Structural insights for HIV-1 therapeutic strategies targeting Vif

•APOBEC binding residues of Vif form contiguous surface regions.•Vif utilizes at least two different interfaces to target APOBEC3 family members.•A potential Vif oligomerization site is revealed in the crystal structure. HIV-1 viral infectivity factor (Vif) is a viral accessory protein that is required for HIV-1 infection due largely to its role in recruiting antiretroviral factors of the APOBEC3 (apolipoprotein B editing catalytic subunit-like 3) family to an E3 ubiquitin ligase complex for polyubiquitylation and proteasomal degradation. The crystal structure of the (near) full-length Vif protein in complex with Elongin (Elo)B/C, core-binding factor (CBF)β and Cullin (Cul)5 revealed that Vif has a novel structural fold. In our opinion the structural data revealed not only the protein–protein interaction sites that determine Vif stability and interaction with cellular proteins, but also motifs driving Vif homodimerization, which are essential in Vif functionality and HIV-1 infection. Vif-mediated protein–protein interactions are excellent targets for a new class of antiretroviral therapeutics to combat AIDS.