UCSF

The retrovirus genus Lentivirus, which includes the human pandemic virus human immunodeficiency virus 1 (HIV-1), infect a wide range of mammals and are characterized by slow infections of host immune systems. HIV-1 encodes the accessory protein Vif, which hijacks a host Cullin-RING ubiquitin ligase (CRL) complex as well as the non-canonical cofactor CBFβ, to antagonize host APOBEC3 anti-viral proteins. To date, non-canonical cofactor recruitment to CRL complexes by viral factors has only been attributed to HIV-1 Vif. To further study this phenomenon, we employed a comparative approach combining proteomic, biochemical, structural, and virological techniques to investigate Vif complexes across representative clades within the Lentivirus genus, including primate (HIV-1, SIVmac) and non-primate (FIV, BIV, and MVV) viruses. We find that CBFβ is completely dispensable for the activity of non-primate lentiviral Vif proteins. Furthermore, we find that BIV Vif does not require any non-canonical cofactor MVV Vif requires a novel cofactor, Cyclophilin A (CYPA), for stable CRL complex formation and anti-APOBEC3 activity. Lastly, we present evidence testing the idea of novel Vif functions associated with non-canonical cofactor use. We propose a model of modular conservation of Vif complexes that allows for exaptation of novel functions through the acquisition of non-CRL associated host cofactors while preserving anti-APOBEC3 activity.