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Hatwell, John N. y Paul M. Sharp. "Evolution of human polyomavirus JC". Microbiology 81, n.º 5 (1 de mayo de 2000): 1191–200. http://dx.doi.org/10.1099/0022-1317-81-5-1191.
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More than 20 near full-length genome sequences have been reported for human polyomavirus JC (JCV). These have previously been classified into seven genotypes, and additional subtypes, which exhibit geographical associations. One of these genotypes, Type 4, has been suggested to be a recombinant of Types 1 and 3. We have investigated the pattern of diversity, and evolutionary relationships, among these sequences. In direct contradiction of a recent report, we found that different phylogenetic methods gave consistent results for the phylogenetic relationships among strains. The single known strain representing Type 5 was shown to be a mosaic of sequences from Types 2 and 6, although whether this recombination occurred in vivo or in vitro is not clear. In contrast, there was no substantial evidence that Type 4 strains are recombinant; rather they seem to be simply divergent examples of Type 1. On the assumption that the major genotypes of JCV diverged with human populations, the rate of synonymous nucleotide substitution was estimated to be around 4×10−7 per site per year, about 10 times higher than a previous estimate for primate polyomaviruses.
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Moens, Ugo, Maria Ludvigsen y Marijke Van Ghelue. "Human Polyomaviruses in Skin Diseases". Pathology Research International 2011 (12 de septiembre de 2011): 1–12. http://dx.doi.org/10.4061/2011/123491.
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Polyomaviruses are a family of small, nonenveloped viruses with a circular double-stranded DNA genome of ∼5,000 base pairs protected by an icosahedral protein structure. So far, members of this family have been identified in birds and mammals. Until 2006, BK virus (BKV), JC virus (JCV), and simian virus 40 (SV40) were the only polyomaviruses known to circulate in the human population. Their occurrence in individuals was mainly confirmed by PCR and the presence of virus-specific antibodies. Using the same methods, lymphotropic polyomavirus, originally isolated in monkeys, was recently shown to be present in healthy individuals although with much lower incidence than BKV, JCV, and SV40. The use of advanced high-throughput sequencing and improved rolling circle amplification techniques have identified the novel human polyomaviruses KI, WU, Merkel cell polyomavirus, HPyV6, HPyV7, trichodysplasia spinulosa-associated polyomavirus, and HPyV9. The skin tropism of human polyomaviruses and their dermatopathologic potentials are the focus of this paper.
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Devireddy, Laxminarayana R., Kotlo U. Kumar, Mary M. Pater y Alan Pater. "BAG-1, a novel Bcl-2-interacting protein, activates expression of human JC virus". Microbiology 81, n.º 2 (1 de febrero de 2000): 351–57. http://dx.doi.org/10.1099/0022-1317-81-2-351.
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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.
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Delbue, Serena, Mariano Ferraresso, Luciana Ghio, Camilla Carloni, Silvia Carluccio, Mirco Belingheri, Alberto Edefonti y Pasquale Ferrante. "A Review on JC Virus Infection in Kidney Transplant Recipients". Clinical and Developmental Immunology 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/926391.
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The polyomavirus (PyV), JC virus (JCV), is a small nonenveloped DNA virus that asymptomatically infects about 80% of healthy adults and establishes latency in the kidney tissue. In case of immunodeficient hosts, JCV can lytically infect the oligodendrocytes, causing a fatal demyelinating disease, known as progressive multifocal leukoencephalopathy (PML). Although the reactivation of another human PyV, BK virus (BKV), is relatively common and its association with the polyomavirus associated nephropathy (PyVAN) following renal transplantation is proven, JCV replication and its impact on graft function and survival are less well studied. Here we describe the biology of JCV and its pathological features and we review the literature regarding the JCV infection analyzed in the setting of transplantations.
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Matos, Ana, Vitor Duque, Cristina Luxo, António Meliço-Silvestre y Eugene O. Major. "Individuals infected with JC polyomavirus do not present detectable JC virus DNA in oropharyngeal fluids". Journal of General Virology 93, n.º 4 (1 de abril de 2012): 692–97. http://dx.doi.org/10.1099/vir.0.036798-0.
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JC virus (JCV) is ubiquitous in the human population. Primary infection normally occurs during childhood and is followed by a lifelong persistent infection. The main mode of transmission remains unknown. Several authors have hypothesized that JCV transmission occurs through the respiratory route, and that respiratory secretions could represent a possible source of viral particles. The present study intended to evaluate oropharyngeal fluids from patients infected with JCV, in order to ascertain if respiratory secretions could indeed constitute a source of exposure to this polyomavirus. Oropharyngeal washing samples from 25 patients co-infected with JCV and human immunodeficiency virus type 1 were evaluated for the presence of JCV DNA. Regardless of the titre of antibodies or the presence of viral urinary excretion, JCV genome was not detected in oropharyngeal samples collected from any of the patients infected with JCV included in this study, which may suggest that oropharyngeal fluids are an unlikely source for JCV infection.
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Pho, M. T., A. Ashok y Walter J. Atwood. "JC Virus Enters Human Glial Cells by Clathrin-Dependent Receptor-Mediated Endocytosis". Journal of Virology 74, n.º 5 (1 de marzo de 2000): 2288–92. http://dx.doi.org/10.1128/jvi.74.5.2288-2292.2000.
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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.
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Khalili, K. y M. K. White. "Human demyelinating disease and the polyomavirus JCV". Multiple Sclerosis Journal 12, n.º 2 (abril de 2006): 133–42. http://dx.doi.org/10.1191/135248506ms1264oa.
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Many human neurological diseases involve demyelination of the central and/or peripheral nervous systems. These include the hereditary leukodystrophies -which have a genetic basis; multiple sclerosis (MS) -where the underlying cause of demyelination remains unknown; and progressive multifocal leukoencephalopathy (PML) -where the etiology is well-established as being viral. The human neurotropic polyomavirus -JC virus (JCV) -is the etiologic agent of PML, a fatal demyelinating disease of the central nervous system that occurs mainly in immunosuppressed patients, especially those with HIV/AIDS. JCV belongs to the polyomavirus family of tumor viruses that are characterized by non-enveloped icosahedral capsids containing small, circular, double-stranded DNA genomes. Serological studies have shown that JCV is widespread throughout the human population, but infections are usually restricted by the immune system, particularly cell-mediated immunity, causing the virus to enter a latent phase. An important corollary of this is that situations of severe immunosuppression may permit JCV to replicate and are thus a risk factor for PML.
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Karalic, Danijela, Ivana Lazarevic, Maja Cupic y Tanja Jovanovic. "The prevalence of human polyomaviruses in urine samples of immunocompetent individuals in the Serbian population". Archives of Biological Sciences 64, n.º 4 (2012): 1383–88. http://dx.doi.org/10.2298/abs1204383k.
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The BK (BKV) and JC viruses (JCV) are human polyomaviruses. After primary infection, they persist as latent infection in the kidneys. Immunosuppression leads to their reactivation, which is associated with life-threatening diseases such as polyomavirus-induced nephropathy and progressive multifocal leukoencephalopathy. However, the behavior of these viruses in immunocompetent individuals is still an open question with no right answer. The aim of this study was to determine the prevalence of BKV and JCV shedding in the urine of immunocompetent individuals from the Serbian population. Sixty-five urine samples were collected and tested for the presence of BKV and JCV DNA by PCR. JCV DNA was detected in 19/65 (29.2%) and BKV DNA in 3/65 (4.6%) of the urine samples. Forty-three (66.2%) urine samples of the immunocompetent donors were negative for both viruses. The present study provides the first results of urinary excretion of human polyomaviruses in the Serbian population.
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Khalili, Kamel. "Human Neurotropic JC Virus and Its Association with Brain Tumors". Disease Markers 17, n.º 3 (2001): 143–47. http://dx.doi.org/10.1155/2001/423875.
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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.
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Ahye, Nicholas, Anna Bellizzi, Dana May y Hassen S. Wollebo. "The Role of the JC Virus in Central Nervous System Tumorigenesis". International Journal of Molecular Sciences 21, n.º 17 (28 de agosto de 2020): 6236. http://dx.doi.org/10.3390/ijms21176236.
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Cancer is the second leading cause of mortality worldwide. The study of DNA tumor-inducing viruses and their oncoproteins as a causative agent in cancer initiation and tumor progression has greatly enhanced our understanding of cancer cell biology. The initiation of oncogenesis is a complex process. Specific gene mutations cause functional changes in the cell that ultimately result in the inability to regulate cell differentiation and proliferation effectively. The human neurotropic Polyomavirus JC (JCV) belongs to the family Polyomaviridae and it is the causative agent of progressive multifocal leukoencephalopathy (PML), which is a fatal neurodegenerative disease in an immunosuppressed state. Sero-epidemiological studies have indicated JCV infection is prevalent in the population (85%) and that initial infection usually occurs during childhood. The JC virus has small circular, double-stranded DNA that includes coding sequences for viral early and late proteins. Persistence of the virus in the brain and other tissues, as well as its potential to transform cells, has made it a subject of study for its role in brain tumor development. Earlier observation of malignant astrocytes and oligodendrocytes in PML, as well as glioblastoma formation in non-human primates inoculated with JCV, led to the hypothesis that JCV plays a role in central nervous system (CNS) tumorigenesis. Some studies have reported the presence of both JC viral DNA and its proteins in several primary brain tumor specimens. The discovery of new Polyomaviruses such as the Merkel cell Polyomavirus, which is associated with Merkel cell carcinomas in humans, ignited our interest in the role of the JC virus in CNS tumors. The current evidence known about JCV and its effects, which are sufficient to produce tumors in animal models, suggest it can be a causative factor in central nervous system tumorigenesis. However, there is no clear association between JCV presence in CNS and its ability to initiate CNS cancer and tumor formation in humans. In this review, we will discuss the correlation between JCV and tumorigenesis of CNS in animal models, and we will give an overview of the current evidence for the JC virus’s role in brain tumor formation.
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Del Valle, Luis, Sahnila Enam, Cesar Lara, Judith Miklossy, Kamel Khalili y Jennifer Gordon. "Primary Central Nervous System Lymphoma Expressing the Human Neurotropic Polyomavirus, JC Virus, Genome". Journal of Virology 78, n.º 7 (1 de abril de 2004): 3462–69. http://dx.doi.org/10.1128/jvi.78.7.3462-3469.2004.
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ABSTRACT B lymphocytes are known as a potential site for latency and reactivation of the human neurotropic polyomavirus, JC virus (JCV). In light of recent studies on the oncogenicity of JCV and the transforming ability of the JCV early protein, T antigen, we investigated the association of JCV with B-cell lymphomas of the central nervous system. Examination of 27 well-characterized clinical specimens by gene amplification and immunohistochemistry revealed the presence of DNA sequences corresponding to the JCV early genome and the late Agnoprotein in 22 samples and the JCV late genome encoding the viral capsid proteins in 8 samples. Expression of T antigen and that of Agnoprotein by immunohistochemistry were each detected in six specimens. No evidence of the production of viral capsid proteins was observed, ruling out productive infection of JCV in the tumor cells. The results from laser capture microdissection verified the presence of JCV T-antigen sequences in tumor cells with positive immunoreactivity to antibodies against the viral proteins T antigen and Agnoprotein. Due to previous reports demonstrating an association of the Epstein-Barr virus (EBV) with transformation of B lymphocytes, EBV DNA sequences and the EBV transforming protein, latent membrane protein 1 (LMP1), were analyzed in parallel. EBV LMP1 DNA sequences were detected in 16 of 23 samples, and LMP1 expression was detected in 16 samples, 5 of which exhibited positive immunoreactivity to JCV proteins. Double labeling demonstrated coexpression of JCV T antigen and EBV LMP1 in the same cells. The detection of the JCV genome in large numbers of B-cell lymphomas and its coexistence with EBV suggest a potential role for JCV in the pathogenesis of primary CNS lymphoma.
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Bofill-Mas, Sı́lvia, Meritxell Formiga-Cruz, Pilar Clemente-Casares, Francesc Calafell y Rosina Girones. "Potential Transmission of Human Polyomaviruses through the Gastrointestinal Tract after Exposure to Virions or Viral DNA". Journal of Virology 75, n.º 21 (1 de noviembre de 2001): 10290–99. http://dx.doi.org/10.1128/jvi.75.21.10290-10299.2001.
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ABSTRACT The mechanism of human-to-human transmission of the polyomaviruses JC virus (JCV) and BK virus (BKV) has not been firmly established with regard to possible human exposure. JCV and BKV have been found in sewage samples from different geographical areas in Europe, Africa, and the United States, with average concentrations of 102 to 103 JCV particles/ml and 101 to 102BKV particles/ml. Selected polyomavirus-positive sewage samples were further characterized. The JCV and BKV present in these samples were identified by sequencing of the intergenic region (the region found between the T antigen and VP coding regions) of JCV and the VP1 region of BKV. The regulatory region of the JCV and BKV strains found in sewage samples presented archetypal or archetype-like genetic structures, as described for urine samples. The stability (the time required for a 90% reduction in the virus concentration) of the viral particles in sewage at 20°C was estimated to be 26.7 days for JCV and 53.6 days for BKV. The presence of JCV in 50% of the shellfish samples analyzed confirmed the stability of these viral particles in the environment. BKV and JCV particles were also found to be stable at pH 5; however, treatment at a pH lower than 3 resulted in the detection of free viral DNA. Since most humans are infected with JCV and BKV, these data indicate that the ingestion of contaminated water or food could represent a possible portal of entrance of these viruses or polyomavirus DNA into the human population.
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Shackelton, Laura A., Andrew Rambaut, Oliver G. Pybus y Edward C. Holmes. "JC Virus Evolution and Its Association with Human Populations". Journal of Virology 80, n.º 20 (15 de octubre de 2006): 9928–33. http://dx.doi.org/10.1128/jvi.00441-06.
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ABSTRACT The ubiquitous human polyomavirus JC (JCV) is a small double-stranded DNA virus that establishes a persistent infection, and it is often transmitted from parents to children. There are at least 14 subtypes of the virus associated with different human populations. Because of its presumed codivergence with humans, JCV has been used as a genetic marker for human evolution and migration. Codivergence has also been used as a basis for estimating the rate of nucleotide substitution in JCV. We tested the hypothesis of host-virus codivergence by (i) performing a reconciliation analysis of phylogenetic trees of human and JCV populations and (ii) providing the first estimate of the evolutionary rate of JCV that is independent from the assumption of codivergence. Strikingly, our comparisons of JCV and human phylogenies provided no evidence for codivergence, suggesting that this virus should not be used as a marker for human population history. Further, while the estimated nucleotide substitution rate of JCV has large confidence intervals due to limited sampling, our analysis suggests that this virus may evolve nearly two orders of magnitude faster than predicted under the codivergence hypothesis.
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Randhawa, Parmjeet, Raphael Viscidi, Joseph J. Carter, Denise A. Galloway, Tim D. Culp, Cathy Huang, Bala Ramaswami y Neil D. Christensen. "Identification of species-specific and cross-reactive epitopes in human polyomavirus capsids using monoclonal antibodies". Journal of General Virology 90, n.º 3 (1 de marzo de 2009): 634–39. http://dx.doi.org/10.1099/vir.0.008391-0.
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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.
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Balis, V., G. Sourvinos, N. Soulitzis, E. Giannikaki, F. Sofras y D. A. Spandidos. "Prevalence of BK Virus and Human Papillomavirus in Human Prostate Cancer". International Journal of Biological Markers 22, n.º 4 (octubre de 2007): 245–51. http://dx.doi.org/10.1177/172460080702200402.
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Polyomaviruses such as the BK virus (BKV), JC virus (JCV) and SV40, as well as the human papillomaviruses (HPV) are frequently detected throughout human populations, causing subclinical persistent infections and inducing oncogenesis in human and other cell lines. To test the involvement of these viruses in prostate tumorigenesis, we investigated the prevalence of BKV, JCV and HPV in a series of human prostatic malignancies. Forty-two samples of diagnosed prostatic malignancies were tested using standard polymerase chain reaction (PCR) protocols. Differentiation between BKV and JCV among the polyomavirus-positive samples was achieved after sequencing analysis of the PCR products. Reconstitution of BKV in vitro was performed and indirect immunofluorescence for the large T-antigen of the virus was applied to confirm the production of progeny virus. Detection and typing of HPV was carried out by PCR. The overall prevalence of polyomaviruses was 19% in the prostate cancer cases. Sequencing analysis of the polyomavirus-positive specimens revealed the presence of BKV in all samples. Reconstitution of the BKV from the BKV-positive prostate samples was successfully achieved in cell culture and progeny viral particles were obtained, confirming the presence of the virus in the human biopsies. HPV was detected in 4.8% of the samples, however, no HPV-11, HPV-16, HPV-18 or HPV-33 types were identified. BKV was frequently detected and could play a relevant role in the development and progression of human prostate cancer, whereas HPV does not seem to be implicated in this type of human neoplasia.
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CHATTARAJ, SUTANUKA y SOUMEN BHATTACHARJEE. "Molecular Analysis of JC Polyomavirus Genotypes Circulating among Tribal Populations of North-Eastern West Bengal, India". Polish Journal of Microbiology 63, n.º 2 (2014): 191–201. http://dx.doi.org/10.33073/pjm-2014-025.
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There is a resurgence of interest in the study of occurrence, genotype and pathogenic associations of human Polyomaviruses in recent years. In the present study, we have ascertained the presence of human Polyomavirus JC (JCV) in the urine and peripheral blood leukocytes of tribal populations, for the first time in the North-Eastern part of West Bengal State of India. We have also characterized the prevalent genotypes of the non-coding controlregions (NCCRs) of these natural isolates. The result suggests a high incidence of JCV reactivation in the populations assayed. Approximately 25% of the non-immunocompromized tribal men and women, tested positive based on polymerase chain reaction (PCR) analysis, and these results were further confirmed by sequencing of PCR products. Pairwise sequence comparison and alignment of the NCCR sequence of these Indian strains appeared to be comparable and related to the archetypal JCV (CY) and the Tibetan LH3 strains, with some alterations in few key positions. The sequence analyses were done with regard to transcription factor binding to DNA sequence elements of endemic JCV NCCRs.
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Bellizzi, Anna, Elena Anzivino, Donatella Maria Rodio, Anna Teresa Palamara, Lucia Nencioni y Valeria Pietropaolo. "New Insights on Human Polyomavirus JC and Pathogenesis of Progressive Multifocal Leukoencephalopathy". Clinical and Developmental Immunology 2013 (2013): 1–17. http://dx.doi.org/10.1155/2013/839719.
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John Cunningham virus (JCV) is a member of thePolyomaviridaefamily. It was first isolated from the brain of a patient with Hodgkin disease in 1971, and since then the etiological agent of the progressive multifocal leukoencephalopathy (PML) was considered. Until the human immunodeficiency virus (HIV) pandemic, PML was rare: in fact HIV-induced immunodeficiency is the most common predisposing factor accounting for 85% of all instances of PML. This data led to intense research on JCV infection and resulted in better understanding of epidemiology and clinic-pathologic spectrum. Recently, cases of PML have been observed after the introduction of monoclonal antibodies, such as natalizumab, rituximab, efalizumab, and infliximab, in the treatment of autoimmune disease, underlining the important role of host immunity in PML pathogenesis. In this review current understanding of the JCV infection and the new findings relating to the pathogenesis of PML has been comprehensively revised, focusing our attention on the interaction between the cellular and viral molecular pathways implicated in the JCV infection and the modulating role of host immune surveillance in the viral reactivation from a latent state.
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Bofill-Mas, Sílvia, Sonia Pina y Rosina Girones. "Documenting the Epidemiologic Patterns of Polyomaviruses in Human Populations by Studying Their Presence in Urban Sewage". Applied and Environmental Microbiology 66, n.º 1 (1 de enero de 2000): 238–45. http://dx.doi.org/10.1128/aem.66.1.238-245.2000.
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ABSTRACT This is the first description, to our knowledge, of the distribution of human polyomavirus and simian virus 40 (SV40) in urban sewage. Using a nested-PCR procedure, we report the detection of human polyomaviruses JC virus (JCV) and BK virus (BKV) but not SV40 in a high percentage of urban sewage samples obtained from widely divergent geographical areas in Europe and Africa. For a total of 28 samples analyzed, JCV was detected in 26, BKV was detected in 22, and none was positive for SV40. All geographical areas showed a high prevalence of these viruses with mean estimated values of JC viral particles per ml on the order of 103 in Barcelona (Spain) and Nancy (France) and 102 in Pretoria (South Africa) and Umeå (Sweden) and mean values of BK viral particles on the order of 102 in Pretoria and Barcelona and 101 in Nancy and Umeå. This compares with estimated mean values of 102 to 103 for human adenovirus that was evaluated as a control. Nucleotide sequence analysis of the amplified DNA from some of the samples is also presented and represents the sequence of the most abundant JC and BK viral strains in these samples. The nucleotide sequence of the JCV detected was also analyzed in a phylogenetic study and for genomic characterization in the regulatory region. This study has shown that human polyomaviruses are spread in high concentrations in the sewage of different geographical areas and are present in contaminated environments. The frequency and concentration of JCV detected in the environment and the absence of described animal hosts suggest that JCV may be useful as a marker for fecal pollution of anthropogenic origin. The results also support the idea previously described that the strains of JCV are closely related to the ethnic origin of the population studied. The procedure applied should also be useful in future studies of population patterns of viral excretion and as a tool in epidemiological studies for the detection of changes in the prevalence of specific viral pathogens.
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Basile, Anna, Nune Darbinian, Rafal Kaminski, Martyn K. White, Antonio Gentilella, Maria Caterina Turco y Kamel Khalili. "Evidence for modulation of BAG3 by polyomavirus JC early protein". Journal of General Virology 90, n.º 7 (1 de julio de 2009): 1629–40. http://dx.doi.org/10.1099/vir.0.008722-0.
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Polyomavirus JC (JCV) infects oligodendrocytes and astrocytes in the brain and is the cause of the demyelinating disease progressive multifocal leukoencephalopathy (PML). In cell culture, JCV infection is characterized by severe damage to cellular DNA, which begins early in infection, and a viral cytopathic effect, which is observed late in infection. Nevertheless, these JCV-infected cells show a low level of apoptosis, at both the early and late stages of infection. This suggests that there is conflicting interplay between viral anti-apoptotic pathways that seek to optimize virus production, e.g. through T antigen (T-Ag)–p53 interaction, and cellular pro-apoptotic pathways that seek to eliminate virally infected cells. The apoptosis regulatory protein BAG3 is a member of the human Bcl-2-associated athanogene (BAG) family of proteins, which function as molecular co-chaperones through their interaction with Hsc70/Hsp70 and function in the regulation of the cellular stress response, proliferation and apoptosis. This study showed that BAG3 protein is downregulated upon JCV infection and that this effect is mediated by JCV T-Ag via repression of the BAG3 promoter. The site of action of T-Ag was mapped to an AP2 site in the BAG3 promoter, and gel shift and chromatin immunoprecipitation assays showed that T-Ag inhibited AP2 binding to this site, resulting in downregulation of BAG3 promoter expression. Using BAG3 and T-Ag expression and BAG3 siRNA, it was found that BAG3 and T-Ag had antagonistic effects on the induction of apoptosis, being anti-apoptotic and pro-apoptotic, respectively. The significance of these interactions to the JCV life cycle is discussed.
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Sadowska, Beata, Robert Barrucco, Kamel Khalili y Mahmut Safak. "Regulation of Human Polyomavirus JC Virus Gene Transcription by AP-1 in Glial Cells". Journal of Virology 77, n.º 1 (1 de enero de 2003): 665–72. http://dx.doi.org/10.1128/jvi.77.1.665-672.2003.
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ABSTRACT 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.
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Manley, Kate, Bethany A. O'Hara, Gretchen V. Gee, Carl P. Simkevich, John M. Sedivy y Walter J. Atwood. "NFAT4 Is Required for JC Virus Infection of Glial Cells". Journal of Virology 80, n.º 24 (11 de octubre de 2006): 12079–85. http://dx.doi.org/10.1128/jvi.01456-06.
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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.
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Gosert, Rainer, Christine Hanssen Rinaldo, Marion Wernli, Eugene O. Major y Hans H. Hirsch. "CMX001 (1-O-Hexadecyloxypropyl-Cidofovir) Inhibits Polyomavirus JC Replication in Human Brain Progenitor-Derived Astrocytes". Antimicrobial Agents and Chemotherapy 55, n.º 5 (14 de marzo de 2011): 2129–36. http://dx.doi.org/10.1128/aac.00046-11.
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ABSTRACTPolyomavirus JC (JCV) replication causes progressive multifocal leukoencephalopathy (PML), a frequently fatal brain disease in immunodeficient patients, yet antiviral drugs are lacking. We characterized the lipid conjugate 1-O-hexadecyloxypropyl-cidofovir (CMX001) regarding JCV (Mad-4) replication in human brain progenitor-derived astrocytes (PDA) and the simian virus 40 (SV40) large-T-antigen-expressing COS-7 cells up to 7 days postinfection (dpi). We examined JCV loads by PCR, the infection rate by immunofluorescence, and host cell toxicity by WST-1 and BrdU incorporation assays. Supernatants from CMX001-treated PDA demonstrated a drug concentration-dependent decrease in JCV loads and infectivity. CMX001 had only a modest effect on host cell metabolism but reduced overall BrdU incorporation. In PDA at 7 dpi, the CMX001 50% effective concentration (EC50) was 5.55 nM, the 50% cytotoxic concentration (CC50) was 184.6 nM, and the 50% selectivity index (SI50) was 33.3. The EC90was 19.7 nM, the CC90was 5,054 nM, and the SI90was 256.1. In COS-7 cells, JCV replication was faster and the EC50and EC90were 18- and 37-fold higher than those in PDA, i.e., 0.1 μM and 0.74 μM (CC50, 0.67 μM; SI50, 6.7; CC90, 12.2 μM; SI90, 16.5) at 5 dpi. We conclude that CMX001 inhibits JCV replication at concentrationsin vitrothat can be attained by oral administration without significant side effects in clinical studies.
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Pavesi, Angelo. "Utility of JC polyomavirus in tracing the pattern of human migrations dating to prehistoric times". Journal of General Virology 86, n.º 5 (1 de mayo de 2005): 1315–26. http://dx.doi.org/10.1099/vir.0.80650-0.
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JC virus (JCV) is a double-stranded DNA polyomavirus co-evolving with humans since the time of their origin in Africa. JCV seems to provide new insights into the history of human populations, as it suggests an expansion of humans from Africa via two distinct migrations, each carrying a different lineage of the virus. A possible alternative to this interpretation could be that the divergence between the two lineages is due to selective pressures favouring adaptation of JCV to different climates, thus making any inference about human history debatable. In the present study, the evolution of JCV was investigated by applying correspondence analysis to a set of 273 fully sequenced strains. The first and more important axis of ordination led to the detection of 61 nt positions as the main determinants of the divergence between the two virus lineages. One lineage includes strains of types 1 and 4, the other strains of types 2, 3, 7 and 8. The distinctiveness of the Caucasian lineage (types 1 and 4), largely diffused in the northern areas of the world, was almost entirely ascribed to synonymous substitutions. The findings provided by the subsequent axes of ordination supported the view of an evolutionary history of JCV characterized by genetic drift and migration, rather than by natural selection. Correspondence analysis was also applied to a set of 156 human mitochondrial genome sequences. A detailed comparison between the substitution patterns in JCV and mitochondria brought to light some relevant advantages of the use of the virus in tracing human migrations.
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Kimla, Lenka J., Taane G. Clark, Sri Banerjee y Susana Campino. "JC Polyomavirus T-antigen protein expression and the risk of colorectal cancer: Systematic review and meta-analysis of case-control studies". PLOS ONE 18, n.º 3 (31 de marzo de 2023): e0283642. http://dx.doi.org/10.1371/journal.pone.0283642.
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JC Polyomavirus (JCV) is a human polyomavirus encoding T-antigen protein, which is implicated in carcinogenesis. JCV is prevalent in the upper and lower gastrointestinal track. Several studies have reported JCV associations with the risk of developing colorectal cancer (CRC), however, these findings remain controversial. Since JCV DNA may be present in healthy tissues as well as transformed tissues, JCV T-antigen expression could be a more useful measure of JCV’s association with cancer development. The aim of this study is to conduct a meta-analysis of case-control studies to investigate if there is a significant association between JCV T-antigen protein expression and risk of CRC. A systematic review was performed to identify studies reporting JCV DNA prevalence in CRC and JCV T-antigen expression. The strength of the association was estimated by odds ratios (ORs). Five (of 66) studies satisfied analysis inclusion criteria, and spanned years 1999 to 2022. Random effects meta-analysis of CRC cases versus controls showed an 11-fold increased risk of CRC development in JCV DNA positive samples with JCV T-antigen expression versus normal tissues (OR 10.95; 95% CI: 2.48–48.24; P = 0.0016). The results of this meta-analysis of JCV infection followed by JCV T-antigen protein expression for the risk of CRC support the argument that JCV infection significantly increases the risk of colorectal cancer in tissues where the JCV T-antigen protein is expressed. Further research with JCV T-antigen expression in relation to CRC development is needed.
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Krymskaya, Ludmila, Madeva C. Sharma, Joy Martinez, Wahajul Haq, Eric C. Huang, Ajit P. Limaye, Don J. Diamond y Simon F. Lacey. "Cross-Reactivity of T Lymphocytes Recognizing a Human Cytotoxic T-Lymphocyte Epitope within BK and JC Virus VP1 Polypeptides". Journal of Virology 79, n.º 17 (1 de septiembre de 2005): 11170–78. http://dx.doi.org/10.1128/jvi.79.17.11170-11178.2005.
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ABSTRACT A transgenic mouse model was used to identify an HLA-A*02-restricted epitope within the VP1 polypeptide of a human polyomavirus, BK virus (BKV), which is associated with polyomavirus-associated nephropathy in kidney transplant patients. Peptide stimulation of splenocytes from mice immunized with recombinant modified vaccinia virus Ankara expressing BKV VP1 resulted in expansion of cytotoxic T lymphocytes (CTLs) recognizing the sequence LLMWEAVTV corresponding to amino acid residues 108 to 116 (BKV VP1p108). These effector T-cell populations represented functional CTLs as assessed by cytotoxicity and cytokine production and were cross-reactive against antigen-presenting cells pulsed with a peptide corresponding to the previously described JC virus (JCV) VP1 homolog sequence ILMWEAVTL (JCV VP1p100) (I. J. Koralnik et al., J. Immunol. 168:499-504, 2002). A panel of 10 healthy HLA-A*02 human volunteers and two kidney transplant recipients were screened for T-cell immunity to this BK virus VP1 epitope by in vitro stimulation of their peripheral blood mononuclear cells (PBMC) with the BKV VP1p108 peptide, followed by tetramer labeling combined with simultaneous assays to detect intracellular cytokine production and degranulation. PBMC from 4/10 subjects harbored CTL populations that recognized both the BKV VP1p108 and the JCV VP1p100 peptides with comparable efficiencies as measured by tetramer binding, gamma interferon production, and degranulation. CTL responses to the JCV VP1p100 epitope have been associated with prolonged survival in progressive multifocal leukoencephalopathy patients (R. A. Du Pasquier et al., Brain 127:1970-1978, 2004; I. J. Koralnik et al., J. Immunol. 168:499-504, 2002). Given that both human polyomaviruses are resident in a high proportion of healthy individuals and that coinfection occurs (W. A. Knowles et al., J. Med. Virol. 71:115-123, 2003), our findings suggest a reinterpretation of this protective T-cell immunity, suggesting that the same VP1 epitope is recognized in HLA-A*02 persons in response to either BK or JC virus infection.
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Ravichandran, Veerasamy, Peter N. Jensen y Eugene O. Major. "MEK1/2 Inhibitors Block Basal and Transforming Growth Factor β1-Stimulated JC Virus Multiplication". Journal of Virology 81, n.º 12 (4 de abril de 2007): 6412–18. http://dx.doi.org/10.1128/jvi.02658-06.
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ABSTRACT The multiplication of the human neurotropic polyomavirus JC virus (JCV) is regulated by cell membrane receptors and nuclear transcription factors. Signaling pathways also play a role in determining the extent to which JCV can productively infect cells. These data show that constitutively active MEK1 protein (CA-MEK1), overexpressed in cultures of human glia, supports a substantial increase in late JCV protein (Vp-1) synthesis. The specificity of this pathway was indicated by no significant enhancement of JCV multiplication through activation of other components of mitogen-activated protein kinase pathways such as p38, Jun N-terminal protein kinase, and protein kinase A. Further evidence supporting the importance of signaling in JCV infection came from addition of transforming growth factor β1 (TGF-β1), which stimulated a 200% increase of Vp-1 expression. Specific MEK1/2 inhibitors, flavenoid PD98059 and U0126, decreased the basal and TGF-β1-stimulated Vp-1 expression by 95% or more. TGF-β1 is known to phosphorylate/activate Smad DNA binding proteins that could subsequently bind or increase binding to JCV promoter sequences, linking the effects of signaling with JCV transcriptional regulation. The effectiveness with which MEK1/2 inhibitors block JCV multiplication provides insight that may contribute to development of compounds directed against JCV.
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Gosert, Rainer, Piotr Kardas, Eugene O. Major y Hans H. Hirsch. "Rearranged JC Virus Noncoding Control Regions Found in Progressive Multifocal Leukoencephalopathy Patient Samples Increase Virus Early Gene Expression and Replication Rate". Journal of Virology 84, n.º 20 (4 de agosto de 2010): 10448–56. http://dx.doi.org/10.1128/jvi.00614-10.
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ABSTRACT Polyomavirus JC (JCV) infects ∼60% of the general population, followed by asymptomatic urinary shedding in ∼20%. In patients with pronounced immunodeficiency, including HIV/AIDS, JCV can cause progressive multifocal leukoencephalopathy (PML), a devastating brain disease of high mortality. While JCV in the urine of healthy people has a linear noncoding control region called the archetype NCCR (at-NCCR), JCV in brain and cerebrospinal fluid (CSF) of PML patients bear rearranged NCCRs (rr-NCCRs). Although JCV NCCR rearrangements are deemed pathognomonic for PML, their role as a viral determinant is unclear. We sequenced JCV NCCRs found in CSF of eight HIV/AIDS patients newly diagnosed with PML and analyzed their effect on early and late gene expression using a bidirectional reporter vector recapitulating the circular polyomavirus early and late gene organization. The rr-NCCR sequences were highly diverse, but all increased viral early reporter gene expression in progenitor-derived astrocytes, glia-derived cells, and human kidney compared to the expression levels with the at-NCCR. The expression of simian virus 40 (SV40) large T antigen or HIV Tat expression in trans was associated with a strong increase of at-NCCR-controlled early gene expression, while rr-NCCRs were less responsive. The insertion of rr-NCCRs into the JCV genome backbone revealed higher viral replication rates for rr-NCCR compared to those of the at-NCCR JCV in human progenitor-derived astrocytes or glia cells, which was abrogated in SV40 large T-expressing COS-7 cells. We conclude that naturally occurring JCV rr-NCCR variants from PML patients confer increased early gene expression and higher replication rates compared to those of at-NCCR JCV and thereby increase cytopathology.
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Kalvatchev, Zlatko N. y Iliya T. Tsekov. "Does Mefloquine (Lariam®) Therapy Improve the Prognosis of Human JC Polyomavirus-Induced Progressive Multifocal Leukoencephalopathy?" Journal of Biomedical and Clinical Research 7, n.º 1 (1 de noviembre de 2014): 3–7. http://dx.doi.org/10.1515/jbcr-2015-0117.
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Abstract Progressive multifocal leukoencephalopathy (PML) is ademyelinating disease caused by infection with Polyomavirus hominis 2, popularly known as JC virus (JCV). The disease is usually fatal as it develops due to the progressive destruction of oligodendrocytes in multiple brain foci. Several substances that show effect against JCV have been investigated. However, only the antimalarial drug mefloquine has been reported to significantly influence the viral replication both in vitro and following in vivo therapy with good penetration and distribution of the drug at efficacious concentrations into the central nervous system (CNS). The current material presents some of the available published data, suggesting that the activity of mefloquine against JCV be considered for treatment of patients with PML.
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Andrei, G., R. Snoeck, M. Vandeputte y E. De Clercq. "Activities of various compounds against murine and primate polyomaviruses." Antimicrobial Agents and Chemotherapy 41, n.º 3 (marzo de 1997): 587–93. http://dx.doi.org/10.1128/aac.41.3.587.
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Polyomavirus infections in humans are due to BK virus (BKV) and JC virus (JCV). Diseases associated with human polyomaviruses occur mostly in immunocompromised adults, e.g., progressive multifocal leukoencephalopathy (PML), caused by JCV, in AIDS patients and hemorrhagic cystitis and uretral stenosis, caused by BKV, in transplant recipients. No therapy is available for these diseases, which necessitates the development of chemical entities that are active against polyomaviruses. Several antiviral compounds were evaluated to determine their effects on the in vitro replication of mouse polyomavirus and the primate viruses simian virus 40 (SV40), SV40 PML-1, and SV40 PML-2. The activity of the different compounds was assessed by a cytopathic effect reduction assay and confirmed in a virus yield assay. Cidofovir [HPMPC; (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] and its cyclic counterpart emerged as the most selective antipolyomavirus agents. The 50% inhibitory concentrations for HPMPC were in the range of 4 to 7 micrograms/ml, and its selectivity index varied from 11 to 20 for mouse polyomavirus and from 23 to 33 for SV40 strains in confluent cell monolayers. Cell cytotoxicity was up to 15-fold greater in growing cells. Other acyclic nucleoside phosphonates (i.e., HPMPA; [(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine] and PMEG [9-(2-phosphonylmethoxyethyl)-guanine]) also showed some activity but had low selectivity. None of the other drugs tested against these animal viruses (i.e., acyclovir, ganciclovir, brivudine, ribavirin, foscarnet, and cytarabine) showed significant activity. Thus, HPMPC deserves further evaluation as a candidate drug for polyomavirus infections in the immunocompromised host.
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Brickelmaier, Margot, Alexey Lugovskoy, Ramya Kartikeyan, Marta M. Reviriego-Mendoza, Norm Allaire, Kenneth Simon, Richard J. Frisque y Leonid Gorelik. "Identification and Characterization of Mefloquine Efficacy against JC Virus In Vitro". Antimicrobial Agents and Chemotherapy 53, n.º 5 (2 de marzo de 2009): 1840–49. http://dx.doi.org/10.1128/aac.01614-08.
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ABSTRACT Progressive multifocal leukoencephalopathy (PML) is a rare but frequently fatal disease caused by the uncontrolled replication of JC virus (JCV), a polyomavirus, in the brains of some immunocompromised individuals. Currently, no effective antiviral treatment for this disease has been identified. As a first step in the identification of such therapy, we screened the Spectrum collection of 2,000 approved drugs and biologically active molecules for their anti-JCV activities in an in vitro infection assay. We identified a number of different drugs and compounds that had significant anti-JCV activities at micromolar concentrations and lacked cellular toxicity. Of the compounds with anti-JCV activities, only mefloquine, an antimalarial agent, has been reported to show sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain. Additional in vitro experiments demonstrated that mefloquine inhibits the viral infection rates of three different JCV isolates, JCV(Mad1), JCV(Mad4), and JCV(M1/SVEΔ), and does so in three different cell types, transformed human glial (SVG-A) cells, primary human fetal glial cells, and primary human astrocytes. Using quantitative PCR to quantify the number of viral copies in cultured cells, we have also shown that mefloquine inhibits viral DNA replication. Finally, we demonstrated that mefloquine does not block viral cell entry; rather, it inhibits viral replication in cells after viral entry. Although no suitable animal model of PML or JCV infection is available for the testing of mefloquine in vivo, our in vitro results, combined with biodistribution data published in the literature, suggest that mefloquine could be an effective therapy for PML.
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Boldorini, Renzo, Sara Allegrini, Umberto Miglio, Alessia Paganotti, Norma Cocca, Mauro Zaffaroni, Francesca Riboni, Guido Monga y Raphael Viscidi. "Serological evidence of vertical transmission of JC and BK polyomaviruses in humans". Journal of General Virology 92, n.º 5 (1 de mayo de 2011): 1044–50. http://dx.doi.org/10.1099/vir.0.028571-0.
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Vertical transmission of JC virus and BK virus has been investigated by few authors, with conflicting results. We performed a combined serological and genomic study of 19 unselected pregnant women and their newborns. Blood and urine samples were collected during each gestational trimester from the pregnant women. Umbilical cord blood, peripheral blood, urine and nasopharyngeal secretion samples were taken from newborns at delivery and after 1 week and 1 month of life. Polyomavirus DNA was detected by nested PCR. Polyomavirus IgG-, IgM- and IgA-specific antibodies were measured in maternal and newborn serum samples using a virus-like-particle-based ELISA method. BKV and JCV DNA were detected in urine from 4 (21 %) and 5 (26 %) women, respectively. BKV and JCV seroprevalences in the pregnant women were 84 % and 42 %, respectively. Using a rise in the IgG level or the transient appearance of an IgA or IgM response as evidence of infection in the newborn, we detected BKV and JCV infections in four (21 %) and three (16 %) newborns, respectively. Three infants had serological evidence of infection with both BKV and JCV. In two of the four possible BKV-infected newborns, the mothers seroconverted during pregnancy, while another mother was viruric and IgA seropositive. The mother of one of the three possible JCV-infected newborns was viruric and IgA seropositive; another mother was viruric. These results suggest JC virus and BK virus can be transmitted from mother to newborn during pregnancy or soon after birth.
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Jiang, Zhi-Gang, Jeffrey Cohen, Leslie J. Marshall y Eugene O. Major. "Hexadecyloxypropyl-Cidofovir (CMX001) Suppresses JC Virus Replication in Human Fetal Brain SVG Cell Cultures". Antimicrobial Agents and Chemotherapy 54, n.º 11 (7 de septiembre de 2010): 4723–32. http://dx.doi.org/10.1128/aac.00837-10.
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ABSTRACT JC virus (JCV) is a polyomavirus that infects human oligodendrocytes, leading to development of progressive multifocal leukoencephalopathy (PML), an often fatal demyelinating disease occurring in immunocompromised individuals. Currently there are no effective therapies for the treatment of PML that result in clearance of JCV from the brain. Cidofovir (CDV) is an acyclic nucleoside phosphonate that inhibits DNA polymerases and has been used for the treatment of PML. However, CDV demonstrated little efficacy as a treatment for PML and causes substantial side effects to patients. To improve efficacy and reduce the toxicity of CDV, a lipid-ester derivative, CMX001, was generated by Chimerix and is currently in multicenter phase II clinical trials for the prevention or control of cytomegalovirus infection in hematopoietic stem cell transplant recipients and of BK virus in the urine of stem cell or renal allograft recipients. CMX001 caused minimal cytotoxic effects in human fetal brain SVG cells when used at concentrations between 0.01 μM and 0.1 μM. CMX001 resulted in a dose-dependent decrease in the number of JCV-infected cells during initial infection and nearly eliminated JCV-infected cells during an established infection. In addition, CMX001 treatment resulted in a 60% reduction in JCV DNA copy number during initial infection, which suggests that suppression of JCV infection by CMX001 is likely due to inhibition of virus DNA replication. This study demonstrates that CMX001 suppresses JCV infection at concentrations that have limited toxicity to human brain cells, indicating its potential use to limit JCV replication in infected patients.
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Dang, Xin y Igor J. Koralnik. "A granule cell neuron-associated JC virus variant has a unique deletion in the VP1 gene". Journal of General Virology 87, n.º 9 (1 de septiembre de 2006): 2533–37. http://dx.doi.org/10.1099/vir.0.81945-0.
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The human polyomavirus JC (JCV) typically infects glial cells and is the aetiological agent of progressive multifocal leukoencephalopathy (PML), which occurs in immunosuppressed individuals. The full-length sequence of a granule cell neuron-tropic JCV variant, JCVGCN1, associated with lytic infection of granule cell neurons and cerebellar atrophy in a human immunodeficiency virus-infected patient with PML was determined and compared with the sequence of the JCV isolate from the classic PML lesions present in the hemispheric white matter of the same individual (JCVHWM). A unique deletion was found in the C terminus of the VP1 gene of JCVGCN1, which encodes the major capsid protein, resulting in a frame shift and a total change of the C-terminal amino acid sequence of this protein. This deletion was not present in JCVHWM, suggesting that this mutation may be instrumental in facilitating entry or replication of JCV into granule cell neurons.
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Koralnik, Igor J., Renaud A. Du Pasquier y Norman L. Letvin. "JC Virus-Specific Cytotoxic T Lymphocytes in Individuals with Progressive Multifocal Leukoencephalopathy". Journal of Virology 75, n.º 7 (1 de abril de 2001): 3483–87. http://dx.doi.org/10.1128/jvi.75.7.3483-3487.2001.
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ABSTRACT Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by a reactivation of the polyomavirus JC (JCV) within a setting of immunosuppression. The nature of the immune response that contains replication of this virus is unknown. We have explored JCV-specific cellular immune responses in patients with PML and control subjects. JCV antigen-stimulated peripheral blood mononuclear cells (PBMC) of four human immunodeficiency virus (HIV)-infected patients who were survivors of PML and one HIV-uninfected patient recently diagnosed with PML lysed autologous B-lymphoblastoid cell lines expressing either the JCV T regulatory protein or the VP1 major capsid protein. This lysis was mediated by CD8+ T lymphocytes and was major histocompatibility complex class I restricted. These cells were therefore cytotoxic T lymphocytes (CTL). JCV-specific CTL could not be detected in PBMC of three HIV-infected PML patients who had progressive neurologic disease and an eventual fatal outcome. These data suggest that the JCV-specific cellular immune response may play a crucial role in the containment of PML. This finding may also prove useful as a favorable prognostic marker in the clinical management of these patients.
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Liu, Christine K., Grant Wei y Walter J. Atwood. "Infection of Glial Cells by the Human Polyomavirus JC Is Mediated by an N-Linked Glycoprotein Containing Terminal α(2-6)-Linked Sialic Acids". Journal of Virology 72, n.º 6 (1 de junio de 1998): 4643–49. http://dx.doi.org/10.1128/jvi.72.6.4643-4649.1998.
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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.
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Lima, Marco A., Angela Marzocchetti, Patrick Autissier, Troy Tompkins, Yiping Chen, Jennifer Gordon, David B. Clifford et al. "Frequency and Phenotype of JC Virus-Specific CD8+ T Lymphocytes in the Peripheral Blood of Patients with Progressive Multifocal Leukoencephalopathy". Journal of Virology 81, n.º 7 (17 de enero de 2007): 3361–68. http://dx.doi.org/10.1128/jvi.01809-06.
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ABSTRACT JC virus (JCV)-specific CD8+ cytotoxic T lymphocytes (CTL) are associated with a favorable outcome in patients with progressive multifocal leukoencephalopathy (PML) and cross-recognize the polyomavirus BK virus (BKV). We sought to determine the frequency and phenotype in fresh blood of CD8+ T cells specific for two A*0201-restricted JCV epitopes, VP1p36 and VP1p100, and assess their impact on JC and BK viremia and viruria in 15 healthy subjects, eight human immunodeficiency virus-positive (HIV+) individuals, and nine HIV+ patients with PML (HIV+ PML patients) classified as survivors. After magnetic preenrichment of CD8+ T cells, epitope-specific cells ranged from 0.001% to 0.22% by tetramer staining, with no significant difference among the three study groups. By use of seven-color flow cytometry, there was no predominant differentiation phenotype subset among JCV-specific CD8+ T cells in healthy individuals, HIV+ subjects, or HIV+ PML patients. However, in one HIV+ PML patient studied in the acute phase, there was a majority of activated effector memory cells. BKV DNA was undetectable in all blood samples by quantitative PCR, while a low JC viral load was found in the blood of only one HIV+ and two HIV+ PML patients. JCV and BKV DNA were detected in 33.3% and 13.3% of all urine samples, respectively, independent of the presence of JCV-specific CTL. The detection of JCV DNA in the urine was associated with the presence of a JCV VP1p100 CTL response. Immunotherapies aiming at increasing the cellular immune response against JCV may be valuable in the treatment of HIV+ individuals with PML.
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Khanna, Nina, Marcel Wolbers, Nicolas J. Mueller, Christian Garzoni, Renaud A. Du Pasquier, Christoph A. Fux, Pietro Vernazza et al. "JC Virus-Specific Immune Responses in Human Immunodeficiency Virus Type 1 Patients with Progressive Multifocal Leukoencephalopathy". Journal of Virology 83, n.º 9 (11 de febrero de 2009): 4404–11. http://dx.doi.org/10.1128/jvi.02657-08.
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ABSTRACT Progressive multifocal leukoencephalopathy (PML) is a frequently fatal disease caused by uncontrolled polyomavirus JC (JCV) in severely immunodeficient patients. We investigated the JCV-specific cellular and humoral immunity in the Swiss HIV Cohort Study. We identified PML cases (n = 29), as well as three matched controls per case (n = 87), with prospectively cryopreserved peripheral blood mononuclear cells and plasma at diagnosis. Nested controls were matched according to age, gender, CD4+ T-cell count, and decline. Survivors (n = 18) were defined as being alive for >1 year after diagnosis. Using gamma interferon enzyme-linked immunospot assays, we found that JCV-specific T-cell responses were lower in nonsurvivors than in their matched controls (P = 0.08), which was highly significant for laboratory- and histologically confirmed PML cases (P = 0.004). No difference was found between PML survivors and controls or for cytomegalovirus-specific T-cell responses. PML survivors showed significant increases in JCV-specific T cells (P = 0.04) and immunoglobulin G (IgG) responses (P = 0.005). IgG responses in survivors were positively correlated with CD4+ T-cell counts (P = 0.049) and negatively with human immunodeficiency virus RNA loads (P = 0.03). We conclude that PML nonsurvivors had selectively impaired JCV-specific T-cell responses compared to CD4+ T-cell-matched controls and failed to mount JCV-specific antibody responses. JCV-specific T-cell and IgG responses may serve as prognostic markers for patients at risk.
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Seth, Pankaj, Frank Diaz, Jung-Hwa Tao-Cheng y Eugene O. Major. "JC Virus Induces Nonapoptotic Cell Death of Human Central Nervous System Progenitor Cell-Derived Astrocytes". Journal of Virology 78, n.º 9 (1 de mayo de 2004): 4884–91. http://dx.doi.org/10.1128/jvi.78.9.4884-4891.2004.
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ABSTRACT JC virus (JCV), a human neurotropic polyomavirus, demonstrates a selective glial cell tropism that causes cell death through lytic infection. Whether these cells die via apoptosis or necrosis following infection with JCV remains unclear. To investigate the mechanism of virus-induced cell death, we used a human central nervous system progenitor-derived astrocyte cell culture model developed in our laboratory. Using in situ DNA hybridization, immunocytochemistry, electron microscopy, and an RNase protection assay, we observed that astrocytes support a progressive JCV infection, which eventually leads to nonapoptotic cell death. Infected astrocyte cell cultures showed no difference from noninfected cells in mRNA expression of the caspase family genes or in any ultrastructural features associated with apoptosis. Infected cells demonstrated striking necrotic features such as cytoplasmic vacuolization, watery cytoplasm, and dissolution of organelles. Furthermore, staining for caspase-3 and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling were not detected in infected astrocyte cultures. Our findings suggest that JCV-induced cell death of these progenitor cell-derived astrocytes does not utilize an apoptosis pathway but exhibits a pattern of cell destruction consistent with necrotic cell death.
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Dang, Xin, Jose E. Vidal, Augusto C. Penalva de Oliveira, David M. Simpson, Susan Morgello, Jonathan H. Hecht, Long H. Ngo y Igor J. Koralnik. "JC virus granule cell neuronopathy is associated with VP1 C terminus mutants". Journal of General Virology 93, n.º 1 (1 de enero de 2012): 175–83. http://dx.doi.org/10.1099/vir.0.037440-0.
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The polyomavirus JC (JCV) infects glial cells and causes progressive multifocal leukoencephalopathy (PML). We described a novel JCV-variant with a 10 bp deletion in the C terminus of the VP1 capsid protein, JCVGCN1. This mutant was associated with lytic infection of cerebellar granule cell neurons and cerebellar atrophy in an human immunodeficiency virus/PML patient. This condition, also observed independently from PML, was named JCV granule cell neuronopathy (JCV GCN). We characterized JCV mutations in cerebrospinal fluid (CSF) of four other JCV GCN patients, and reviewed the literature on 10 reported cases. The strain from one patient harboured the identical GCN1-deletion, while the other patients had novel mutations in the same area, named JCVGCN2–4, causing variable changes in VP1 structure. One patient also had wild-type JCV in the CSF. To study the mechanisms leading to JCV GCN, we compared viral replication kinetics from JCVGCN1 with the prototype JCVMad1, the PML isolate JCVHWM and the prototype JCVMad1D engineered with the GCN1-deletion. While all strains replicated at low levels in the medulloblastoma cell line DAOY from a cerebellar neuronal tumour, JCVMad1 replicated better in astroglial SVG cells than JCVMad1D or JCVGCN1 and all strains replicated at higher levels in COS-7 kidney cells, suggesting that the GCN1-deletion confers a disadvantage for viral growth in central nervous system white matter. The GCN1-deletion remained stable after 100 days in culture and VP1 protein was produced in all cell lines, indicating that JCVGCN1 is replication-competent in vitro. These data highlight an important and previously overlooked aspect of JCV-pathogenesis. Detection of GCN-type JCV strains in CSF may help clinicians diagnose JCV GCN.
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Monaco, Maria Chiara G., Peter N. Jensen, Jean Hou, Linda C. Durham y Eugene O. Major. "Detection of JC Virus DNA in Human Tonsil Tissue: Evidence for Site of Initial Viral Infection". Journal of Virology 72, n.º 12 (1 de diciembre de 1998): 9918–23. http://dx.doi.org/10.1128/jvi.72.12.9918-9923.1998.
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ABSTRACT Progressive multifocal leukoencephalopathy is a demyelinating disease of the human central nervous system that results from lytic infection of oligodendrocytes by the polyomavirus JC (JCV). Originally, JCV was thought to replicate exclusively in human glial cells, specifically oligodendrocytes. However, we have recently shown that JCV can replicate in cells of lymphoid origin such as hematopoietic precursor cells, B lymphocytes, and tonsillar stromal cells. To determine whether tonsils harbor JCV, we tested a total of 54 tonsils, 38 from children and 16 from adult donors. Nested PCRs with primer sets specific for the viral T protein and regulatory regions were used for the detection of JCV DNA. JCV DNA was detected in 21 of 54 tonsil tissues, or 39% (15 of 38 children and 6 of 16 adults) by using regulatory-region primers and in 19 of 54 tonsil tissues, or 35% (13 of 38 children and 6 of 16 adults) by using the T-protein primers. The DNA extracted from children’s nondissected tonsil tissue, isolated tonsillar lymphocytes, and isolated stromal cells that demonstrated PCR amplification of the JCV regulatory region underwent cloning and nucleotide sequencing. Of the regulatory-region sequences obtained, nearly all contained tandem repeat arrangements. Clones originating from nondissected tonsil tissue and tonsillar lymphocytes were found to have sequences predominantly of the Mad-1 prototype strain, whereas the majority of clones from the DNA of tonsillar stromal cells had sequences characteristic of the Mad-8br strain of JCV. A few clones demonstrated structures other than tandem repeats but were isolated only from tonsillar lymphocytes. These data provide the first evidence of the JCV genome in tonsil tissue and suggest that tonsils may serve as an initial site of viral infection.
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Tyagarajan, Shiva K. y Richard J. Frisque. "Stability and Function of JC Virus Large T Antigen and T′ Proteins Are Altered by Mutation of Their Phosphorylated Threonine 125 Residues". Journal of Virology 80, n.º 5 (1 de marzo de 2006): 2083–91. http://dx.doi.org/10.1128/jvi.80.5.2083-2091.2006.
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ABSTRACT JC virus (JCV), a human polyomavirus, exhibits oncogenic activity in rodents and primates. The large tumor antigens (TAgs) of the polyomaviruses play key roles in viral replication and oncogenic transformation. Analyses of JCV TAg phosphorylation mutants indicated that the amino-terminal phosphorylation site at threonine 125 (T125) is critical to TAg replication function. This site is also conserved in the TAg splice variants T′135, T′136, and T′165. By constructing stable cell lines expressing JCV T125A and T125D mutants, we show that mutation of this phosphorylation site to alanine generates an unstable TAg; however, the stability of the three T′ proteins is unaffected. JCV T125A mutant proteins bind the retinoblastoma protein (RB) family members p107 and p130 with slightly reduced efficiencies and fail to induce the release of transcriptionally active E2F from RB-E2F complexes. On the other hand, cell lines expressing JCV T125D mutant proteins produce stable TAg and T′ proteins which bind p107 and p130 more efficiently than do the wild-type proteins. In addition, T125D mutant proteins efficiently induce the release of E2F from RB-E2F complexes. T125D mutant cell lines, unlike the T125A mutant lines, continue to grow under conditions of low serum concentration and anchorage independence. Finally, both T125A and T125D mutant viruses are replication defective. Phosphorylation of the T125 site is likely mediated by a cyclin-cyclin-dependent kinase, suggesting that JCV TAg and T′ protein functions that mediate viral replication and oncogenic transformation events are regulated in a cell cycle-dependent manner.
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Boldorini, Renzo, Claudia Veggiani, Diana Barco y Guido Monga. "Kidney and Urinary Tract Polyomavirus Infection and Distribution: Molecular Biology Investigation of 10 Consecutive Autopsies". Archives of Pathology & Laboratory Medicine 129, n.º 1 (1 de enero de 2005): 69–73. http://dx.doi.org/10.5858/2005-129-69-kautpi.
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Abstract Context.—Distinct human polyomavirus genotypes cause different diseases in patients with renal transplants: BK virus (BKV) causes tubulointerstitial nephritis and ureteral stenosis, whereas both JC virus (JCV) and BKV are responsible for hemorrhagic cystitis. These findings could result from a selective infection of kidney and urinary tract segments by JCV or BKV. Objective.—To verify this hypothesis, 10 complete, unselected, consecutive autopsies from 9 immunocompetent patients and 1 patient affected by acquired immunodeficiency syndrome were investigated. Design.—Samples from kidneys (n = 80), renal pelvis (n = 20), ureter (n = 40), and urinary bladder (n = 30) obtained from 10 consecutive autopsies were investigated by means of multiplex nested polymerase chain reaction to detect polyomavirus DNA and to distinguish different species of the Polyomavirus genus. In situ hybridization and immunohistochemistry were also carried out to define the viral status of the infected tissues. Results.—Polyomavirus DNA was detected in all of the subjects (positive samples ranging from 2 to 7 samples), for a total of 43 of 170 samples (25.3%), distributed as follows: urinary bladder (10/30, 33%), renal pelvis (6/20, 30%), ureter (10/40, 25%), and kidney tissue (17/80, 21%). We found that JCV was most frequently detected overall (23/43 samples, 53.5%) and was also detected most frequently within the kidney (8/17 positive samples, 47%), the renal pelvis (5/6 positive samples, 70%), and the ureter (7/10 positive samples, 70%), whereas BKV was found in 14 samples (32.5%), and it was the prevailing genotype in urinary bladder (6/10 positive samples, 60%). Coinfection of BKV-JCV was found in 6 samples (14%). Immunohistochemistry and in situ hybridization returned negative results. Conclusions.—The viruses JCV and BKV latently persist randomly in kidney and urinary tract. Distinct diseases induced by them could be related more closely to molecular viral rearrangements than to the topographic distribution of latent viruses.
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Özdemir, Mehmet, Uğur Ayan y Murat Şevik. "Comparative Evaluation of In-House and Commercial Real-Time PCR Methods for the Detection of the BK and JC Viruses in Clinical Samples". Journal of Laboratory Physicians 12, n.º 02 (agosto de 2020): 079–83. http://dx.doi.org/10.1055/s-0040-1716603.
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Abstract Aim The two most common human polyomaviruses are the BK (BKV) and JC viruses (JCV). Diseases associated with polyomavirus usually occur in cases of severe cellular immunosuppression. BKV and JCV can cause many diseases, especially if they are reactivated in an immunosuppressed host. The aim of this study is to compare and evaluate the results of real-time polymerase chain reaction (PCR) methods targeting the small and large T gene regions of the viral genome, considering polymorphisms occurring in the viral genome of BKV and JCV. Materials and Methods Urinary specimens of 82 patients were taken from immunosuppressed patient and sent to molecular microbiology laboratory of Meram Medical Faculty. The small t gene was investigated using a commercial kit (LightMix, Roche) by real-time PCR method. Large T gene was investigated by using the optimized in-house real-time PCR method. Sequence analysis was accepted as the standard method. Results BKV positivity was detected in 9 samples and JCV positivity in 61 samples by real-time PCR method specific to small t gene region; BKV positivity in 21 samples and JCV positivity in 67 samples were determined by real-time PCR method specific to the large T gene region. Statistically, there was a significant difference for BKV, but not significant difference for JCV detection between the two methods. Conclusion Different polymorphisms in the target gene regions were responsible for the different outcomes obtained from this study. With this sensitivity and specificity, in-house PCR method which we used is a candidate for routine diagnosis.
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Chapagain, Moti L. y Vivek R. Nerurkar. "Human Polyomavirus JC (JCV) Infection of Human B Lymphocytes: A Possible Mechanism for JCV Transmigration across the Blood‐Brain Barrier". Journal of Infectious Diseases 202, n.º 2 (15 de julio de 2010): 184–91. http://dx.doi.org/10.1086/653823.
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Ashok, Aarthi y Walter J. Atwood. "Contrasting Roles of Endosomal pH and the Cytoskeleton in Infection of Human Glial Cells by JC Virus and Simian Virus 40". Journal of Virology 77, n.º 2 (15 de enero de 2003): 1347–56. http://dx.doi.org/10.1128/jvi.77.2.1347-1356.2003.
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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.
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Stoner, Gerald L., Hansjürgen T. Agostini, Caroline F. Ryschkewitsch y Samuel Komoly. "JC virus excreted by multiple sclerosis patients and paired controls from Hungary". Multiple Sclerosis Journal 4, n.º 2 (abril de 1998): 45–48. http://dx.doi.org/10.1177/135245859800400201.
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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.
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Uleri, Elena, Claudia Piu, Maurizio Caocci, Gabriele Ibba, Francesca Sanges, Giovanna Pira, Luciano Murgia et al. "Multiple Signatures of the JC Polyomavirus in Paired Normal and Altered Colorectal Mucosa Indicate a Link with Human Colorectal Cancer, but Not with Cancer Progression". International Journal of Molecular Sciences 20, n.º 23 (27 de noviembre de 2019): 5965. http://dx.doi.org/10.3390/ijms20235965.
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The JC polyomavirus (JCV) has been repeatedly but discordantly detected in healthy colonic mucosa, adenomatous polyps, and colorectal cancer (CRC), and proposed to contribute to oncogenesis. The controversies may derive from differences in JCV targets, patient’s cohorts, and methods. Studies of simultaneous detection, quantification, and characterization of JCV presence/expression in paired samples of normal/altered tissues of the same patient are lacking. Therefore, we simultaneously quantified JCV presence (DNA) and expression (mRNA and protein) of T-antigen (T-Ag), Viral Protein 1 (Vp1), and miR-J1-5p in paired normal/altered tissues of CRC or polyps, and from controls. JCV signatures were found in most samples. They increased in patients, but were higher in normal mucosa than in corresponding polyp or CRC lesions. JCV non-coding control region (NCCR) DNA rearrangements increased in CRC patients, also in normal mucosa, thus before the onset of the lesion. A new ∆98bp NCCR DNA rearrangement was detected. T-Ag levels were higher in normal mucosa than in adenoma and adenocarcinoma lesions, but decreased to levels of controls in established CRC lesions. In CRC, miR-J1-5p expression decreased with CRC progression. Vp1 expression was not detected. The data indicate a JCV link with the disease, but possible JCV contributes to oncogenesis should occur at pre-polyp stages.
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Monaco, Maria Chiara G., Bruce F. Sabath, Linda C. Durham y Eugene O. Major. "JC Virus Multiplication in Human Hematopoietic Progenitor Cells Requires the NF-1 Class D Transcription Factor". Journal of Virology 75, n.º 20 (15 de octubre de 2001): 9687–95. http://dx.doi.org/10.1128/jvi.75.20.9687-9695.2001.
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ABSTRACT 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.
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Maginnis, Melissa S., Sheila A. Haley, Gretchen V. Gee y Walter J. Atwood. "Role of N-Linked Glycosylation of the 5-HT2A Receptor in JC Virus Infection". Journal of Virology 84, n.º 19 (21 de julio de 2010): 9677–84. http://dx.doi.org/10.1128/jvi.00978-10.
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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.
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Querbes, W., B. A. O'Hara, G. Williams y W. J. Atwood. "Invasion of Host Cells by JC Virus Identifies a Novel Role for Caveolae in EndosomalSorting of Noncaveolar Ligands". Journal of Virology 80, n.º 19 (1 de octubre de 2006): 9402–13. http://dx.doi.org/10.1128/jvi.01086-06.
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ABSTRACT Invasion of glial cells by the human polyomavirus, JC virus (JCV), leads to a rapidly progressing and uniformly fatal demyelinating disease known as progressive multifocal leukoencephalopathy. The endocytic trafficking steps used by JCV to invade cells and initiate infection are not known. We demonstrated that JCV infection was inhibited by dominant defective and constitutively active Rab5-GTPase mutants that acted at distinct steps in endosomal sorting. We also found that labeled JCV colocalized with labeled cholera toxin B and with caveolin-1 (cav-1) on early endosomes following internalization by clathrin-dependent endocytosis. JCV entry and infection were both inhibited by dominant defective mutants of eps15 and Rab5-GTPase. Expression of a dominant-negative scaffolding mutant of cav-1 did not inhibit entry or infection by JCV. A single-cell knockdown experiment using cav-1 shRNA did not inhibit JCV entry but interfered with a downstream trafficking event important for infection. These data show that JCV enters cells by clathrin-dependent endocytosis, is transported immediately to early endosomes, and is then sorted to a caveolin-1-positive endosomal compartment. This latter step is dependent on Rab5-GTPase, cholesterol, caveolin-1, and pH. This is the first example of a ligand that enters cells by clathrin-dependent endocytosis and is then sorted from early endosomes to caveosomes, indicating that caveolae-derived vesicles play a more important role than previously realized in sorting cargo from early endosomes.