Explore Anti-HIV Activity of APOBECS for Novel AIDS Therapy

Xiaojiang Chen, University of Southern California, Los Angeles
Basic Biomedical Sciences
Innovative, Developmental, Exploratory Award (IDEA)

APOBEC3G (A3G), a human protein that has the capability of restricting HIV-1, is a promising candidate for future anti-HIV therapeutics. A3G is a powerful DNA mutating enzyme that can block the replication of HIV-1 under certain conditions. However, the HIV-1 encodes a viral infectivity factor (Vif) that overcomes the A3G-imposed replication block primarily by targeting A3G for degradation by the 26S proteosome. In the absence of Vif, A3G effectively inhibits HIV replication by inhibiting reverse transcription, disrupting provirus integration, and introducing multiple cytidine deaminations on the HIV-1 minus strand cDNA to inactivate the provirus. Therefore, blocking the protein-protein interaction of A3G and Vif may effectively restore the body¡¯s natural defenses against an HIV-1 infection. Recent new A3G structural advances from the Chen laboratory begin to offer the possibility for structure-based drug design to block A3G-Vif interaction. However, more high-resolution structures and biochemical information are necessary for an efficient rational drug design approach in developing new drugs for HIV/AIDS prevention and therapy. To facilitate progress in developing novel anti-HIV/AIDS drugs that will block A3G/Vif interactions and restore A3G anti-HIV activity, we plan to gain a detailed understanding of the structural basis for A3G functions, including interactions with viral RNA/cDNA, deaminase activity, and interactions with HIV-Vif. In addition, we plan to take advantage of our recent progress in solving the long-standing problem of obtaining large quantities of soluble pure reagents (full length A3G and HIV-Vif) by developing an in vitro assay system for screening inhibitors of A3G-Vif interactions. To achieve these goals, we are taking an innovative approach in combining the state of the art technology in X-ray protein crystallography with computational biology, molecular biology, biophysics, and functional biochemistry, an approach that has been successfully applied by this group of scientists to achieve the preliminary results described in the proposal as well as in recent publications.