The switch from HIV latency to active replication in CD4+ T cell, which results in the manifestation of AIDS, requires the function of the two viral regulatory gene products, tatIII and art. In addition, the HIV-LTR promoter has sequences specific for ubiquitous, and possibly T cell-specific, cellular factor. An understanding of tatIII and art mechanisms of action and the interaction between viral regulatory proteins and cellular factors is crucial to the design of effective therapeutic agents. AIDS patients are often afflicted with progressive degeneration of the central nervous system that mimics the low productive, persistent, in vitro infection of human glial cells. This type of infection appears to ne different from the T-cell infection. Design of effective inhibitors for the viral replication in neural cells requires knowledge of the viral pathogenesis and regulation of viral gene expression in these cells. Members of this consortium propose to: 1) study the mechanism of action of the tatIII gene product; 2) study the mechanism of action of the art gene product; 3) study regulatory elements in the HIV-LTR promoter that interact with ubiquitous and T cell-specific cellular factors and characterize the interaction of these factors with the tatIII gene product; 4) identify and purify cellular factors which might be required for tatIII or art activity 5) study the regulation of HIV expression and pathogenesis in neural cells; 6) determine the physical structure of the tatIII and the art proteins; 7) develop cell-free, in vitro assays for tatIII and art function; 8) develop a high-capacity, cell-free assay to identify antagonists of tatIII and art function; 9) carry out a rational drug design program; and, lO) compare antagonists of tatIII or art function in HIV-infected hematopoietic vs. neural cells. The Core Facility will serve this consortium by screening for tatIII/art inhibitors, providing team members with inhibitors and reagents, and developing for clinical evaluation in AIDS patients promising drug candidates.
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