP-1 family members c-Jun and c-Fos in transcriptional regulation of the JC virus (JCV) promoter in glial cells. DNA binding studies demonstrated the specific association of c-Jun with its DNA sequences corresponding to the AP-1 site within the JCV promoter. Functional analysis of the promoter showed that ectopic expression of c-Jun and c-Fos results in an additive activation of the JCV early and late promoters. Further functional assays indicated that the JCV AP-1 binding site is sufficient to confer responsiveness to both c-Jun/c-Fos- and UV-induced activation when transposed to a heterologous promoter. Analysis of c-Jun expression during the viral infection cycle by Western blotting revealed that c-Jun is posttranslationally modified by phosphorylation and its protein level is substantially increased at the late phases of infection cycle. Altogether, our findings indicate that AP-1 family members may play a role in the pathogenesis of JCV-induced disease in the human brain by modulating JCV gene transcription.

scholarly journals JC Virus Enters Human Glial Cells by Clathrin-Dependent Receptor-Mediated Endocytosis

2000 ◽  
Vol 74 (5) ◽  
pp. 2288-2292 ◽  
Author(s):  
M. T. Pho ◽  
A. Ashok ◽  
Walter J. Atwood
Keyword(s):  
Glial Cells ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Etiologic Agent ◽  
Lytic Replication ◽  
Human Polyomavirus ◽  
Virus Binding ◽  
Infectious Entry

ABSTRACT The human polyomavirus JC virus (JCV) is the etiologic agent of a fatal central nervous system (CNS) demyelinating disease known as progressive multifocal leukoencephalopathy (PML). PML occurs predominantly in immunosuppressed patients and has increased dramatically as a result of the AIDS pandemic. The major target cell of JCV infection and lytic replication in the CNS is the oligodendrocyte. The mechanisms by which JCV initiates and establishes infection of these glial cells are not understood. The initial interaction between JCV and glial cells involves virus binding to N-linked glycoproteins containing terminal α(2-6)-linked sialic acids. The subsequent steps of entry and targeting of the viral genome to the nucleus have not been described. In this report, we compare the kinetics and mechanisms of infectious entry of JCV into human glial cells with that of the related polyomavirus, simian virus 40 (SV40). We demonstrate that JCV, unlike SV40, enters glial cells by receptor-mediated clathrin-dependent endocytosis.

scholarly journals Transcriptional Regulation of BK Virus by Nuclear Factor of Activated T Cells

2009 ◽  
Vol 84 (4) ◽  
pp. 1722-1730 ◽  
Author(s):  
Joslynn A. Jordan ◽  
Kate Manley ◽  
Aisling S. Dugan ◽  
Bethany A. O'Hara ◽  
Walter J. Atwood
Keyword(s):  
T Cells ◽  
Promoter Activity ◽  
Mutational Analysis ◽  
Adult Population ◽  
Bk Virus ◽  
Human Polyomavirus ◽  
Luciferase Reporter ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Transplant Patients

ABSTRACT The human polyomavirus BK virus (BKV) is a common virus for which 80 to 90% of the adult population is seropositive. BKV reactivation in immunosuppressed patients or renal transplant patients is the primary cause of polyomavirus-associated nephropathy (PVN). Using the Dunlop strain of BKV, we found that nuclear factor of activated T cells (NFAT) plays an important regulatory role in BKV infection. Luciferase reporter assays and chromatin immunoprecipitation assays demonstrated that NFAT4 bound to the viral promoter and regulated viral transcription and infection. The mutational analysis of the NFAT binding sites demonstrated complex functional interactions between NFAT, c-fos, c-jun, and the p65 subunit of NF-κB that together influence promoter activity and viral growth. These data indicate that NFAT is required for BKV infection and is involved in a complex regulatory network that both positively and negatively influences promoter activity and viral infection.

scholarly journals Functional Interaction between JC Virus Late Regulatory Agnoprotein and Cellular Y-Box Binding Transcription Factor, YB-1

2002 ◽  
Vol 76 (8) ◽  
pp. 3828-3838 ◽  
Author(s):  
Mahmut Safak ◽  
Beata Sadowska ◽  
Robert Barrucco ◽  
Kamel Khalili
Keyword(s):  
Transcription Factor ◽  
Glial Cells ◽  
Gene Transcription ◽  
Jc Virus ◽  
Lytic Cycle ◽  
Human Polyomavirus ◽  
Regulatory Function ◽  
Infection Cycle ◽  
Functional Interaction ◽  
Amino Terminal

ABSTRACT Human polyomavirus JC virus (JCV) is a causative agent of progressive multifocal leukoencephalopathy which results from lytic infection of glial cells. Although significant progress has been made in understanding the regulation of JCV gene transcription, the mechanism(s) underlying the viral lytic cycle remains largely unknown. We recently reported that the JCV late auxiliary Agnoprotein may have a regulatory role in JCV gene transcription and replication. Here, we investigated its regulatory function in viral gene transcription through its physical and functional interaction with YB-1, a cellular transcription factor which contributes to JCV gene expression in glial cells. Time course studies revealed that Agnoprotein is first detected at day 3 postinfection and that its level increased during the late stage of the infection cycle. Agnoprotein is mainly localized to the cytoplasmic compartment of the infected cell, with high concentrations found in the perinuclear region. While the position of Agnoprotein throughout the infection cycle remained relatively unaltered, the subcellular distribution of YB-1 between the cytoplasm and nucleus changed. Results from coimmunoprecipitation and glutathione S-transferase pull-down experiments revealed that Agnoprotein physically interacts with YB-1 and that the amino-terminal region of Agnoprotein, between residues 1 and 36, is critical for this association. Further investigation of this interaction by functional assays demonstrated that Agnoprotein negatively regulates YB-1-mediated gene transcription and that the region corresponding to residues 1 to 36 of Agnoprotein is important for the observed regulatory event. Taken together, these data demonstrate that the interaction of the viral late regulatory Agnoprotein and cellular Y-box binding factor YB-1 modulates transcriptional activity of JCV promoters.

scholarly journals Human Neurotropic JC Virus and Its Association with Brain Tumors

2001 ◽  
Vol 17 (3) ◽  
pp. 143-147 ◽  
Author(s):  
Kamel Khalili
Keyword(s):  
Brain Tumors ◽  
Tumor Suppressors ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
T Antigen ◽  
Human Polyomavirus ◽  
Laboratory Animals ◽  
Oncogenic Potential ◽  
Early Protein ◽  
Overwhelming Evidence

JC virus (JCV) is a human polyomavirus known as the causative agent of the fatal demyelinating disease, Progressive Multifocal Leukoencephalopathy (PML). Further, in experimental animals this virus causes a broad range of tumors of central nervous system origin. Recent studies have suggested the association of JCV with several human tumors most notably malignant brain tumors of childhood, medulloblastoma. The development of tumors by JCV is most likely through mechanisms involving inactivation of tumor suppressors and de-regulation of signaling pathways such as Wnt by the viral early protein, T-antigen. The neurotropic nature of JCV along with the overwhelming evidence for its oncogenic potential in laboratory animals and its detection in significant numbers of human medulloblastomas invite the re-evaluation of the role for JCV in the development of human brain tumors.

JC virus excreted by multiple sclerosis patients and paired controls from Hungary

1998 ◽  
Vol 4 (2) ◽  
pp. 45-48 ◽  
Author(s):  
Gerald L. Stoner ◽  
Hansjürgen T. Agostini ◽  
Caroline F. Ryschkewitsch ◽  
Samuel Komoly
Keyword(s):  
Demyelinating Disease ◽  
Clinical Course ◽  
Jc Virus ◽  
Human Polyomavirus ◽  
European Origin ◽  
The Usa ◽  
Multiple Sclerosis Patients ◽  
Type 3

JC virus (JCV), a human polyomavirus, is the agent of the demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV exists in four main genotypes in the USA. Type 1, including subtypes Type 1A and Type 1B, makes up about 64% of strains in the USA and is thought to be of European origin. Type 2 is found in Asia, and Type 3 in Africa. A fourth type is found only in the USA. In general, these genotypes differ in 1-2.5% of their DNA sequence. Thirty MS patients and 30 paired controls from Budapest were studied. The clinical course of MS was mainly secondary progressive, and patients were stable at the time of testing. Most of the controls were relatives of the probands: a spouse, parent, or child. Overall, 25 of 60 (42%) of the urines tested positive for JCV by PCR. These included 13 of 30 MS patients, and 12 of 30 controls. Genotyping in the VP1 gene showed all 25 JCV strains to be Type 1. Among the MS patients, seven were Type 1A and six were Type 1B. Among the controls, nine were Type 1A and three were Type 1B. In five pairs of MS patients and controls, both were positive for JCV by PCR. Two of these were husband/wife pairs of which one pair was matched for subtype (both Type 1A), and the other was not. Two of them were mother/daughter pairs, and both were matched for subtype (both Type 1B). These findings demonstrate that JCV Type 1 predominates among Hungarians, and suggest that parent/child pairs can be used to trace JCV transmission within the MS family.

scholarly journals Role of N-Linked Glycosylation of the 5-HT2A Receptor in JC Virus Infection

2010 ◽  
Vol 84 (19) ◽  
pp. 9677-9684 ◽  
Author(s):  
Melissa S. Maginnis ◽  
Sheila A. Haley ◽  
Gretchen V. Gee ◽  
Walter J. Atwood
Keyword(s):  
Cell Surface ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Surface Expression ◽  
Host Cells ◽  
Human Polyomavirus ◽  
Cell Surface Expression ◽  
Tunicamycin Treatment ◽  
Infection Treatment ◽  
Glycosylation Sites

ABSTRACT JC virus (JCV) is a human polyomavirus and the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV infection of host cells is dependent on interactions with cell surface asparagine (N)-linked sialic acids and the serotonin 5-hydroxytryptamine2A receptor (5-HT2AR). The 5-HT2AR contains five potential N-linked glycosylation sites on the extracellular N terminus. Glycosylation of other serotonin receptors is essential for expression, ligand binding, and receptor function. Also, glycosylation of cellular receptors has been reported to be important for JCV infection. Therefore, we hypothesized that the 5-HT2AR N-linked glycosylation sites are required for JCV infection. Treatment of 5-HT2AR-expressing cells with tunicamycin, an inhibitor of N-linked glycosylation, reduced JCV infection. Individual mutation of each of the five N-linked glycosylation sites did not affect the capacity of 5-HT2AR to support JCV infection and did not alter the cell surface expression of the receptor. However, mutation of all five N-linked glycosylation sites simultaneously reduced the capacity of 5-HT2AR to support infection and altered the cell surface expression. Similarly, tunicamycin treatment reduced the cell surface expression of 5-HT2AR. Mutation of all five N-linked glycosylation sites or tunicamycin treatment of cells expressing wild-type 5-HT2AR resulted in an altered electrophoretic mobility profile of the receptor. Treatment of cells with PNGase F, to remove N-linked oligosaccharides from the cell surface, did not affect JCV infection in 5-HT2AR-expressing cells. These data affirm the importance of 5-HT2AR as a JCV receptor and demonstrate that the sialic acid component of the receptor is not directly linked to 5-HT2AR.

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 Members of the AP-1 Family, c-Jun and c-Fos, Functionally Interact with JC Virus Early Regulatory Protein Large T Antigen

2003 ◽  
Vol 77 (9) ◽  
pp. 5241-5252 ◽  
Author(s):  
Joanne Kim ◽  
Stefanie Woolridge ◽  
Renato Biffi ◽  
Elisa Borghi ◽  
Adam Lassak ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Jc Virus ◽  
Regulatory Protein ◽  
T Antigen ◽  
Immediate Early ◽  
Human Polyomavirus ◽  
Viral Gene ◽  
Large T Antigen ◽  
Functional Interaction ◽  
Transcription And Replication

ABSTRACT The activating protein 1 (AP-1) family of regulatory proteins is characterized as immediate-early inducible transcription factors which were shown to be activated by a variety of stress-related stimuli and to be involved in numerous biological processes, including cellular and viral gene expression, cell proliferation, differentiation, and tumorigenesis. We have recently demonstrated the involvement of the AP-1 family members c-Jun and c-Fos in transcriptional regulation of the human polyomavirus, JC virus (JCV), genome. Here, we further examined their role in JCV gene regulation and replication through their physical and functional interaction with JCV early regulatory protein large T antigen (T-Ag). Transfection and replication studies indicated that c-Jun and c-Fos can significantly diminish T-Ag-mediated JCV gene transcription and replication. Affinity chromatography and coimmunoprecipitation assays demonstrated that c-Jun and T-Ag physically interact with each other. Results from band shift assays showed that the binding efficiency of c-Jun to the AP-1 site was reduced in the presence of T-Ag. In addition, we have mapped, through the use of a series of deletion mutants, the regions of these proteins which are important for their interaction. While the c-Jun interaction domain of T-Ag is localized to the middle portion of the protein, the T-Ag interacting domain of c-Jun maps to its basic-DNA binding region. Results of transient-transfection assays with various c-Jun mutants and T-Ag expression constructs further confirm the specificity of the functional interaction between c-Jun and T-Ag. Taken together, these data demonstrate that immediate-early inducible transcription factors c-Jun and c-Fos physically and functionally interact with JCV major early regulatory protein large T-Ag and that this interaction modulates JCV transcription and replication in glial cells.

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