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J. Virol. doi:10.1128/JVI.01456-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

NFAT4 is required for JCV infection of glial cells

Graduate Program in Molecular Biology, Cell Biology and Biochemistry, and Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA

^* To whom correspondence should be addressed. Email: Walter_Atwood{at}Brown.edu.

	Abstract

The human polyomavirus, 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 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, Cyclosporin 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, 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 signalling and the activation of NFAT in glial cells are required for JCV infection of the central nervous system (CNS).