Traffic of JC virus from sites of initial infection to the brain: the path to progressive multifocal leukoencephalopathy.
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Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of the human brain caused by infection with the human polyomavirus, JC. Up to 80% of humans express serum antibodies to JC virus (JCV), yet considerably fewer people develop PML-predominantly those under immunosuppressive conditions. Recent research showed JCV infection in multiple tissues throughout the body, suggesting sites for viral latency. These observations allow the proposal of pathways that JCV may use from sites of initial infection to the brain. Results from investigations into cell-surface receptors, intracellular DNA-binding proteins, and variant viral regulatory regions also suggest mechanisms that may regulate cellular susceptibility to JCV infection. Together, these data elucidate how JCV may establish infection in various cell types, persist latently or become reactivated, and ultimately reach the brain to cause PML. (+info)
Detection of JC polyomavirus DNA sequences and cellular localization of T-antigen and agnoprotein in oligodendrogliomas.
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PURPOSE: Productive infection of the human neurotropic polyomavirus JCPyV in oligodendrocytes leads to the development of progressive multifocal leukoencephalopathy, a fatal demyelinating disorder of the central nervous system. In addition to its role in viral infection, JCPyV T-antigen can transform cells in vitro and induce tumors in experimental animals in the absence of viral DNA replication and late gene expression. The goal of this study is to examine the presence of JCPyV DNA sequences and viral antigens in a series of human oligodendrogliomas. EXPERIMENTAL DESIGN: A total of 20 well-characterized oligodendrogliomas were examined for detection of the JCPyV genome by PCR and immunohistochemistry for expression of viral proteins. RESULTS: Gene amplification has revealed the presence of JCPyV DNA sequences corresponding to the NH2-terminal of T-antigen in 15 of 20 samples. DNA sequences corresponding to late regions, which are responsible for production of the capsid protein, VP1, were detected in 14 of 20 samples. Sequencing of the viral control region determined the presence of JCPyV Mad-4 or JCPyV(CY) in these tumors. By immunohistochemistry, T-antigen expression was detected in the nuclei of tumor cells from 10 samples that also contained corresponding DNA sequences by PCR. Eleven of 20 tumors exhibited immunoreactivity for the late auxiliary gene product, agnoprotein. None of the samples showed immunoreactivity for the capsid proteins, ruling out productive infection of neoplastic cells by JCPyV. CONCLUSIONS: Collectively, these observations provide new evidence in support of the association of the oncogenic human neurotropic JCPyV and oligodendrogliomas. (+info)
Oligosaccharides as receptors for JC virus.
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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 alpha1-acid glycoprotein, fetuin, and transferrin receptor, and that this binding depended on alpha2-3-linked sialic acids and N-linked sugar chains. Neoglycoproteins were synthesized by using ovalbumin and conjugation with oligosaccharides containing the terminal alpha2-3- or alpha2-6-linked sialic acid or the branched alpha2-6-linked sialic acid. We show that the neoglycoprotein containing the terminal alpha2-6-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 alpha2-6-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. (+info)
Association of human polyomavirus JCV with colon cancer: evidence for interaction of viral T-antigen and beta-catenin.
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Infection of the gastrointestinal tract by the human polyomavirus, JCV, which has been frequently detected in raw urban sewage, can occur via intake of contaminated water and food. In light of earlier reports on the tumorigenecity of JCV, we investigated the presence of the JCV genome and the expression of viral proteins in a collection of 27 well-characterized epithelial malignant tumors of the large intestine. Results from gene amplification revealed the presence of the viral early genome in 22 of 27 samples. Expression of the viral oncogenic early protein, T-antigen, and the late auxiliary protein, Agnoprotein, was observed in >50% of the samples. The absence of the viral capsid protein in the tumor cells excludes productive replication of the virus in neoplastic cells. Laser capture microdissection confirmed the presence of the JCV genome and expression of T-antigen in precancerous villous adenomas and regions of invasive adenocarcinoma. The ability of JCV T-antigen to interact with beta-catenin and the nuclear detection of beta-catenin in T-antigen-positive cells suggests dysregulation of the Wnt pathway in the tumor cells. The coproduction of T-antigen and beta-catenin in colon cancer cells enhanced transcription of the c-myc promoter, the downstream target of beta-catenin. These observations provide evidence for a possible association of JCV with colon cancer and suggest a novel regulatory role for T-antigen in the deregulation of the Wnt signaling pathway through beta-catenin in tumors of the gastrointestinal tract. (+info)
Progressive multifocal leukoencephalopathy after stem cell transplantation, unsuccessfully treated with cidofovir.
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We report a patient with progressive multifocal leukoencephalopathy (PML) after autologous stem cell transplantation (SCT) for non-Hodgkin's lymphoma (NHL). This is an unusual association, and to date only seven cases have been reported. This is the first case of PML after SCT treated with cidofovir, and the fifth case treated with this drug in a patient without human immunodeficiency virus (HIV) infection. In the previous four patients treated with cidofovir the outcome was discouraging, as was the case in this patient. (+info)
Regulation of human polyomavirus JC virus gene transcription by AP-1 in glial cells.
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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. (+info)
Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature.
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BACKGROUND: Immunosuppressive treatment of rheumatic diseases may be associated with several opportunistic infections of the brain. The differentiation between primary central nervous system (CNS) involvement and CNS infection may be difficult, leading to delayed diagnosis. OBJECTIVE: To differentiate between CNS involvement and CNS infection in systemic rheumatic diseases. METHODS AND RESULTS: Three patients with either longstanding or suspected systemic rheumatic diseases (systemic lupus erythematodes, Wegener's granulomatosis, and cerebral vasculitis) who presented with various neuropsychiatric symptoms are described. All three patients were pretreated with different immunosuppressive drugs (leflunomide, methotrexate, cyclophosphamide) in combination with corticosteroids. Magnetic resonance imaging of the brain was suggestive of infectious disease, which was confirmed by cerebrospinal fluid analysis or stereotactic brain biopsy (progressive multifocal leucoencephalopathy (PML) in two and nocardiosis in one patient). DISCUSSION: More than 20 cases of PML or cerebral nocardiosis in patients receiving corticosteroids and cytotoxic drugs for rheumatic disease have been reported. The clinical aspects of opportunistic CNS infections and the role of brain imaging, cerebrospinal fluid analysis and stereotactic brain biopsy in the differential diagnosis are reviewed. (+info)
Contrasting roles of endosomal pH and the cytoskeleton in infection of human glial cells by JC virus and simian virus 40.
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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. (+info)