The fundamental importance of HIV gene expression and replication in the progression of AIDS disease in infected subjects is well recognized - the rate of HIV replication directly determines the level of CD4+ T lymphocytes decrease and therefore the extent of immunodeficiency. The profound effects elicited by HIV protease inhibitors in viral inhibition and clinical improvements validate the therapeutic approaches based on the concept of inhibiting viral production. Because of the development of resistance to the available anti-HIV drugs due to mutations in the targeted viral proteins, however, continued viral production by chronically infected cells contributes to HIV-mediated immune dysfunction, and there is still no cure for AIDS. An AIDS epidemic demands rapid improvement of the existing anti-HIV drugs and calls for new therapeutic strategies that target different steps in the viral life cycle. Therapeutic intervention at the stage of HIV gene expression could complement the existing therapy by interfering with virus production. In this multidisciplinary Program Project Grant (PPG), we propose a multifaceted approach addressing the biology of HIV transcriptional activation to attain both mechanistic insight and the design of drugs targeting a specific protein. The emphasis is on the role of the Tat protein, an HIV-encoded transcriptional activator of the HIV promoter. To attain its goals, this PPG, constructed around three component Projects, proposes to simultaneously: (i) address the structure-activity basis of the activated, lysine-acetylated HIV Tat in its interaction with the nuclear transcriptional co-activator PCAF (human); (ii) validate this highly specific association as a potential therapeutic target for intervening HIV transcriptional activation and replication; and (iii) perform structure- based functional design of chemical inhibitors that can selectively block such an important interaction that is essential for viral production. The outcomes emerging from the proposed structure-based drug design paradigm in this PPG will have broad implications for drug discovery for the rational treatment and prevention of HIV AIDS, and will be generalizable as well as to structure-based design of therapies for other human.
