The discovery of the anti-viral APOBECS proteins is one of the most therapeufically promising breakthroughs in HIV/AIDS molecular virology in recent years. Humans have seven APOBECS proteins and at least two, APOBECSG and APOBECSF, are capable of inhibifing the replication of Vif-deficient HIV. However, HIV pathogenesis is due at least in part to the fact that the viral Vif protein counteracts these APOBECS proteins and triggers their degradation. The molecular approaches described in this proposal are an integral part of a larger program project to provide comprehensive knowledge of the structural, biophysical, biochemical and molecular features of these APOBECS proteins and their relation to HIV-1. First, we will test the hypothesis that APOBECSG dimerizafion occurs through multiple direct protein-protein interacfions, and we will determine the relevance of these interacfions to HIV restricfion. Second, we will disfinguish between two models for how APOBECSG binds single-strand DNA substrates analogous to HIV cDNA. Third, we will test the hypothesis that HIV Vif recognizes a common structural motif that is present in APOBECSF, APOBECSG, and other APOBECS proteins. We will use structural informafion from our program collaborafions to guide the construcfion of APOBECS and Vif mutants. These studies will be aided in part by a panel of novel APOBECSG inhibitory small molecules that will be used as molecular probes to dissect these crifical steps of the AP0BEC3G/F-mediated HIV-1 restriction mechanism. These studies will advance our fundamental understanding of APOBECSG and APOBECSF and facilitate the development of novel HIV/AIDS therapeufics that work by modulating the APOBECS-Vif pathway.
A therapeutically relevant host-pathogen conflict occurs between APOBECSF/APOBECSG and HIV-1 Vif. An intimate understanding of these APOBECS proteins and HIV-1 Vif is critical for ultimately designing and testing anti-retroviral drugs that work through this pathway.
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