Apobec 3G is a cellular cytidine deaminase that potently antagonizes infection by primate lentiviruses including HIV-1 and SIV. The antiviral activity of Apobec 3G involves the induction of extensive G to A deamination of nascent viral cDNA, rendering it biologically inactive. To counteract the antiviral activity of Apobec proteins, lentiviruses have evolved the vif protein that ubiquitylates and targets apobec 3G for proteasomal degradation. Despite the potent antiviral activity of these cellular restrictions, they have yet to be exploited for therapeutic management of HIV-1 infection. We previously identified a lead compound (RN18) that inhibits viral replication only in the presence of the apobec 3G protein. Structure Activity Relationship (SAR) studies have identified potent RN18 analogs (IC50 <100 nm) that also exhibit antiviral activity only in the presence of apobec 3G. While resistance to the lead molecule, RN18 is governed by mutations in RT, resistance to RN18 analogs is governed by an amino acid substitution in a region of vif that mediates binding to the ubiquitylation apparatus. Mutations in RT were found to markedly increase viral fitness over wild-type viruses but only in the presence of apobec 3G. This suggests that Apobec 3G exhibits pressure on HIV-1 even in the presence of a fully competent vif protein. We further demonstrate that virions made in the presence of these agents are non- infectious. Therefore, vif antagonists may have utility in limiting the spread of virions from long-lived reservoirs in infected individuals on suppressive therapy. Preclinical studies indicate that these agents have very low toxicity in vivo. Studies to assess efficacy in the SIV/macaque model are underway.
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