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PubMed1983

Regulatory sequences and virus-cell interactions of JC virus.

A set of recombinant DNAs, representing several isolates of JCV, has been constructed. Some of these cloned DNAs transform nonpermissive primary hamster brain cells. Analysis of the early viral mRNAs and proteins isolated from these transformants revealed similarities with the large and small T messages and proteins of SV40. The region of the JCV genome from 0.63 to 0.73 map units was sequenced by the Maxam-Gilbert technique. This segment of DNA specifies several regulatory elements and the amino-terminal portion of the early viral proteins. Comparisons with the analogous regions in the polyomaviruses SV40 and BKV, confirm the close evolutionary relationship of these three viruses. Similarities include palindromic and symmetrical sequences near the origins of DNA replication, binding sites for the large T proteins, and AT-rich region (the Goldberg-Hogness or TATA box), and a large tanden duplication or triplication to the late side of the replication origin (however, these sequences differ). Homology between the sequences coding for the early proteins is also evident (27 of the first 33 amino acids are shared). Of greater interest are features of the JCV genome which differ from those of other polyomaviruses. Absent in JCV and BKV are sequences which resemble the third T antigen-binding site of SV40. In addition, a set of sequences present in JCV and BKV DNA (33 nucleotides in JCV, 22 nucleotides in BKV), and located near a 17 base pair palindrome shared by all three viruses, is missing in SV40 DNA. Another sequence, GGGXGGAG, which is repeated several times in many polyomaviruses and adenoviruses, and which is thought to play a role in DNA replication and/or transcription, is not found in the JCV sequence presented. Finally, the tandem repeat of JCV, unlike those of BKV and SV40, includes the Goldberg-Hogness sequence.

Animals↗
PubMed1995

[Analysis of the cellular tropism of human polyoma JC virus (JCV)].

Human polyomavirus JC virus (JCV) is the causative agent of the demyelinating disorder progressive multifocal leukoencephalopathy (PML). In vivo the cellular tropism of JCV has been shown to be very narrow, and replication appears to be essentially restricted to oligodendrocytes. To investigate the detail cellular tropism of JCV, we employed transfection, microinjection and CAT assays using JCV permissive cells, and several non-permissive cell lines. IMR-32 (human neuroblastoma cells) was permissive for IMR-32 adapted JC virus. A431 (human epidermoid carcinoma) and COS-7 (a SV40 transformed African green monkey kidney cell line) were used as non-permissive cells. Employing infection it could be confirmed that the virus proliferated in IMR-32, but not in A431 and COS-7 cells as measured by immunofluorescence methods. However, after microinjection of IMR-32 adapted JCV it could be shown that virus could replicate not only in IMR-32 but also in COS-7 cells. Virus could not be replicated in A431 cells. Using CAT assays the regulatory region of IMR-32 adapted JCV was shown to be active in IMR-32 and COS-7 cells, but inactive in A431 cells. The result suggests that nuclear transcription factors are also determinant of JCV cell tropism in vivo in addition to specific cellular receptors.

Animals↗
PubMed2003

Glial cell-specific regulation of the JC virus early promoter by histone deacetylase inhibitors.

The human polyomavirus JC virus is the etiologic agent of the fatal disease demyelinating progressive multifocal leukoencephalopathy. Although multiple transcription factors have been shown to interact with the JC virus promoter and regulate transcriptional activity, their relevance to cell specificity remains elusive. To investigate whether chromatin structure controls glial cell-specific expression of JC virus early genes, glial and nonglial cells were transfected with a reporter plasmid containing the JC virus early promoter and then treated with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate. TSA and butyrate induced 20- to 30-fold activation of the JC virus promoter in nonglial cells, whereas less than 2-fold induction was observed in glial cells. These results indicate that the JC virus early promoter might be highly suppressed in nonglial cells by hypoacetylated chromatin and activated by hyperacetylation. In support of this, chromatin immunoprecipitation assays demonstrated acetylation of the JC virus promoter region in U87MG cells but no acetylation in HeLa cells. In addition, treatment of HeLa cells with TSA induced hyperacetylation of the JC virus promoter, whereas minimal induction was seen in U87MG cells. Deletional and site-directed mutational analyses revealed that the enhancer region and Sp1 binding site upstream of the TATA box were important for TSA-mediated activation. We confirmed TSA-mediated activation of the JC virus promoter in the context of natural chromatin structure in stable cell lines. Thus, it appears that chromatin structure may control JC virus transcription in a cell-specific manner.

Acetylation↗
PubMed2000

Glial cell-specific regulation of the JC virus early promoter by large T antigen.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease that results from an oligodendrocyte infection caused by JC virus. The JC virus early promoter directs cell-specific expression of the viral replication factor large T antigen, and thus transcriptional regulation constitutes a major mechanism of glial tropism in PML. We have previously demonstrated that T antigen controls the JC virus basal promoter in a glial cell-specific manner, since T antigen repressed the JC virus and simian virus 40 (SV40) early promoters in glioma cells but induced strong activation of the JC virus early promoter in nonglial cells. To further analyze these findings, T antigen and nuclear extracts from glial and nonglial cells were used to examine DNase I footprints on the proximal promoter. T-antigen binding to site II was more extensive than expected based on sequence homology with SV40, and nuclear proteins protected several regions of the proximal promoter in a cell-specific manner. Multiple Sp1 binding domains were identified. Site-directed mutagenesis revealed that T-antigen-mediated activation required a TATA box sequence, a pentanucleotide repeat immediately upstream of the TATA box, and an Sp1 binding site downstream of the TATA box. When footprints were obtained with mutant promoters which blocked T-antigen-induced transactivation, no change in T-antigen binding was observed. These results suggest that T antigen activates the JC virus basal promoter in nonglial cells by interaction with the transcription initiation complex.

Antigens, Polyomavirus Transforming↗
PubMed2005

Detection of JC virus DNA sequences in brain tumors in pediatric patients.

OBJECT: The JC virus is a human neurotropic polyomavirus that causes progressive multifocal leukoencephalopathy and is closely related to simian virus 40. Several recent reports have indicated a possible association between the JC virus and the development of various human brain tumors. The authors examined the presence of JC virus DNA sequences in primary brain tumors in pediatric patients to evaluate the hypothesis that particular brain tumors can arise in the pediatric population as a consequence of infection with the JC virus. METHODS: Genomic DNA sequences were isolated from 62 brain tumors (32 medulloblastomas, 18 ependymomas, five choroid plexus papillomas, and seven pilocytic astrocytomas) and analyzed for the presence of JC virus DNA by Southern blot hybridization and direct sequencing. The JC virus DNA sequence was detected in five ependymomas and one choroid plexus papilloma. Immunohistochemical studies revealed nuclear expression of the large T-antigen in a choroid plexus papilloma. None of the medulloblastomas or pilocytic astrocytomas contained JC virus DNA. CONCLUSIONS: The results of this study provide molecular evidence of the association between JC virus and the development of certain ependymomas and choroid plexus papillomas.

Antigens, Viral, Tumor↗
PubMed2000

Packaging of small molecules into VP1-virus-like particles of the human polyomavirus JC virus.

Recombinantly expressed VP1-virus-like particles (VP1-VLP) of human polyomavirus JC virus (JCV) were described recently as a new DNA transporter system. It was shown that DNA molecules could be packaged into VP1-VLP during a controlled chemical reassociation/dissociation process. In the present study VP1-VLP were studied as carriers for pharmaceutical substances. Propidium iodide (PI) was packaged into VP1-VLP as a reporter molecule. The PI-containing VP1-VLP could be detected directly by flow cytometry. The fluorescence intensity of the VP1-VLP depended strongly on the initial PI concentration. This packaging method is easy to handle and applicable to viruses and VP1-VLP which can be dissociated and reassociated chemically.

Capsid↗
PubMed1989

Direct isolation and characterization of JC virus from urine samples of renal and bone marrow transplant patients.

JC virus DNA was extracted from urine-derived cells of bone marrow and renal transplant patients and cloned directly into the plasmid vector pBR322. These clones represent the first JC virus isolates obtained directly from individuals that did not have progressive multifocal leukoencephalopathy (PML). Three of the clones appeared to be identical to the prototype JC virus Mad 1, and the fourth clone was identical to the type II JC virus variant Mad8-Br. Importantly, the same JC virus strains have been identified both in the urine of non-PML patients and in the brain tissue of PML patients. These results indicate that different organs may be infected with the same JC virus subtype and implies that an adaptation process involving the alteration of viral regulatory signals is not required in the pathogenesis of PML. Furthermore, both a type I and a type II variant were obtained from the same patient, suggesting that an individual may be infected with more than one strain of JC virus at a given time.

BK Virus↗
PubMed1997

[Analysis of the cellular tropism of JC virus with archetypal regulatory region].

JC virus (JCV) with an archetypal regulatory region (archetype) has been cloned from urines of a healthy individual. It has been suggested that the regulatory region of prototype JC virus (PML type) isolated from brain of PML patient was derived from that of the archetype by deletion and duplication. Biological characteristics of archetypal JCV, however, have not been fully studied. In the present study we examined the infectivity of archetypal JCV (CY), PML-type JCV (Mad-1) and Chimera JCV (Mad-1/CR-CY), in which the regulatory region is composed of CY and the other region Mad-1. DNAs from the three JCV types were transfected into COS-7 (monkey kidney cells transformed with SV40 T) and IMR-32 (human neuroblastoma cell). COS-7 was permissive for all three types, but IMR-32 was only infected with Mad-1. Infected DNAs were confirmed by Southern blotting, and the constancy of the regulatory regions before and after transmission was verified by DNA sequencing. The results showed that the viral regulatory region was related to viral cell tropism and that PML type regulatory region would be necessary for IMR-32 to propagate. The fact that COS-7 was susceptible for all three types may be explained by the function of SV40 T protein. In addition, we first succeeded in the propagation of CY in COS-7, which would provide a useful system to analyze the mechanism of persistent infection of archetypal JCV.

Animals↗
PubMed1992

Persistence of archetypal JC virus DNA in normal renal tissue derived from tumor-bearing patients.

JC virus DNAs derived from the urine of nonimmunosuppressed individuals generally contain an archetypal regulatory region which may have generated various regulatory regions of JC virus from from the brain with progressive multifocal leukoencephalopathy (PML). In this study, we examined whether JC virus persisting in normal human kidney tissue contains the archetypal regulatory region. Renal medulla, cortex, and tumor from 32 patients bearing renal tumors were screened for JC virus DNA by blot hybridization. Viral DNA was detected in the medulla in 13 cases (41%), in the cortex in 2 cases (6%), but not at all from the tumor. A number of viral DNA-positive specimens (8 from the medulla and 2 from the cortex) were used to amplify and sequence viral regulatory regions by polymerase chain reaction. Structures of the regulatory regions from all the specimens were, with a few nucleotide variations, identical with that of the archetypal region which was previously detected in the JC virus DNA from urine. This finding supports the hypothesis that the JC virus associated with PML evolved from the archetypal JC virus during persistence in human hosts. Furthermore, we present evidence that renal JCV is replicating and that progeny virions are excreted into the urine.

Adult↗
PubMed1988

Unusual DNA structure in the regulatory region of the human papovavirus JC virus.

The human papovavirus JC virus (JCV) was analyzed for the presence of unusual DNA conformations. Recombinant plasmids containing 60% of the JCV prototype Mad-1 strain DNA were constructed and analyzed with both enzymatic and chemical probes. Fine-mapping studies revealed that the most prominent S1 nuclease-sensitive and bromoacetaldehyde-modified sites were located within the TATA boxes of each 98-base-pair tandem repeat. Further studies revealed that the S1 nuclease-sensitive site in the first TATA box (proximal to the origin) was approximately 50-fold stronger than the site in the second TATA box (distal from the origin). Deletion of the first TATA box drastically reduced the extent of bromoacetaldehyde modification in the second TATA box, whereas deletion of the second TATA box had little or no effect on the reactivity at the first TATA box. Hence, the biological and conformational role of the second TATA box remains unclear. No supercoil-induced relaxation was found, and reactions with the probes were not pH dependent. Also, fragments containing this regulatory region did not appear to be bent, although the A+T-rich segment contained a tract of eight consecutive A's. We conclude that the regulatory region of JCV contains non-B, but right-handed, DNA conformations which account for this behavior.

BK Virus↗
PubMed1987

Derivation and characterization of POJ cells, transformed human fetal glial cells that retain their permissivity for JC virus.

The study of the medically important polyomavirus JC virus is limited to only a few laboratories, primarily because the permissive cell system most often used, primary human fetal glial cells, is difficult to obtain and propagate. We have introduced mutations at the origin of DNA replication of JC virus and transformed glial cells with the replication-defective genomes. Although normal glial cell cultures rapidly lose their permissivity for the virus after subculture, the transformed cells (designated POJ) had a greatly expanded life span and remained permissive for JC virus even after 30 passages in vitro. POJ cells constitutively express a functional T protein that complements the replication defect of lethal early-region mutations in JC virus. We expect that these cells will greatly facilitate the study of this human virus.

Antigens, Polyomavirus Transforming↗
PubMed1980

Integration pattern of human JC virus sequences in two clones of a cell line established from a JC virus-induced hamster brain tumor.

The physical state of the JC virus (JCV) genome was studied in two clonal cell lines (clones 2 and 7) derived from a tissue culture cell line (HJC-15) established from a hamster brain tumor induced by JCV. Saturation-hybridization and reassociation kinetic analyses, using in vitro (32)P-labeled JCV DNA, indicated that clone 7 and 2 cells contain 9 to 10 and 4 to 5 copies per cell, respectively, of all or most of the viral genome. Both cell DNAs were analyzed by using the Southern blotting procedure with three restriction endonucleases: XhoI, which does not cleave JCV DNA; EcoRI, which cleaves once; and HindIII, which cleaves three times. With each DNA, a variety of JCV-specific DNA fragments were detected. The following conclusions are possible: (i) JCV DNA is integrated into cell DNA in both clonal lines; (ii) both clonal lines contain multiple copies of the viral genome integrated in a tandem head-to-tail orientation; (iii) neither clonal line contains detectable free-form I, II, or III JCV DNA; (iv) each clonal line contains multiple independent sites of JCV DNA integration; and (v) most or all of the sites of integration on the cellular or the viral genome, or both, are different in clone 7 DNA than in clone 2 DNA. Thus, although both clone 7 and clone 2 cells were established from the HJC-15 tumor cell line, they differ in the copy number and integration pattern of JCV DNA.

Animals↗
PubMed1983

Comparison of infectious JC virus DNAs cloned from human brain.

We cloned JC virus DNA obtained directly from brain tissue of 10 cases of progressive multifocal leukoencephalopathy and compared DNAs by restriction endonuclease mapping. Before cloning, each DNA preparation was homogeneous with respect to restriction patterns, but with the cloned DNAs we found variability in three regions of the genome among DNAs from different cases. There was a region of hypervariability between 0.67 and 0.725 map units; no two DNAs were exactly alike in this region. We determined that the origin of DNA replication also was in this region at 0.69 +/- 0.02 map units. In 4 of the 10 DNAs examined there was a deletion of approximately 75 base pairs between 0.14 and 0.235 map units, the region presumed to contain the codons for the C-terminal ends of the structural protein Vpl and for T antigen. JC virus DNA from these same four cases had an additional HincII-HpaI site at 0.895 map units in the presumptive Vp3 and Vp2 coding regions. Overall, no two JC virus genomes were identical although all were from fatal central nervous system infections and were infectious in vitro. Our restriction patterns suggest that there are two subtypes of JC virus circulating in the population.

Base Sequence↗
PubMed2004

No evidence of an association of JC virus and colon neoplasia.

JC virus (JCV) is an ubiquitous human polyomavirus that frequently resides in the kidneys of healthy individuals and is excreted in the urine of a large proportion of the adult population. Polyomaviruses are associated with disease largely in immunocompromised individuals (progressive multifocal leukoencephalopathy). Colorectal cancers can show chromosome instability and it was hypothesized that JCV may account for some of this instability. We screened urine from 45 healthy donors and 233 colorectal cancer/normal tissue pairs for the presence of JCV sequences using a Taqman assay. This assay could detect 1 virus genome in 10 human genomes. In the urine samples, we found an infection rate of approximately 70%. The JCV isolates in these samples could be categorized into four JCV types (2B, 4, 7, and 8), none of which had a rearranged regulatory region. Among the colon tissues, one normal tissue (<0.5%) and none of the matched tumors tested positive for JCV. There is no evidence in these data to indicate that JCV is the cause of genetic instability in colorectal cancer.

Adult↗
PubMedDate not supplied

Analysis of a mutant p53 protein arising in a medulloblastoma from a mouse transgenic for the JC virus early region.

BACKGROUND: JC virus (JCV) is a polyomavirus that causes progressive multifocal leukoencephalopathy (PML) in humans and is highly oncogenic in experimental animals. Transgenic mice with JCV T-antigen develop cerebellar tumors, which resemble human medulloblastomas, containing two distinct cell subpopulations, T-antigen positive and negative. In T-negative clones, a novel mutant p53 was detected (p53(mt)). MATERIALS AND METHODS: We have compared p53(mt) to wild-type p53 (p53wt) in p53-null cells. RESULTS: p53(mt) had lost the transcriptional transactivation activity of p53(wt), and unlike p53(wt), partially localized to the cytoplasm. Unlike mutant p53 from many human cancers, p53(mt) did not show a gain of function or a dominant negative phenotype. Adenovirus expressing p53(wt) but not p53(mt) inhibited cell growth and induced apoptosis of p53-null cells. CONCLUSION: During the course of tumor evolution of the JCV T-antigen mouse medulloblastoma, a mutation occurred that inactivated p53 allowing tumor progression even in the absence of continued T-antigen expression.

Animals↗
PubMed1992

JC virus associated meningoencephalitis in an immunocompetent girl.

JC virus is most commonly acquired during childhood, and no clinical illness has been associated with primary infection, which is assumed to be asymptomatic. The only disease associated with JC virus to date is progressive multifocal leucoencephalopathy (PML), which is usually caused by viral reactivation in immunocompromised adults. A chronic meningoencephalitis associated with an active JC virus infection in an immunocompetent 13 year old girl is described.

Adolescent↗
PubMed2001

Molecular genotyping of BK and JC viruses in human polyomavirus-associated interstitial nephritis after renal transplantation.

The human polyomaviruses BK virus (BKV) and JC virus (JCV) have been linked to ureteric stenosis and allograft interstitial nephritis, but molecular characterization of the species involved has not been performed. We studied paraffin-embedded renal tissue from 19 cases of allograft viral interstitial nephritis. Histological sections were subjected to polymerase chain reaction amplification using consensus, BKV-, and JCV-specific primers, with subsequent DNA sequencing for strain determination. BKV was present in all (100%) interstitial nephritis kidneys and placed in genotypes corresponding to serological groups I (n = 11), II (n = 1), and IV (n = 5). Fourteen of 17 isolates (82%) showed sequence variations in the viral capsid protein-1 (VP1) capsid region, with predicted changes in the encoded amino acids and sometimes with potential implications for the secondary and tertiary structure of the corresponding protein molecules. An additional case showed a previously reported glutamine-->leucine T-antigen region mutation. JCV was seen in seven interstitial nephritis kidneys (37%), with types 4 (n = 3), 3A (n = 2), and 2A (n = 1) identified. Most white individuals with asymptomatic infection are reported to shed type 1 JCV in the urine. Simian 40 polyomavirus was not identified in any case. These observations may have pathogenic relevance to the development of an extremely refractory form of polyomavirus interstitial nephritis seen after kidney transplantation.

Amino Acid Sequence↗
PubMed2001

Coordinate effects of human immunodeficiency virus type 1 protein Tat and cellular protein Puralpha on DNA replication initiated at the JC virus origin.

JC virus (JCV) causes progressive multifocal leukoencephalopathy, a demyelinating disease in brains of individuals with AIDS. Previous work has shown that the Tat protein, encoded by human immunodeficiency virus type 1 (HIV-1), can interact with cellular protein Puralpha to enhance both TAR-dependent HIV-1 transcription and JCV late gene transcription. Tat has been shown to activate JCV transcription through interaction with Puralpha, which binds to promoter sequence elements near the JCV origin of replication. DNA footprinting has shown that Puralpha and large T-antigen cooperatively interact at several binding sites in the origin and transcriptional control region. Overexpression of Puralpha inhibits replication initiated at the JCV origin by T-antigen. In transfected glial cells Tat reversed this inhibition and enhanced DNA replication. In an in vitro replication system maximal activation by Tat, more than sixfold the levels achieved with T-antigen alone, was achieved in the presence of Puralpha. Effects of mutant Tat proteins on both activation of replication and binding to Puralpha have revealed that Cys22 exerts a conformational effect that affects both activities. The origin of an archetypal strain of JCV was less susceptible to activation of replication by Tat relative to the rearranged Mad-1 strain. These results have revealed a previously undocumented role for Tat in DNA replication and have indicated a regulatory role for JCV origin auxiliary sequences in replication and activation by Tat.

Antigens, Viral, Tumor↗