NFAT4 Is Required for JC Virus Infection of Glial Cells

Manley, Kate; O’Hara, Bethany A.; Gee, Gretchen V.; Simkevich, Carl P.; Sedivy, John M.; Atwood, Walter J.

doi:10.1128/jvi.01456-06

Cited by 39 publications

(52 citation statements)

References 39 publications

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“…In addition to the recent identification of Egr-1 as an important regulator as described above (98), other studies have implicated NFAT4 as being important for JCV infection of glial cells (69). In contrast, the transcription factor NF-1A was found to negatively regulate JCV (94).…”

Section: Recent Studies Of Primate Polyomavirusesmentioning

confidence: 82%

Regulation of Gene Expression in Primate Polyomaviruses

White

Safak

Khalili

2009

J Virol

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Polyomaviruses are a growing family of small DNA viruses with a narrow tropism for both the host species and the cell type in which they productively replicate. Species host range may be constrained by requirements for precise molecular interactions between the viral T antigen, host replication proteins, including DNA polymerase, and the viral origin of replication, which are required for viral DNA replication. Cell type specificity involves, at least in part, transcription factors that are necessary for viral gene expression and restricted in their tissue distribution. In the case of the human polyomaviruses, BK virus (BKV) replication occurs in the tubular epithelial cells of the kidney, causing nephropathy in kidney allograft recipients, while JC virus (JCV) replication occurs in the glial cells of the central nervous system, where it causes progressive multifocal leukoencephalopathy. Three new human polyomaviruses have recently been discovered: MCV was found in Merkel cell carcinoma samples, while Karolinska Institute Virus and Washington University Virus were isolated from the respiratory tract. We discuss control mechanisms for gene expression in primate polyomaviruses, including simian vacuolating virus 40, BKV, and JCV. These mechanisms include not only modulation of promoter activities by transcription factor binding but also enhancer rearrangements, restriction of DNA methylation, alternate early mRNA splicing, cis-acting elements in the late mRNA leader sequence, and the production of viral microRNA.Polyomaviruses comprise a family of small nonenveloped DNA tumor viruses which have small, circular, doublestranded DNA genomes, have been isolated from many species of mammals and birds, and are characterized by a very limited host range with respect to the species that they can productively infect (48). We will focus mainly on three primate viruses, simian vacuolating virus 40 (SV40), BK virus (BKV), and JC virus (JCV), not only because they have taught us important lessons about eukaryotic molecular biology but also because BKV and JCV cause important human diseases. SV40 was discovered almost 50 years ago (115) and was the first primate polyomavirus to be described. SV40 differs significantly from the previously discovered mouse polyoma virus (111) in that it does not possess a middle T antigen in the early region and it expresses an accessory regulatory protein, agnoprotein, which is encoded in the late region. The species of origin of SV40 is the rhesus macaque, and the virus was discovered as a contaminant in early batches of polio vaccine. While the polio vaccinations at that time likely infected many people, the prevalence of SV40 infections in humans today has been debated (36,122). In 1971, two bona fide human polyomaviruses were discovered. BKV, also known as polyomavirus BK, was first isolated by Gardner et al. (37) by culture in Vero cells from the urine of a patient receiving immunosuppressive therapy following kidney transplantation. BKV is widespread throughout the human population around...

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Section: Recent Studies Of Primate Polyomavirusesmentioning

confidence: 82%

Regulation of Gene Expression in Primate Polyomaviruses

White

Safak

Khalili

2009

J Virol

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“…The reactivation of BKV occurs under these conditions, resulting in the onset of the disease polyomavirus-associated nephropathy. Previous studies have demonstrated that NFAT contributes to the regulation of polyomaviruses, JC virus, and SV40 (34,35).…”

Section: Discussionmentioning

confidence: 99%

“…Previous research in our laboratory identified nuclear factor of activated T-cells (NFAT) as an important transcription factor in the regulation of both JCV and SV40 infection (34,35). The NFAT family of transcription factors is composed of five proteins, of which NFAT1 (NFATc2), NFAT 2 (NFATc1), NFAT 3 (NFATc4), and NFAT4 (NFATc3) are regulated by calcium (5,22,30,31).…”

Section: The Human Polyomavirus Bk Virus (Bkv) Is a Common Virus For mentioning

confidence: 99%

“…NFAT has been shown previously to regulate JCV and SV40 transcription (34,35). To determine whether NFAT mediates BKV transcription, Vero cells were cotransfected with either the early promoter (pluc2/ Dunlop E ) or the late promoter (pluc2/Dunlop L ) and a construct that expresses the NFAT inhibitor peptide sequence (pGFP-VIVIT) or a control construct expressing only GFP (phMGFP).…”

Section: Inhibition Of Nfat Reduces Bk Virus Infectionmentioning

confidence: 99%

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Transcriptional Regulation of BK Virus by Nuclear Factor of Activated T Cells

Jordan

Manley

Dugan

et al. 2010

J Virol

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The human polyomavirus BK virus (BKV) is a common virus for which 80 to 90% of the adult population is seropositive. BKV reactivation in immunosuppressed patients or renal transplant patients is the primary cause of polyomavirus-associated nephropathy (PVN). Using the Dunlop strain of BKV, we found that nuclear factor of activated T cells (NFAT) plays an important regulatory role in BKV infection. Luciferase reporter assays and chromatin immunoprecipitation assays demonstrated that NFAT4 bound to the viral promoter and regulated viral transcription and infection. The mutational analysis of the NFAT binding sites demonstrated complex functional interactions between NFAT, c-fos, c-jun, and the p65 subunit of NF-B that together influence promoter activity and viral growth. These data indicate that NFAT is required for BKV infection and is involved in a complex regulatory network that both positively and negatively influences promoter activity and viral infection.

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“…Pretreatment of cells with HD5 modestly neutralized infection, suggesting that HD5 also has potential indirect effects on the target cell promoting an antiviral response. Nuclear factor of activated T cells (NFAT) and NF-B are transcription factors that are known to coordinate immune responses and are vital for JCPyV infection (57)(58)(59). Alpha defensin genes have NFAT and NF-B binding sites, so the modest reduction in infection could be attributed to the beginning of a cellular response initiated by these factors due to exogenous HD5 addition.…”

Section: Discussionmentioning

confidence: 99%