The structural mechanism of HIV-2 Vif antagonism of human APOBEC3H.

Abstract

Human APOBEC3 (A3) proteins restrict retrovirus infection by inducing hypermutations in viral cDNA. To counteract this restriction, lentiviruses, such as HIV-1 and HIV-2 encode the viral infectivity factor (Vif), which hijacks a host Cullin-RING E3 ubiquitin ligase complex to target A3 proteins for proteasomal degradation. Here, we present the cryo-EM structure of HIV-2 Vif in complex with human A3H and CBFβ. The structure reveals that A3H forms a dimer mediated by dsRNA where each A3H monomer directly interacts with an HIV-2 Vif and the host protein CBFβ. Both HIV-2 Vif-A3H and CBFβ-A3H interfaces are critical for A3H degradation. Notably, however, the HIV-2 Vif-A3H interface is entirely distinct from the previously determined cryo-EM structure of the HIV-1 Vif and A3H complex. These findings suggest that HIV-1 and HIV-2 Vif, which are the result of distinct cross-species transmissions from species with different A3H characteristics, have followed separate evolutionary trajectories to counteract human A3H.