HIV-1 Vif global diversity and possible APOBEC-mediated response since 1980

HIV-1 Vif's principal function is to counter the antiretroviral activities of DNA-editing APOBEC3 cytidine deaminases. Unconstrained APOBEC3 activity introduces premature stop codons in HIV-1 genes and can lead to viral inactivation. To investigate the evolution and diversification of Vif over the HIV-1 pandemic and document evidence of APOBEC3-mediated pressure, we analyzed 4612 publicly available sequences derived from 10 dominant subtypes and circulating recombinant forms (CRFs) using the Hervé platform. We found widespread evidence of diversifying selection that was convergent across subtypes and CRFs, but remarkable stability in consensus sequences over time. Divergence and selection did not favor APOBEC3-interacting sites. We furthermore found that APOBEC3-induced substitutions in env and gag-pol genes increased over time and were positively associated with vif diversity. These results suggest that APOBEC3-driven adaptation in Vif is relatively rare and that permissiveness to human APOBEC3-induced substitution as a mechanism for generating diversity may be advantageous to HIV-1 evolution.