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 Infection of Glial Cells by the Human Polyomavirus JC Is Mediated by an N-Linked Glycoprotein Containing Terminal α(2-6)-Linked Sialic Acids

1998 ◽  
Vol 72 (6) ◽  
pp. 4643-4649 ◽  
Author(s):  
Christine K. Liu ◽  
Grant Wei ◽  
Walter J. Atwood
Keyword(s):  
Sialic Acid ◽  
Glial Cells ◽  
Demyelinating Disease ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Sialic Acids ◽  
Human Polyomavirus ◽  
Direct Result ◽  
Critical Event ◽  
Virus Binding

ABSTRACT The human JC polyomavirus (JCV) is the etiologic agent of the fatal central nervous system (CNS) demyelinating disease progressive multifocal leukoencephalopathy (PML). PML typically occurs in immunosuppressed patients and is the direct result of JCV infection of oligodendrocytes. The initial event in infection of cells by JCV is attachment of the virus to receptors present on the surface of a susceptible cell. Our laboratory has been studying this critical event in the life cycle of JCV, and we have found that JCV binds to a limited number of cell surface receptors on human glial cells that are not shared by the related polyomavirus simian virus 40 (C. K. Liu, A. P. Hope, and W. J. Atwood, J. Neurovirol. 4:49–58, 1998). To further characterize specific JCV receptors on human glial cells, we tested specific neuraminidases, proteases, and phospholipases for the ability to inhibit JCV binding to and infection of glial cells. Several of the enzymes tested were capable of inhibiting virus binding to cells, but only neuraminidase was capable of inhibiting infection. The ability of neuraminidase to inhibit infection correlated with its ability to remove both α(2-3)- and α(2-6)-linked sialic acids from glial cells. A recombinant neuraminidase that specifically removes the α(2-3) linkage of sialic acid had no effect on virus binding or infection. A competition assay between virus and sialic acid-specific lectins that recognize either the α(2-3) or the α(2-6) linkage revealed that JCV preferentially interacts with α(2-6)-linked sialic acids on glial cells. Treatment of glial cells with tunicamycin, but not with benzylN-acetyl-α-d-galactosaminide, inhibited infection by JCV, indicating that the sialylated JCV receptor is an N-linked glycoprotein. As sialic acid containing glycoproteins play a fundamental role in mediating many virus-cell and cell-cell recognition processes, it will be of interest to determine what role these receptors play in the pathogenesis of PML.

scholarly journals Contrasting Roles of Endosomal pH and the Cytoskeleton in Infection of Human Glial Cells by JC Virus and Simian Virus 40

2003 ◽  
Vol 77 (2) ◽  
pp. 1347-1356 ◽  
Author(s):  
Aarthi Ashok ◽  
Walter J. Atwood
Keyword(s):  
Glial Cells ◽  
Intracellular Transport ◽  
Jc Virus ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Human Polyomavirus ◽  
Cellular Functions ◽  
Cytoplasmic Transport ◽  
Endosomal Ph ◽  
Sv40 Infection

ABSTRACT Infection of eukaryotic cells by pathogens requires the efficient use of host cell endocytic and cytoplasmic transport mechanisms. Understanding how these cellular functions are exploited by microorganisms allows us to better define the basic biology of pathogenesis while providing better insight into normal cellular functions. In this report we compare and contrast intracellular transport and trafficking of the human polyomavirus JC virus (JCV) with that of simian virus 40 (SV40). We have previously shown that infection of human glial cells by JCV requires clathrin-dependent endocytosis. In contrast, infection of cells by SV40 proceeds by caveola-dependent endocytosis. We now examine the roles of endosomal pH and the cellular cytoskeleton during infection of glial cells by both viruses. Our results demonstrate that JCV infection is sensitive to disruption of endosomal pH, whereas SV40 infection is pH independent. Infection by JCV is inhibited by treatment of glial cells with cytochalasin D, nocodazole, and acrylamide, whereas SV40 infection is affected only by nocodazole. These data point to critical differences between JCV and SV40 in terms of endocytosis and intracellular trafficking of their DNA genomes to the nucleus. These data also suggest a unique sequential involvement of cytoskeletal elements during infection of glial cells by JCV.

scholarly journals A JC Virus-Induced Signal Is Required for Infection of Glial Cells by a Clathrin- and eps15-Dependent Pathway

2004 ◽  
Vol 78 (1) ◽  
pp. 250-256 ◽  
Author(s):  
W. Querbes ◽  
A. Benmerah ◽  
D. Tosoni ◽  
P. P. Di Fiore ◽  
Walter J. Atwood
Keyword(s):  
Glial Cells ◽  
Kinase Inhibitor ◽  
Jc Virus ◽  
Virus Entry ◽  
Dominant Negative ◽  
Virus Binding ◽  
Defective Mutant ◽  
Mitogen Activated Protein ◽  
Infectious Entry ◽  
Induced Signal

ABSTRACT Infectious entry of JC virus (JCV) into human glial cells occurs by receptor-mediated clathrin-dependent endocytosis. In this report we demonstrate that the tyrosine kinase inhibitor genistein blocks virus entry and inhibits infection. Transient expression of dominant-negative eps15 mutants, including a phosphorylation-defective mutant, inhibited both virus entry and infection. We also show that the JCV-induced signal activates the mitogen-activated protein kinases ERK1 and ERK2. These data demonstrate that JC virus binding to human glial cells induces an intracellular signal that is critical for entry and infection by a ligand-inducible clathrin-dependent mechanism.

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 Development of a Nucleic Acid Lateral Flow Immunoassay for the Detection of Human Polyomavirus BK

Diagnostics ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 403 ◽  
Author(s):  
Yi-Huei Huang ◽  
Kuan-Yi Yu ◽  
Shou-Ping Huang ◽  
Hui-Wen Chuang ◽  
Wen-Zhi Lin ◽  
...  
Keyword(s):  
Pathogen Detection ◽  
Jc Virus ◽  
Point Of Care ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Cross Reactivity ◽  
Bk Virus ◽  
Lateral Flow ◽  
Human Polyomavirus ◽  
Lateral Flow Immunoassay

The BK virus (BKV) is an emerging pathogen in immunocompromised individuals and widespread in the human population. Polymerase chain reaction is a simple and highly sensitive method for detecting BKV, but it is time consuming and requires expensive instruments and expert judgment. The lateral flow assay, a rapid, low-cost, minimal-labor, and easy-to-use diagnostic method, was successfully applied for pathogen detection. In this study, we used oligonucleotide probes to develop a simple and rapid sandwich-type lateral flow immunoassay for detecting BKV DNA within 45 minutes. The detection limit for the synthetic single-stranded DNA was 5 nM. The specificity study showed no cross-reactivity with other polyomaviruses, such as JC virus and simian virus 40. For the Escherichia coli containing BKV plasmid cultured samples, the sensitivity was determined to be 107 copies/mL. The approach offers great potential for BKV detection of various target analytes in point-of-care settings.

scholarly journals Identification of species-specific and cross-reactive epitopes in human polyomavirus capsids using monoclonal antibodies

2009 ◽  
Vol 90 (3) ◽  
pp. 634-639 ◽  
Author(s):  
Parmjeet Randhawa ◽  
Raphael Viscidi ◽  
Joseph J. Carter ◽  
Denise A. Galloway ◽  
Tim D. Culp ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Jc Virus ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Bk Virus ◽  
Human Polyomavirus ◽  
Human Antibody ◽  
Identification Of Species ◽  
Species Specific

The human antibody response to polyomavirus capsid proteins is not well characterized. Recombinant BK virus (BKV), JC virus (JCV) and simian virus 40 (SV40) virus-like particles (VLP) were produced in a baculovirus system, and mouse monoclonal antibodies (mAbs) to these proteins were generated using standard methods. Nine of 12 BKV mAbs showed neutralizing activity. The non-neutralizing antibodies also bound BKV pseudocapsids in an ELISA binding assay. Most antibodies recognized conformational species-specific epitopes, but several exceptions were found: (i) BKV mAb BK-F11 cross-reacted with a linear buried epitope common to both JCV and SV40 pseudocapsids, (ii) two of six JCV antibodies (JC-6.7 and JC-7.9) and two of 13 SV40 antibodies (VP1-H2 and VP1-I2) recognized linear buried epitopes common to all three viruses and (iii) SV40 antibody VP1-E5 recognized a linear surface epitope on JCV pseudocapsids.

DNA Replication of Chimeric JC Virus-Simian Virus 40 Genomes

Virology ◽  
1994 ◽  
Vol 204 (2) ◽  
pp. 819-822 ◽  
Author(s):  
Kevin J. Lynch ◽  
Sheryl Haggerty ◽  
Richard J. Frisque
Keyword(s):  
Dna Replication ◽  
Jc Virus ◽  
Simian Virus 40 ◽  
Simian Virus

scholarly journals N-Glycolyl GM1 Ganglioside as a Receptor for Simian Virus 40

2007 ◽  
Vol 81 (23) ◽  
pp. 12846-12858 ◽  
Author(s):  
Maria A. Campanero-Rhodes ◽  
Alicia Smith ◽  
Wengang Chai ◽  
Sandro Sonnino ◽  
Laura Mauri ◽  
...  
Keyword(s):  
Simian Virus 40 ◽  
High Specificity ◽  
Simian Virus ◽  
Receptor Expression ◽  
Host Cells ◽  
Gm1 Ganglioside ◽  
Ganglioside Gm1 ◽  
Virus Binding ◽  
Host Interactions ◽  
Sv40 Infection

ABSTRACT Carbohydrate microarrays have emerged as powerful tools in analyses of microbe-host interactions. Using a microarray with 190 sequence-defined oligosaccharides in the form of natural glycolipids and neoglycolipids representative of diverse mammalian glycans, we examined interactions of simian virus 40 (SV40) with potential carbohydrate receptors. While the results confirmed the high specificity of SV40 for the ganglioside GM1, they also revealed that N-glycolyl GM1 ganglioside [GM1(Gc)], which is characteristic of simian species and many other nonhuman mammals, is a better ligand than the N-acetyl analog [GM1(Ac)] found in mammals, including humans. After supplementing glycolipid-deficient GM95 cells with GM1(Ac) and GM1(Gc) gangliosides and the corresponding neoglycolipids with phosphatidylethanolamine lipid groups, it was found that GM1(Gc) analogs conferred better virus binding and infectivity. Moreover, we visualized the interaction of NeuGc with VP1 protein of SV40 by molecular modeling and identified a conformation for GM1(Gc) ganglioside in complex with the virus VP1 pentamer that is compatible with its presentation as a membrane receptor. Our results open the way not only to detailed studies of SV40 infection in relation to receptor expression in host cells but also to the monitoring of changes that may occur with time in receptor usage by the virus.

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