Divergent interfaces and convergent outcome in the structural basis of HIV-2 Vif antagonism of APOBEC3H

Abstract Primate lentiviruses counteract antiviral APOBEC3 (A3) cytidine deaminases through virion infectivity factor (Vif), which recruits A3 proteins to a Cullin–RING E3 ubiquitin ligase for proteasomal degradation. While HIV-1 Vif is well characterized, HIV-2 Vif remains poorly defined due to divergent sequences. Here we report a 3.08 Å cryo-EM structure of HIV-2 Vif bound to chimpanzee A3H (cpzA3H) and E3 ligase components. HIV-2 Vif adopts a conserved global fold but engages cpzA3H through a binding interface distinct from HIV-1 Vif, achieving target recognition through numerous weak contacts distributed across an extended interface. The structure reveals a direct CBFβ–cpzA3H interface absent in HIV-1 Vif-A3H complexes, establishing CBFβ as a bivalent adaptor that actively contributes to substrate recruitment. Despite these structural differences, lysine 50 of cpzA3H is the shared ubiquitination target of both HIV-1- and HIV-2 Vif-induced degradation, revealing convergent function achieved through divergent structural solutions.