MB&B Seminar: Resolving the Molecular Arms Race Between Human APOBEC3G and HIV-1 Vif

We are interested in how viruses hijack the ubiquitin-proteasome pathway to suppress innate immunity. A paradigmatic example of this phenomenon is provided by the primate lentiviral Vif protein and its suppression of the antiviral gene APOBEC3G. In this seminar, I will outline our 20-year odyssey aimed at understanding the mechanism of the primate lentiviral Vif protein. This problem is important because APOBEC3G acts as a barrier for cross-species transmission of primate lentiviruses while adaptations in Vif gave rise to the birth of HIV-1 and the AIDS pandemic. We recently determined the cryoEM structure of HIV-1 Vif bound to APOBEC3G and discovered RNA is a cofactor for the interaction. We show that APOBEC3G binding to Vif is not restricted to the evolutionary dynamic interface predicted by genetic studies, but rather, also includes a conserved interface through RNA binding that helps position key residues necessary for viral antagonism of a host antiviral gene. The structural and functional studies suggest Vif binds APOBEC3G in its most dangerous form for the virus, when bound to genomic RNA en route to packaging. This work reveals that virus-host interaction interfaces may be far larger than what is gleaned from modeling genetic signatures of molecular arms races onto protein surfaces, an important consideration for drug-discovery.