Control and Prevention of HIV/AIDS, STDs & STIs

The human host is invaded by a wide range of microbial pathogens and has evolved a number of defensive mechanisms to survive these infections. In addition to adaptive immunity, it is becoming increasingly clear that innate immunity plays an important role in protecting host organisms from infections. One of the innate immune response mechanisms against viral infections involves a protein family, APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide 3). Th e APOBEC3 family of proteins can restrict replication of exogeneous retorviruses as well as Hepatitis B, a DNA virus that replicates through an RNA intermediate, and inhibit replication of retrotransposons. APOBEC3G (A3G) protein exhibits the most potent block to HIV-1 replication. To counteract host defense, HIV-1 expresses Vif protein that targets A3G for proteasomal degradation. Since HIV-1 Vif has no known cellular homologs, this protein represents an extremely attractive, yet unrealized, target for antiviral intervention. I will discuss the strategies to develop therapeutics that antagonize HIV-1 Vif function to inhibit HIV-1 replication. Further mechanistic investigation will be presented showing that Vif inhibitors’ function requires Vif-A3G interactions and restores A3G function. Th ese studies provide proof of principle that the HIV-1 Vif-A3G axis is a valid target for developing small molecule-based new therapies for AIDS or for enhancing innate immunity against viruses.