Structure of HIV-1 Vif and Interactions with APOBEC Proteins

Michelle Gomes, University of Southern California, Los Angeles
Mentor: Xiaojiang Chen
Basic Biomedical Sciences
Postdoctoral Fellowship Award

To establish an infection, viruses must overcome innate host defense mechanisms. The human immunodeficiency virus type-1 (HIV-1) encodes a protein called Viral infectivity factor (Vif), which neutralizes the anti-viral activity of the human APOBEC proteins, such as APOBEC3G (A3G) and APOBEC3F (A3F). In the absence of Vif, A3G and A3F are incorporated into the budding virions where they cause multiple mutations of the nascent viral DNA and prevent its replication. Vif overcomes this replication block by binding to the APOBEC proteins and targeting them for destruction by the cellular degradation machinery. Therefore, a novel approach to AIDS therapy would be to target the Vif-APOBEC interactions, while maintaining the anti-viral properties of the DNA mutating APOBEC proteins. Towards this end, we will use protein X-ray crystallography to determine the three-dimensional structure of Vif. Furthermore, using a series of biochemical assays including a deamination assay, DNA, RNA gel-shift assays and rotational anisotropy we will elucidate the effects of Vif binding on APOBEC’s anti-viral properties. Together our structural and biochemical studies will provide a detailed picture of the Vif-APOBEC interaction and will enable us to design inhibitors/drugs that will target this interaction, but protect the anti-viral properties of the APOBEC proteins. These studies will lay the groundwork for future AIDS therapeutics that will preserve the host innate immune defenses.