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PubMed1993

Large T-antigen and sequences within the regulatory region of JC virus both contribute to the features of JC virus DNA replication.

The requirements for the DNA replication of the human papovavirus JC were analyzed using JC T-antigen as well as the T-antigens of the related viruses SV40 and BK. With all three T-antigens, the boundary of the core origin mapped on the early side to position 5093 of the viral genome. In conjunction with earlier studies, the core origin of DNA replication was therefore defined as a 68-bp region which, similar to the SV40 core origin, contains three major structural elements, early palindrome, T-antigen binding site II, and A/T-rich tract. Replication was stimulated by sequences flanking the core origin on the early side. Specifically, the stimulating sequences on the early side were identified as T-antigen binding site I. The degree to which flanking sequences were able to stimulate viral DNA replication was dependent on the T-antigen used in the experiment, with JC T-antigen relying most and BK T-antigen relying least on the flanking sequences. SV40 T-antigen showed an intermediate dependence. The same hierarchy was observed when replication activities were compared. BK T-antigen was more active in replicating DNA than SV40 T-antigen, which in turn was more effective than JC T-antigen. Dependence on flanking sequences is, thus, inversely correlated to the replicating activity of the respective T-antigen, showing that, in addition to the origin, the T-antigen contributes to the characteristics of JC virus DNA replication.

Antigens, Viral, Tumor↗
PubMed2006

Rarity of JC virus DNA sequences and early proteins in human gliomas and medulloblastomas: the controversial role of JC virus in human neurooncogenesis.

JC virus (JCV), the agent of progressive multifocal leucoencephalopathy (PML), exerts an oncogenic effect in several laboratory animal models. Moreover, JCV genomic DNA and early viral protein T-antigen have been detected in various types of human central nervous system (CNS) neoplasms. To further explore this association we have studied paraffin-embedded brain biopsy tissue from 60 neoplasms (55 gliomas and five medulloblastomas) and 15 reactive gliosis cases for the presence of JCV DNA sequences and proteins. Four post mortem cases of HIV-associated PML were used as positive controls. Samples were assessed by polymerase chain reaction (PCR) amplification of early (large T antigen) and late (virion protein 3) sequences and immunohistochemistry (IHC) with both PAb 2024 and anti-SV40 large T antigen monoclonal antibodies. Five cases (three neoplasms and two reactive gliosis instances) showed low viral DNA levels when PCR-tested for VP3 or large T, while no case was immunoreactive for any of the two antibodies used. The four PML cases yielded positive results with both PCR and IHC. Additionally, IHC with both antibodies was applied to a tissue micro-array including 109 CNS tumours and 21 reactive gliosis samples. No immunoreactivity was detected in any of these tissue micro-array samples. The rarity of JCV DNA sequences and early proteins in our brain tumours enriches the controversy over the role of JCV in human neurooncogenesis, whose clarification is in need of further molecular and epidemiologic studies.

Adult↗
PubMed1997

JC virus regulatory region rearrangements and genotypes in progressive multifocal leukoencephalopathy: two independent aspects of virus variation.

JC virus (JCV) causes the central demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV strains excreted in the urine are distinguishable from those in PML tissue by the configuration of their regulatory region to the right of ori: the archetypal regulatory region, 267 nucleotides long, is rearranged in PML tissue by deletion and duplication. Within the coding region JCV shows variations as a result of virus evolution. Four major genotypes are distinguishable of which Type 1 is based in Europe and Type 2 in Asia. Here, the regulatory region rearrangements and the viral genotypes of 29 JCV strains from PML brain were determined. Rearrangement patterns and genotypes were not associated. In general, deletions occurred before duplications, but exceptions to this rule exist. Each configuration of the 29 rearranged regulatory regions was unique and could be derived directly from the non-rearranged, archetypal form.

Gene Rearrangement↗
PubMed2006

Discovery and epidemiology of the human polyomaviruses BK virus (BKV) and JC virus (JCV).

Although discovered over thirty years ago, many aspects of the epidemiology of BKV and JCV in the general population, such as the source of infectious virus and the mode of transmission, are still unknown. Primary infection with both BKV and JCV is usually asymptomatic, and so age seroprevalence studies have been used to indicate infection. BKV commonly infects young children in all parts of the world, with the exception of a few very isolated communities, adult seroprevalence rates of 65-90% being reached by the age of ten years. In contrast, the pattern of JCV infection appears to vary between populations; in some anti-JCV antibody is acquired early as for BKV, but in others anti-JCV antibody prevalence continues to rise throughout life. This indicates that the two viruses are probably transmitted independently and by different routes. Whilst BKV DNA is found infrequently in the urine of healthy adults, JCV viruria occurs universally, increasing with age, with adult prevalence rates often between 20% and 60%. Four antigenic subtypes have been described for BKV and eight genotypes are currently recognized for JCV. The latter have been used to trace population movements and to reconstruct the population history in various communities.

BK Virus↗
PubMed2003

Propagation of archetype and nonarchetype JC virus variants in human fetal brain cultures: demonstration of interference activity by archetype JC virus.

In immunologically normal individuals, the polyomavirus, JC virus (JCV), produces an asymptomatic primary infection followed by lifelong persistence of the virus in renal tubular epithelial cells. In some immunocompromised patients, however, in particular acquired immunodeficiency syndrome (AIDS) patients, JCV causes an opportunistic central nervous system (CNS) disorder, progressive multifocal leukoencephalopathy (PML). JCV DNA as it persists in kidneys (archetypal JCV) and JCV DNA isolated from PML lesions show differences in their regulatory regions in which transcription and replication are controlled. Archetypal JCV DNA has a single enhancer and no rearrangements or deletions in the regulatory region. In contrast, JCV DNA from PML isolates is characterized by alterations in the regulatory region. Some PML-associated JCVs can be grown in cultures of human fetal brain (HFB) cells. Growth of archetypal JCV in cultured cells has not been reported, however. Here we demonstrate successful propagation of the archetypal JCV, strain GS/K, in HFB cells. Growth occurred more slowly and to lower titers than is seen with the prototypical PML JCV strain Mad-1, with relatively few cells containing viral T antigen (T-Ag) or viral capsid protein, Vp1. Interestingly, GS/K growth could be enhanced, with a large increase in viral DNA and cytopathic effect, by coinfection with GS/B, a nonarchetypal brain-derived JCV variant isolated from the same PML patient as GS/K. The amount of GS/K DNA was also greatly enhanced when it was cotransfected with Mad-1 JCV DNA, the prototypical PML isolate. In contrast to GS/K plus GS/B-cotransfected cells, in GS/K plus Mad-1-infected cells, cytopathic effect was not increased. On subsequent passage of culture lysates to naïve cells, however, the infection produced by either combination of viral DNAs slowed, no cytopathic effect (CPE) was present, and the amount of GS/B or Mad-1 viral DNA was greatly reduced as compared to that of GS/K DNA. These data suggest that GS/K was able to use either GS/B or Mad-1 as a helper and that GS/K was in turn able to interfere with the growth of either helper virus. Archetype JCV can be successfully propagated in HFB cells, although infection develops much more slowly than that caused by the PML JCV variant Mad-1. The ability of archetypal and variant JCVs to enhance or retard each other's replication may have implications in vivo for the maintenance of JCV persistence and the growth of JCV variants.

Brain↗
PubMed1996

p53 inhibits JC virus DNA replication in vivo and interacts with JC virus large T-antigen.

The onset of DNA replication is an important step within the life cycle of the human neurotropic polyomavirus JC. In this report, evidence that both the human and the murine tumor suppressor protein p53 strongly inhibit JCV DNA replication in vivo is presented. This inhibition is dose-dependent and not a secondary effect of a decreased expression of JCV large T-antigen in response to p53. Using deletion mutants of murine p53 and tumor-derived point mutations of human p53, the basis of the suppression of JCV DNA replication by p53 was dissected. Deletion of either the amino- or the carboxy-terminal domain of murine p53 did not interfere with the repression of JCV DNA replication. However, deletion of the highly conserved central region of p53 abolished the inhibitory effect on replication. The tumor-derived human mutant p53(His273) inhibited JCV DNA replication significantly, whereas another tumorigenic mutant, p53(His175), had no inhibitory effect Concomitantly, a direct protein-protein interaction between p53 and JCV large T-antigen was lost in mutants which did not affect JCV DNA replication. These results strongly suggest that p53 inhibits JCV DNA replication by interacting with JCV large T-antigen.

Animals↗
PubMed2004

Modeling a sialic acid binding pocket in the external loops of JC virus VP1.

JC virus (JCV) is a common human polyomavirus that infects over 70% of the population worldwide. JCV has a restricted cell tropism that is caused partly by the initial interaction between the virus and sialic acid-containing host cell receptors. To identify the molecular interactions between the virus and its cellular receptor, we used a combined approach of site-directed mutagenesis and homology-based molecular modeling. A model of the major viral capsid protein VP1 based on sequence alignment with other closely related polyomaviruses allowed us to target specific amino acids in the extracellular loops of VP1 for mutagenesis. An analysis of the growth rates of 17 point mutants led to the identification of VP1 amino acids that are critical in virus-host cell receptor interactions. Molecular dynamics simulations were then used to build and confirm a model of the interaction between VP1 and the sialic acid component of the JCV receptor.

Binding Sites↗
PubMed2003

T' proteins influence JC virus biology.

The JC virus early mRNA is alternatively spliced to yield five transcripts that encode large T antigen, small t antigen, T'(135), T'(136), and T'(165). The splicing process is regulated differentially in transformed versus lytically infected cells and temporally during the course of a productive infection. The authors have identified a potential exonic splicing enhancer near the 3' end of the early viral mRNA that, when mutated, results in altered splice site usage. The authors have only recently begun investigating the function of the three T' proteins using genetic and biochemical approaches. These studies indicate that the T' proteins enhance viral DNA replication and bind differentially to the pRB family of cellular tumor suppressor proteins in vitro. Using a G418 selection scheme, the authors have created cell lines that express either T antigen or each of the T' proteins individually. Preliminary analyses of these lines suggest that T antigen may induce apoptosis in rodent cells, an activity that may be blocked by other JC virus early proteins. Furthermore, examination of protein-protein interactions within the G418-selected cells reveal differences in binding of the viral proteins to the pRB family members relative to that seen in vitro.

Alternative Splicing↗
PubMed2005

Frequent detection of Epstein-Barr Virus and cytomegalovirus but not JC virus DNA in cerebrospinal fluid samples from human immunodeficiency virus-infected patients in northern Thailand.

Applying nested-PCRs, we frequently detected DNA of Epstein-Barr virus and cytomegalovirus but not JC virus in cerebrospinal fluid samples from 140 human immunodeficiency virus-infected patients with central nervous system symptoms in northern Thailand. Despite the low incidence of primary central nervous system lymphoma or cytomegalovirus encephalitis among Thai AIDS patients, Epstein-Barr virus and cytomegalovirus infections in the central nervous system are common.

Adult↗
PubMed1993

Human cytomegalovirus induces JC virus DNA replication in human fibroblasts.

JC virus, a human papovavirus, is the causative agent of the demyelinating brain disease progressive multifocal leucoencephalopathy (PML). PML is a rare but fatal disease which develops as a complication of severe immunosuppression. Latent JC virus is harbored by many asymptomatic carriers and is transiently reactivated from the latent state upon immunosuppression. JC virus has a very restricted host range, with human glial cells being the only tissue in which it can replicate at reasonable efficiency. Evidence that latent human cytomegalovirus is harbored in the kidney similar to latent JC virus led to the speculation that during episodes of impaired immunocompetence, cytomegalovirus might serve as helper virus for JC virus replication in otherwise nonpermissive cells. We show here that cytomegalovirus infection indeed leads to considerable JC virus DNA replication in cultured human fibroblasts that are nonpermissive for the replication of JC virus alone. Cytomegalovirus-mediated JC virus replication is dependent on the JC virus origin of replication and T antigen. Ganciclovir-induced inhibition of cytomegalovirus replication is associated with a concomitant inhibition of JC virus replication. These results suggest that reactivation of cytomegalovirus during episodes of immunosuppression might lead to activation of latent JC virus, which would enhance the probability of subsequent PML development. Ganciclovir-induced repression of both cytomegalovirus and JC virus replication may form the rational basis for the development of an approach toward treatment or prevention of PML.

Antigens, Viral, Tumor↗
PubMed1979

Infectivity of the DNA from four isolates of JC virus.

The infectivity of JC virus DNA was demonstrated in its most permissive cell culture, primary human fetal glial cells. The amount of infectivity observed in these heterogeneous cultures varied considerably between batches of cells. Contrary to results obtained with the papovaviruses simian virus 40 and BK virus, the calcium technique (F. L. Graham and A. J. van der Eb, Virology 52:456--467, 1973) was found to be more efficient at promoting JC virus DNA infectivity than the DEAE-dextran method (J. H. McCutchan and J. S. Pagano, J. Natl. Cancer Inst. 41:351--357, 1968): maximum infectivity titers of 4 x 10-(4) and 6 x 10(3) fluorescent cell units per microgram of DNA, respectively. These values represent an approximate recovery of infectivity from virus of between 0.02 and 0.14%. Comparisons of infectivity of DNAs obtained from four isolates of JC virus and which differed in their degrees of heterogeneity did not reveal significant differences. The JC virus DNA was not infectious in primary human fetal lung and kidney cells.

Antigens, Viral↗
PubMed2006

Role of the interaction between large T antigen and Rb family members in the oncogenicity of JC virus.

Human polyomaviruses (JC virus, BK virus and simian virus 40) are causative agents of some human diseases and, interestingly, are involved in processes of cell transformation and oncogenesis. These viruses need the cell cycle machinery of the host cell to complete their replication; so they evolved mechanisms that can interfere with the growth control of infected cells and force them into DNA replication. The retinoblastoma family of proteins (pRb), which includes pRb/p105, p107 and pRb2/p130, acts as one of the most important regulators of the G1/S transition of the cell cycle. Rb proteins represent an important target for viral oncoproteins. Early viral T antigens can bind all members of the pRb family, promoting the activation of the E2F family of transcription factors, thus inducing the expression of genes required for the entry to the S phase. The interaction between early viral antigens and cell cycle regulators represents an important mechanism through which viruses deregulate cell cycle and lead to cell transformation. In this review, we will discuss the effects of the interaction between large T antigen and Rb proteins in JC virus-mediated oncogenesis.

Antigens, Polyomavirus Transforming↗
PubMed2002

Transcriptional regulation of the glial cell-specific JC virus by p53.

The human polyomavirus JC virus is the etiologic agent of progressive multifocal leukoencephalopathy (PML). As the JC virus early promoter directs cell-specific expression of the viral replication factor large T antigen, transcriptional regulation constitutes a major mechanism of glial tropism in PML. It has been demonstrated that SV40 or JC virus large T antigen interacts with p53 protein and regulates many viral and cellular genes. In this study we found that p53 represses the JC virus early promoter in both glial and nonglial cells. To identify the cis-regulatory elements responsible for p53-mediated repression, deletional and site-directed mutational analyses were performed. Deletion of the enhancer region diminished p53-mediated transcriptional repression. However, point mutations of several transcription factor binding sites in the basal promoter region did not produce any significant changes. In support of this observation, when the enhancer was fused to a heterologous promoter, p53 reduced the promoter activity about three fold. These results indicate that the enhancer region is important for the repression of JC virus transcription by p53. Furthermore, coexpression of JC virus T antigen with a p53 protein abolished p53-mediated repression of the JC virus early promoter in non-glial cells, but not in glial cells. This finding suggests that T antigen interacts with p53 and regulates JC virus transcription in a cell-specific manner.

Antigens, Viral, Tumor↗
PubMed2006

JC virus minor capsid proteins Vp2 and Vp3 are essential for virus propagation.

Virus-encoded capsid proteins play a major role in the life cycles of all viruses. The JC virus capsid is composed of 72 pentamers of the major capsid protein Vp1, with one of the minor coat proteins Vp2 or Vp3 in the center of each pentamer. Vp3 is identical to two-thirds of Vp2, and these proteins share a DNA binding domain, a nuclear localization signal, and a Vp1-interacting domain. We demonstrate here that both the minor proteins and the myristylation site on Vp2 are essential for the viral life cycle, including the proper packaging of its genome.

Base Sequence↗
PubMedDate not supplied

JC virus genotyping offers a new paradigm in the study of human populations.

A small DNA virus, named JC virus (JCV) and belonging to the Polyomaviridae, is attracting the attention of anthropologists worldwide, as JCV genotyping appears to be a novel means of elucidating human migrations and the origins of various ethnic groups. The basic properties of JCV, the regional distributions of JCV genotypes, and the phylogenetic relationships among various JCV genotypes are described. Then, a study is described in which the origin of the modern Japanese was extensively investigated using the JCV genotyping method. Based on JCV genotypes in neighboring areas, the origins of people who carried JCV genotypes to the Japanese Archipelago are discussed. Finally, the relationships between JCV genotypes and Y-chromosome haplogroups are examined, as genetic variation on the Y chromosome has recently been examined in detail to investigate ancient human migrations and the population structures of human groups.

Chromosomes, Human, Y↗
PubMed2001

JC virus multiplication in human hematopoietic progenitor cells requires the NF-1 class D transcription factor.

JCV, a small DNA virus of the polyomavirus family, has been shown to infect glial cells of the central nervous system, hematopoietic progenitor cells, and immune system lymphocytes. A family of DNA binding proteins called nuclear factor-1 (NF-1) has been linked with site-coding specific transcription of cellular and viral genes and replication of some viruses, including JC virus (JCV). It is unclear which NF-1 gene product must be expressed by cells to promote JCV multiplication. Previously, it was shown that elevated levels of NF-1 class D mRNA were expressed by human brain cells that are highly susceptible to JCV infection but not by JCV nonpermissive HeLa cells. Recently, we reported that CD34(+) precursor cells of the KG-1 line, when treated with the phorbol ester phorbol 12-myristate 13-acetate (PMA), differentiated to cells with macrophage-like characteristics and lost susceptibility to JCV infection. These studies have now been extended by asking whether loss of JCV susceptibility by PMA-treated KG-1 cells is linked with alterations in levels of NF-1 class D expression. Using reverse transcription-PCR, we have found that PMA-treated KG-1 cells express mRNA that codes for all four classes of NF-1 proteins, although different levels of RNA expression were observed in the hematopoietic cells differentiated into macrophages. Northern hybridization confirms that the expression of NF-1 class D gene is lower in JCV nonpermissive PMA-treated KG-1 cells compared with non-PMA-treated cells. Further, using gel mobility shift assays, we were able to show the induction of specific NF-1-DNA complexes in KG-1 cells undergoing PMA treatment. The binding increases in direct relation to the duration of PMA treatment. These results suggest that the binding pattern of NF-1 class members may change in hematopoietic precursor cells, such as KG-1, as they undergo differentiation to macrophage-like cells. Transfection of PMA-treated KG-1 cells with an NF-1 class D expression vector restored the susceptibility of these cells to JCV infection, while the transfection of PMA-treated KG-1 cells with NF-1 class A, B, and C vectors was not able to restore JCV susceptibility. These data collectively suggest that selective expression of NF-1 class D has a regulatory role in JCV multiplication.

Blotting, Northern↗
PubMed1988

Dysmyelination in transgenic mice containing JC virus early region.

JC virus (JCV) causes the chronic human demyelinating disease progressive multifocal leukoencephalopathy. Because of host range restrictions, experimental models of JCV-induced demyelination have not been available. The restricted tropism of JCV infectivity has recently been overcome by the production of transgenic mice that contain the early region of JCV in all cells. This portion of the DNA encodes JCV T-antigens. These mice display a dysmyelinating phenotype, the severity of which is related to the level of JCV early region expression in brain. With the use of immunocytochemistry and in situ hybridization, we characterized morphologically myelin-specific and JCV gene expression in a severely affected strain of these mice. Our results suggest that expression of JCV T-antigens occurs predominantly in oligodendrocytes and is the primary cause of dysmyelination. Affected oligodendrocytes do not myelinate axons properly. However, they express myelin-specific genes and display some of the morphological phenotypes of early stages of myelination. A decreased ratio between levels of transcriptional and translational products of genes encoding the major structural proteins of central nervous system myelin was apparent. These results suggest that JCV T-antigens arrest the maturation of oligodendrocytes and inhibit the production of myelin. These results also demonstrate that JCV transgenic mice are a good model for investigating mechanisms of JCV-induced demyelinating lesions in progressive multifocal leukoencephalopathy.

Animals↗
PubMed1995

Cell-specific activation of the glial-specific JC virus early promoter by large T antigen.

JC virus causes the human demyelinating disease progressive multifocal leukoencephalopathy by selective infection of glial cells. This cell specificity results from glial-specific expression of viral early genes (large and small T antigens). Analysis of transcriptional regulation by the MH1 JC virus early promoter demonstrates that glial specificity is directed by the basal promoter. Because T antigen regulates the basal region of several viral and cellular promoters, we investigated whether it controls the JC virus basal promoter in a glial-specific manner. A JC virus T antigen expression plasmid generated a 95-kDa protein which exhibited nuclear localization and physical association with p53. T antigen repressed the JC virus and SV40 early promoters 4- to 5-fold in glioma cells. Conversely, T antigen induced 100- to 200-fold activation of the JC virus early promoter in nonglial cells, whereas the SV40 promoter was repressed. Activation required the JC virus TATA box sequence and a pentanucleotide repeat immediately upstream of the TATA box, but was independent of the upstream enhancer region. These data demonstrate that the JC virus basal promoter is responsible for glial-specific gene expression and suggest a mechanism for this regulation.

Antigens, Polyomavirus Transforming↗