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.

scholarly journals Intracellular Approach for Blocking JC Virus Gene Expression by Using RNA Interference during Viral Infection

2004 ◽  
Vol 78 (13) ◽  
pp. 7264-7269 ◽  
Author(s):  
Sujatha Radhakrishnan ◽  
Jennifer Gordon ◽  
Luis Del Valle ◽  
Jianqi Cui ◽  
Kamel Khalili
Keyword(s):  
Rna Interference ◽  
Viral Infection ◽  
Protein Production ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Combined Treatment ◽  
T Antigen ◽  
Human Polyomavirus ◽  
Viral Capsid ◽  
Infected Cells

ABSTRACT 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.

scholarly journals Induction of Brain Tumors by the Archetype Strain of Human Neurotropic JCPyV in a Transgenic Mouse Model

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 162
Author(s):  
Luis Del Valle ◽  
Kamel Khalili
Keyword(s):  
Brain Tumors ◽  
Transgenic Mouse ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Regulatory Region ◽  
Pituitary Tumors ◽  
Infectious Agent ◽  
Transgenic Animals ◽  
T Antigen ◽  
Peripheral Nerve Sheath Tumors

JC Virus (JCPyV), a member of the Polyomaviridiæ family, is a human neurotropic virus with world-wide distribution. JCPyV is the established opportunistic infectious agent of progressive multifocal leukoencephalopathy, a fatal demyelinating disease, which results from the cytolytic infection of oligodendrocytes. Mutations in the regulatory region of JCPyV determine the different viral strains. Mad-1 the strain associated with PML contains two 98 base pair repeats, whereas the archetype strain (CY), which is the transmissible form of JCPyV, contains only one 98 tandem with two insertions of 62 and 23 base pairs respectively. The oncogenicity of JCPyV has been suspected since direct inoculation into the brain of rodents and primates resulted in the development of brain tumors and has been attributed to the viral protein, T-Antigen. To further understand the oncogenicity of JCPyV, a transgenic mouse colony containing the early region of the archetype strain (CY), under the regulation of its own promoter was generated. These transgenic animals developed tumors of neural crest origin, including: primitive neuroectodermal tumors, medulloblastomas, adrenal neuroblastomas, pituitary tumors, malignant peripheral nerve sheath tumors, and glioblastomas. Neoplastic cells from all different phenotypes express T-Antigen. The close parallels between the tumors developed by these transgenic animals and human CNS tumors make this animal model an excellent tool for the study of viral oncogenesis.

BAG-1, a novel Bcl-2-interacting protein, activates expression of human JC virus

Microbiology ◽  
2000 ◽  
Vol 81 (2) ◽  
pp. 351-357 ◽  
Author(s):  
Laxminarayana R. Devireddy ◽  
Kotlo U. Kumar ◽  
Mary M. Pater ◽  
Alan Pater
Keyword(s):  
Embryonal Carcinoma ◽  
Jc Virus ◽  
Cell Types ◽  
T Antigen ◽  
Human Polyomavirus ◽  
Expression Plasmid ◽  
Interacting Protein ◽  
Ec Cells ◽  
Nuclear Factor 1 ◽  
Promoter Mutations

Transcription of the human polyomavirus JC virus (JCV) genome is regulated by cellular proteins and the large tumour (T) antigen. Earlier studies led to the identification of nuclear factor-1 (NF-1)-binding sites in the JCV enhancer by DNase I protection assays of extracts from retinoic acid (RA)-differentiated P19 embryonal carcinoma (EC) cells. In this study, a cDNA clone that encodes a protein capable of binding to the JCV NF-1 sites was isolated from an RA-differentiated EC cell cDNA library. Sequence analysis revealed that the cDNA isolated was identical to the previously described Bcl-2-interacting protein BAG-1 (Bcl-2-associated athano gene-1). Results from RNA studies indicated that BAG-1 is expressed in several cell types. Co-transfection of a recombinant BAG-1 expression plasmid with JCV promoters indicated that BAG-1 stimulates transcription of the JCVE promoter and to a lesser extent the JCVL promoter. Mutations in the NF-1 sites in the JCVE promoter eliminated the activation by BAG-1. Thus, BAG-1 is a novel transcription factor that may play a role in JCV expression.

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.

Brain tumors in owl monkeys inoculated with a human polyomavirus (JC virus)

Science ◽  
1978 ◽  
Vol 201 (4362) ◽  
pp. 1246-1249 ◽  
Author(s):  
W. London ◽  
S. Houff ◽  
D. Madden ◽  
D. Fuccillo ◽  
M Gravell ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Jc Virus ◽  
Human Polyomavirus ◽  
Polyomavirus Jc ◽  
Owl Monkeys

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.

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 Physical and Functional Interaction between the Y-Box Binding Protein YB-1 and Human Polyomavirus JC Virus Large T Antigen

1999 ◽  
Vol 73 (12) ◽  
pp. 10146-10157 ◽  
Author(s):  
Mahmut Safak ◽  
Gary L. Gallia ◽  
Sameer A. Ansari ◽  
Kamel Khalili
Keyword(s):  
Rna Binding ◽  
Jc Virus ◽  
Binding Protein ◽  
Regulatory Protein ◽  
T Antigen ◽  
Human Polyomavirus ◽  
Gene Promoters ◽  
Large T Antigen ◽  
Functional Interaction ◽  
Polyomavirus Jc

ABSTRACT Y-box binding protein YB-1 is a member of a family of DNA and RNA binding proteins which have been shown to affect gene expression at both the transcriptional and translational levels. We have previously shown that YB-1 modulates transcription from the promoters of the ubiquitous human polyomavirus JC virus (JCV). Here we investigate the physical and functional interplay between YB-1 and the viral regulatory protein large T antigen (T-antigen), using JCV as a model system. Results of mobility band shift assays demonstrated that the efficiency of binding of YB-1 to a 23-bp single-stranded viral target sequence was significantly increased when T-antigen was included in the binding reaction mixture. Affinity chromatography and coimmunoprecipitation assays demonstrated that YB-1 and T-antigen physically interact with each other. Additionally, results of transcription studies demonstrated that these two proteins interact functionally on the JCV early and late gene promoters. Whereas ectopic expression of YB-1 and T-antigen results in synergistic transactivation of the viral late promoter, YB-1 alleviates T-antigen-mediated transcriptional suppression of the viral early promoter activity. Furthermore, we have localized, through the use of a series of deletion mutants, the sequences of these proteins which are important for their interaction. The T-antigen-interacting region of YB-1 is located in the cold shock domain of YB-1 and its immediate flanking sequences, and the YB-1-interacting domain of T-antigen maps to the carboxy-terminal half of T-antigen. Results of transient transfection assays with various YB-1 mutants and T-antigen expression constructs confirm the specificity of the functional interaction between YB-1 and T-antigen. Taken together, these data demonstrate that the cellular factor YB-1 and the viral regulatory protein T-antigen interact both physically and functionally and that this interaction modulates transcription from the JCV promoters.

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.

Sign in / Sign up

Export Citation Format

Share Document