Accessories to the crime: recent advances in HIV accessory protein biology

Abstract

Recent advances in understanding the roles of the lentiviral accessory proteins have provided fascinating insight into the molecular biology of the virus and uncovered previously unappreciated innate immune mechanisms by which the host defends itself. HIV-1 and other lentiviruses have developed accessory proteins that counterattack the antiviral defenses in a sort of evolutionary battle. The virus is remarkably adept at co-opting cellular degradative pathways to destroy the protective proteins. This review focuses on recent advances in understanding three of the accessory proteins-virion infectivity factor (Vif), viral protein R (Vpr), and viral protein U (Vpu)-that target different restriction factors to ensure virus replication. These proteins may provide promising targets for the development of novel classes of antiretroviral drugs.

Figure 1

Virion infectivity factor (Vif), viral protein R (Vpr), viral protein X (Vpx), and viral protein U (Vpu) counteract cellular restriction factors. Vif, Vpr, Vpx, and Vpu associate with E3 ubiquitin (Ub) ligases to induce the proteasomal degradation of restriction factors (the E3 Ub ligase for Vpu is not shown). Vpr and Vpx overcome a postentry block to reverse transcription by targeting a yet-unidentified restriction factor indicated by question marks. Vif induces the degradation of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) to prevent its packaging into the virion and the subsequent C→U deamination of the reverse transcribed viral DNA. Vpu antagonizes tetherin and calcium-modulating cyclophilin ligand (not shown), which hold the virus onto the cell surface. DCAF1— DDB1 cullin-associated factor 1; DDB1—damage DNA–specific binding protein 1; Elo—elongin; Env—envelope; LTR—long terminal repeat.