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.
| Rom, Slava; Rom, Inna; Passiatore, Giovanni et al. (2010) CCL8/MCP-2 is a target for mir-146a in HIV-1-infected human microglial cells. FASEB J 24:2292-300 |
| Sariyer, Ilker K; Safak, Mahmut; Gordon, Jennifer et al. (2009) Generation and characterization of JCV permissive hybrid cell lines. J Virol Methods 159:122-6 |
| White, Martyn K; Johnson, Edward M; Khalili, Kamel (2009) Multiple roles for Puralpha in cellular and viral regulation. Cell Cycle 8:1-7 |
| Piña-Oviedo, Sergio; Khalili, Kamel; Del Valle, Luis (2009) Hypoxia inducible factor-1 alpha activation of the JCV promoter: role in the pathogenesis of progressive multifocal leukoencephalopathy. Acta Neuropathol 118:235-47 |
| Del Valle, Luis; White, Martyn K; Khalili, Kamel (2008) Potential mechanisms of the human polyomavirus JC in neural oncogenesis. J Neuropathol Exp Neurol 67:729-40 |
| Mukerjee, Ruma; Deshmane, Satish L; Fan, Shongshan et al. (2008) Involvement of the p53 and p73 transcription factors in neuroAIDS. Cell Cycle 7:2682-90 |
| Fischer-Smith, Tracy; Bell, Christie; Croul, Sidney et al. (2008) Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies. J Neurovirol 14:318-26 |
| Khalili, Kamel; Sariyer, Ilker Kudret; Safak, Mahmut (2008) Small tumor antigen of polyomaviruses: role in viral life cycle and cell transformation. J Cell Physiol 215:309-19 |
| Kaminski, Rafal; Darbinyan, Armine; Merabova, Nana et al. (2008) Protective role of Puralpha to cisplatin. Cancer Biol Ther 7:1926-35 |
| Perez-Liz, Georgina; Del Valle, Luis; Gentilella, Antonio et al. (2008) Detection of JC virus DNA fragments but not proteins in normal brain tissue. Ann Neurol 64:379-87 |
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