The anti-APOBEC3 activity of HIV-1 Vif proteins

APOBEC3 cytidine deaminases restrict HIV-1 replication by editing and non-editing mechanisms. The HIV-1 Virion Infectivity Factor (Vif) protein counteracts APOBEC3 action by preventing their incorporation into HIV-1 virus particles. The Vif-APOBEC3 interaction is of great interest because it may impact AIDS pathogenesis and could be a potential new drug target.;Previous studies have shown variation in the anti-APOBEC3G activity of naturally-occurring subtype B Vif proteins but little is known about non-B subtype Vifs. Because of the pronounced sequence diversity between HIV-1 subtypes, we hypothesized that Vif proteins of different subtypes vary in their anti-APOBEC3 activity. We assessed Vif proteins of six subtypes (A, B, C, D, F and G) and one circulating recombinant form (CRF01_AE) for their ability to degrade APOBEC3 enzymes as well as to rescue HIV-1 infectivity in the presence of these cytidine deaminases. We also assessed the molecular mechanisms underlying any differences we observed. We demonstrated that the Vif proteins of different subtypes have varying levels of activity against different APOBEC3 cytidine deaminases. We also identified the molecular determinants for HIV-1 Vif interaction with APOBEC3H haplotype II.;Our work highlights the importance of assessing 'Vif-APOBEC3' phenotypes since Vif proteins from different HIV-1 subtypes differ in their ability to counteract APOBEC3G, APOBEC3F and APOBEC3H haplotype II. Several Vif proteins were preferentially active against certain APOBEC3 cytidine deaminases. The differences in Vif activity observed in single cycle infection experiments are likely to be amplified in the context of spreading infections and in vivo. Variability in Vif function may have a significant impact on the transmission, replication and pathogenesis of HIV-1.