The acquired immune deficiency syndrome (AIDS) is associated with a variety of clinical disorders involving the peripheral and central nervous system. Opportunistic infection of the central nervous systems and primary CNS lymphoma are often found in the later stages of the disease. In addition to inducing these secondary manifestations of immune suppression, HIV is thought to play a direct role in neuropathogenesis. The presence of HIV in brain appears to be associated with white matter changes, including vacuolar degeneration, enlarged astrocytes and demyelination. Quite similar histopathology is also observed in patients with progressive multifocal leukoencephalopathy (PML). While PML is a relatively infrequent disorder, latent infection with JCV appears to be fairly common. Virus reactivation and resulting neuropathology appears to be a consequence of immune suppression. The striking similarity between PML and AIDS leukoencephalopathy is suggestive of JCV reactivation as a consequence of HIV infection, either secondarily through the cell depletion, or directly by HIV encoded trans-acting factors. Since glial cells are productively infected by JCV and HIV, JCV reactivation through superinfections could be an in vivo mechanism of pathogenesis. Further support for this hypothesis stems from our observation which suggests that the HIV-1 encoded protein, tat, tranactivates expression of the JCV promoter in glial cells.
The aim of the research outlined in this proposal is to define the mechanisms by which the JCV genome is activated transcriptionally by HIV-1 encoded protein in glial cells. The experimental designs include: (1) identification of the cis-acting responsive elements to the tat protein; (2) characterization and purification of the trans-acting regulatory proteins from tat producing glial cells, that interact with the cis-acting sequences and trans-activates JCV promoter. The information gained from these manipulations and analyses should increase our understanding about molecular mechanisms involved in the development of AIDS dementia and other neurological disorders prevalent in AIDS patients.
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