Structural Adaptability in HIV-2 Vif Drives Broad Antagonism of APOBEC3G

APOBEC3G (A3G), a restriction factor, is a barrier for zoonosis and targeted for degradation by the lentiviral protein Vif. Human Immunodeficiency Virus Type 1 (HIV-1) and HIV-2 arose from transmissions of lentiviruses from Old World monkeys to hominid primates. While HIV-1 Vif needed to adapt to specific residues in the arms race interface with A3G, HIV-2 Vif has greater tolerance for diversity there. Here, our cryo-EM structure of HIV-2 Vif and human A3G allows us to explore the mechanism underlying HIV-2 Vif broad specificity. While HIV-2 Vif does bind the arms race interface on A3G, HIV-2 Vif encodes tryptophans with low backbone stability to engage another interface on A3G. We propose a model where flexible loops in HIV-2 Vif undergo conformational selection to recognize diverse A3Gs, whereas the equivalent loops in HIV-1 Vif are preorganized to bind hA3G.