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This Article Full Text (Papers in Press[PDF]) All Versions of this Article: vir.0.011072-0v1 90/8/2005    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Stettner, M. R Articles by Johnson, E. M Search for Related Content PubMed PubMed Citation Articles by Stettner, M. R Articles by Johnson, E. M Agricola Articles by Stettner, M. R Articles by Johnson, E. M

SMAD Proteins of Oligodendroglial Cells Regulate Transcription of JC Viral Early and Late Genes Coordinately with the Tat Protein of Human Immunodeficiency Virus Type I

¹ Eastern Virginia Medical School;
² Mount Sinai School of Medicine;
³ Temple University School of Medicine

⁴ E-mail: johnsoem{at}evms.edu

SummaryJC virus (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the brain in AIDS. Although immunosuppression is involved in infection of the brain by JCV, a direct influence of human immunodeficiency virus type I (HIV-1) has also been established. The Tat protein of HIV-1 has been implicated in activation of the cytokine, TGF-β, in HIV-1-infected cells and in stimulating JCV gene transcription and DNA replication in oligodendroglia, the primary CNS cell type infected by JCV in PML. Here we demonstrate that Tat can cooperate with SMAD proteins, the intracellular effectors of TGF-β, at the JCV DNA control region (CR) to stimulate JCV gene transcription. Tat stimulates JCV early gene transcription in KG-1 oligodendroglial cells when either expressed via transfection or added exogenously. Using chromatin immunoprecipitation we show that exogenous Tat enhances binding of SMAD proteins 2, 3 and 4 and their binding partner Fast1 to the JCV CR in living cells. When SMADs 2, 3 and 4 are expressed together, Tat, expressed from plasmid pTat, stimulates transcription from both early and late gene promoters, the early promoter exhibiting stimulation of >100-fold. Tat, SMAD4 and polyoma JCV large T-antigen are all visualized in oligodendroglial cells at the border of an active PML lesion in the cerebral frontal lobe. These results reveal a positive reinforcement system in which the SMAD mediators of the TGF-β system act cooperatively with Tat to stimulate JCV gene transcription.

Received 17 February 2009; accepted 1 May 2009.