Progressive Multifocal Leukoencephalopathy (PML) is a subacute demyelinating disease of the human central nervous system (CNS). PML primarily afflicts individuals with defects in cell-mediated immunity and there is strong evidence suggesting that PML results from infection of glial-origin cells, i.e., oligodendrocytes and astrocytes with the human neurotropic virus, JCV. Evidently, these cells are destroyed or transformed during the course of this disease, resulting in demyelinating lesions in the brain. Previous observations by us and others have indicated that the neurotropism of JCV is determined primarily at the level of viral early and late gene transcription. Analysis of viral RNAs during the course of infection indicate differential activation of major viral early and late promoters during the course of infection. Since the early and late promoters are divergent and overlapping, it is of particular interest to determine the mechanism(s) responsible for the preferential use of the early and late promoters before and after DNA replication, respectively. since the transition from early to late occurs during/after DNA replication, when the viral early gene product, T-antigen, is present in the cells, we hypothesize that T-antigen, in concert with cellular factor(s), orchestrates differential expression of viral promoters. The central goal of this research proposal is to identify the mechanism(s) that mediates viral gene expression during the course of infection, and determines the regulatory components (cis- and trans- elements) that are participating in this process. The experimental design utilizes a variety of biochemistry, molecular virology and genetics techniques to identify the key regulatory component(s) that plays a critical role in the stimulation of viral RNA synthesis and viral DNA replication. The information obtained from these experiments should increase our current understanding of cell-type specific gene transcription in the CNS and should provide insight into the replication of viral and cellular DNA in the brain.
| 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 |
| 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 |
| 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 |
| 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 |
Showing the most recent 10 out of 34 publications
