Identification of the HIV-1 Vif and Human APOBEC3G Protein Interface

• Three specific HIV Vif-A3G contact points were identified using functional assays
• Protein docking using Vif-A3G anchor points reveals the Vif-A3G interface
• The A3G binding site on Vif consists of a defined, positively charged pocket
• The negatively charged species-specific β4-α4 A3G loop fits within the Vif pocket

SummaryHuman cells express natural antiviral proteins, such as APOBEC3G (A3G), that potently restrict HIV replication. As a counter-defense, HIV encodes the accessory protein Vif, which binds A3G and mediates its proteasomal degradation. Our structural knowledge on how Vif and A3G interact is limited, because a co-structure is not available. We identified specific points of contact between Vif and A3G by using functional assays with full-length A3G, patient-derived Vif variants, and HIV forced evolution. These anchor points were used to model and validate the Vif-A3G interface. The resultant co-structure model shows that the negatively charged β4-α4 A3G loop, which contains primate-specific variation, is the core Vif binding site and forms extensive interactions with a positively charged pocket in HIV Vif. Our data present a functional map of this viral-host interface and open avenues for targeted approaches to block HIV replication by obstructing the Vif-A3G interaction.

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