REGULATION OF HIV-1 GENE EXPRESSION IN HUMAN T-CELLS AND MACROPHAGES

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We have continued studies on the regulation of HIV gene expression and the effects of HIV infection on cellular gene expression. We have focused our more recent efforts on defining the molecular mechanism by which herpes viruses transactivate the HIV gene regulatory regions in the LTR. DNA binding sites responsive to the ICPO HSV early protein have been identified and define a heirarchy of promoter and enhancer sites which include the NFKB, AP-2, SP-1 and TATA binding sites. HSV transactivation involves a generalized cellular activation cascade which can modify and activate multiple DNA-binding proteins thereby initiating HIV gene expression. We have also defined another cellular DNA-binding protein complex which appears to associate with specific DNA-binding proteins to stabilize transcriptionally active proviral chromosomal regions. This protein complex is interesting in that it is also an autoantigen in a number of autoimmune diseases such as systemic lupus erythematosis and scleroderma. We have continued studies on the role of HIV in activating cellular genes. In collaboration with Dr. Francis at the Dental Institute, we have found that HIV can activate nuclear DNA-binding proteins to initiate the production of a variety of cytokines including TNF and IL-1. We are currently studying the mechanism for this induction pathway, which appears to be related to the transactivation mechanisms used by the herpes early proteins.