The human polyomavirus, JCV, is the etiologic agent of Progressive Multifocal Leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system (CNS) that usually affects immunosuppressed patients. JCV has an unusually narrow tissue tropism which restricts its productive replication to oligodendrocytes, a subclass of glial cells in the CNS which are responsible for production of the myelin sheath. Earlier studies by us and others have indicated that the cell type-specific tropism of JCV to glial cells is determined at the level of viral early gene transcription, which is responsible for the production of T-antigen. In collaboration with host regulatory proteins, T-antigen orchestrates subsequent events during the viral lytic cycle including viral DNA replication and late gene transcription and leads to the destruction of oligodendrocytes and demyelination of the brain. Histological analysis of PML brains has revealed that in addition to demyelination of white matter, a number of abnormalities are observed in both surviving oligodendrocytes and the other subclass of glial cells, astrocytes, suggesting dyregulation of pathways responsible for host cell homeostasis including control of the cell cycle and DNA repair. In support of this notion, results from immunohistochemical staining of clinical samples revealed the presence of double-strand breaks, indicative of dysfunctionality of DNA repair, an unusual expression of proteins which are in control of cellular proliferation, and apoptosis. Accordingly, results from in vitro cell culture infection revealed that the JCV early protein, T-antigen, and the viral non-structural protein, Agnoprotein, by dysregulating the level of expression and activities of factors involved in cell cycle control and DNA repair may affect a process that leads to the development of some of the pathological features that are seen in oligodendrocytes and astrocytes of PML. In this research project we aim to: (i) investigate the effect of JCV early protein on process involved in genomic stability at the early stage of viral infection by analyzing its interaction with IRS-1, p53, and Rad51, three critical proteins that, by communicating with T-antigen, can influence the process of homologous recombination;(ii) determine the molecular mechanisms by which the JCV late protein, Agnoprotein, through its association with p53 and Ku70 dysregulates non-homologous end joining during the course of infection. Such comprehensive studies of viral -host interaction at the molecular level should enable us to understand the molecular pathogenesis of JCV-CNS disorders and provide us with pivotal information for therapeutic intervention.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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Special Emphasis Panel (ZNS1)
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Temple University
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