THE VIF-APOBEC NEXUS ABSTRACT: The discovery of the antiviral APOBEC3 (A3) enzymes is one of the most therapeutically promising breakthroughs in HIV/AIDS molecular virology because of the direct and potent nature of their virus restriction activities. Four different A3 enzymes have the ability to package into nascent HIV-1 particles and restrict the virus by physically interfering with the progression of reverse transcription and deaminating viral cDNA cytosines to uracils. A3 catalysis of C-to-U lesions in minus strand viral cDNA is the defining hallmark of A3-mediated restriction, explaining genomic plus strand G-to-A mutations in patient-derived viral sequences. However, the virus deploys a counteraction strategy that utilizes the virus encoded ?virion infectivity factor? (Vif) to polyubiquitinate and degrade the A3s through a cellular E3-ubiquitin ligase complex. Here, I will use robust and unbiased experimental approaches to 1) delineate the molecular surfaces used by Vif to recognize and degrade the restrictive A3s and 2) define the cellular mechanisms that regulate anti-HIV-1 activity of the A3s. My studies will utilize both hypothesis- and technology-driven approaches and a combination of fundamental virology, genetics/genome engineering, cell biology, and biochemistry techniques. I anticipate that a better understanding of the Vif/A3 surfaces and the underlying cellular mechanisms that govern A3 antiviral activity has the potential to lead to novel strategies to boost the anti-HIV-1 activities of these enzymes and contribute to the overall NIAID priority of ?supporting innovative strategies for treating or curing HIV infection.?