The investigator hypothesizes that HIV infection in the central nervous system (CNS) in AIDS patients results in astrogliosis and microglial nodule formation as the result of induction of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF alpha) and IL-6. The author suggests that binding of HIV to glial cells and triggering of brain disorders occurs through a molecule other than, or in addition to, CD4. Dr. Merrill proposes to study the interaction of HIV with both rat and human glial cells by examining binding, entry, infection (productive or latent, labile), and induction of morphological and functional changes in vitro. Induction of gliosis, microglial fusion, proliferation and cytokine production will be correlated with virus binding and either entry into glial cells or crosslinking of cell surface molecules in the absence of entry and reverse transcription. Cytokines induced by virus and responsible for morphological changes will be determined by specific bioassays, by Northern blot and by in situ hybridization analyses. If virus-induced changes correlate with specific cytokines, recombinant cytokines will be used to mimic these events and cytokine- specific antibodies will be used to inhibit the virus-induced changes. Since it is possible that HIV binding, induction of fusion, proliferation or cytokine response are governed by more than one viral epitope, the author will try to map the epitopes involved by blocking these events with a battery of monoclonal and polyclonal antibodies. The investigator proposes using hybrid constructs of high and low inducer recombinant virus isolates to map inductive epitopes.
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