This is a competing continuation of a program project seeking support to further our investigation of the molecular biology and genetics of the interaction between viruses and host cells in the central nervous system. The major thrust of this program remains the study of the mechanism of two viral-induced diseases of the CNS: i) Progressive multifocal leukoencephalopathy (PML), which is caused by replication of the human neurotropic JCV in glial cells; and ii) the Acquired Immune Deficiency Syndrome (AIDS) associated dementia and encephalopathy which is induced by the presence of HIV-1 in brain. The clinical ties between PML and AIDS, the association of PML with HIV-1 infection, and the utilization of common regulatory pathways by these two viruses in the CNS underscores the rationale for the simultaneous investigation of the molecular biology of these two viruses and the mechanism of the diseases. During the first period of funding (1993 to 1999), we focused our attention on deciphering the molecular pathways involved in the control of viral gene expression in brain. In the second period of funding (1999 to 2004), our emphasis has been on the interaction of viral proteins with the host cell cycle and cross-communication between infected and uninfected CNS cells via cytokines and viral proteins. Through highly interactive and synergistic collaboration, the participants of this program have discovered several cellular proteins including Pur-alpha that modulate JCV and HIV-1 gene expression by associating with T-antigen and Tat, respectively; and uncovered several regulatory pathways that modulate HIV-1 gene expression in glial cells, such as TAR-independent pathway that enables Tat to augment expression of TAR-negative genes such as cytokines and JCV in CNS cells. In this current program, our emphasis on studying viral-host interaction rests on the impact of viral infection and viral proteins involved in the maintenance of host cells genomic stability, and the effect of factors involved in the control of gene integrity on regulation of viral gene expression and replication. This novel avenue of research was chosen based on the most current discoveries pointing to the cross-talk between viruses and DNA repair machinery that contributes to dysregulation of pathways involved in the integrity of the host genome and activation of viral gene expression and regulation. In Project #1 (K. Khalili et al.), we will investigate the effects of T-antigen and Agnoprotein of JCV which are produced at the early and late phases of infection, respectively, on homologous recombination and non-homologous end-joining. In Project #2 (S. Amini et al.), we will investigate the molecular interaction between HIV-1 Tat and RadSl, a key component of homologous recombination pathway, and their impact on HIV-1 gene transcription and replication via several cellular proteins including C/EBPbeta and NF- kappaB whose function is implicated in AIDS CNS disease. In Project #3 (J. Rappaport), we will investigate the physical and functional communication of the regulatory proteins of HIV-1 (Tat) and JCV (T-antigen and Agnoprotein) with Pur-alpha and their impact on DNA repair and genomic stability in CNS cells. These three highly integrated but independent projects will utilize a central Neuropathology and Tissue Culture Core which will provide a reliable source for distribution of clinical samples and preparation of primary and established cells from the CNS. This program project brings together basic scientists and physicians with expertise in neurovirology, molecular retrovirology, CNS cell biology, and pathology to perform the studies.
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