The major thrust of this program project is to investigate the molecular biology of viral-glial gene interaction in the central nervous system (CNS), using a comprehensive and multi-disciplinary approach. Questions such as how viruses replicate in CNS-derived cells must be addressed through studies on the molecular biology of virus gene expression and replication and also in the context of how virus-encoded proteins may alter biological function of the infected cells. Therefore, the most pertinent information will be gathered by parallel studies of viruses with similar, but not identical neurohistopathology in brains from infected individuals. The clinical similarity between progressive multifocal leukoencephalopathy (PML) and AIDS encephalopathy, and the association of PML with HIV-1 infection underscores the rationale for simultaneous studies of the etiological agents of these diseases. We therefore propose to use two human viruses in our studies: (1) JCV, which causes the degenerative CNS demyelinating disease PML, in immunocompromised individuals and; (2) HIV-1, which is associated with a number of neurological disorders and encephalopathy, to investigate the molecular circuits that support viral replication in CNS-derived cells and result in a wide range of neurological disorders such as hypomyelination. The central goal of Project #1 is to understand the mode of JCV early and late gene regulation during the course of infection. Expression of the viral early protein, T-antigen, is critical for the transition from non-productive early phase to productive late phase. Moreover, previous studies using transgenic mice have demonstrated that the production of the JCV T-antigen in the CNS is associated with brain dysmyelination. Thus, experiments are proposed in Project #2 to examine the effect of T-antigen on expression of myelin- associated genes, such as myelin basic protein, proteolipid protein, and myelin-associated glycoprotein in a whole animal system. In Project #3 we propose to study transcriptional regulation of the HIV-1 LTR in glial cells, since our recent observations have indicated the involvement of a novel regulatory pathway in CNS cells that potentiates expression of the viral promotor. Finally, in Project #4, we propose experiments to identify the pattern of HIV-1 replication in astrocytic glial cells from brain of patients with AIDS and examine determinants of latency/productive infection by HIV-1. Together, the information gained from these studies will contribute to our understanding of the molecular pathways that are involved in regulation of viral gene transcription and replication in CNS-derived cells, viral-glial gene interaction, and represent an initial step in devising strategies to block viral replication in these cells.
Showing the most recent 10 out of 34 publications
