The powerful anti-viral effects of the cytidine deaminase APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) can be counteracted by Vif (viral infectivity factor) — a protein encoded by HIV-1. The mechanisms by which Vif suppresses the host defence have remained poorly defined, but now three studies published in Molecular Cell and Nature Medicine have shown that Vif depletes cells of APOBEC3G, thereby preventing its anti-viral function.

Cells expressing endogenous APOBEC3G are 'non-permissive' for the production of fully infectious Vif-mutant virus, whereas cells deficient for APOBEC3G are 'permissive' for virus production. To elicit its anti-viral effect, APOBEC3G must be incorporated into Vif-mutant virion particles for transport to the virion's target cell. After entry into a new host cell, APOBEC3G deaminates cytidine residues in the viral DNA generated during reverse transcription, causing calamitous mutations to the viral DNA-replication intermediates.

In each of these new reports, APOBEC3G was found to be absent from virions that were generated in the presence of Vif and so its anti-viral potential was suppressed. Vif-mediated exclusion of APOBEC3G from virions was shown to occur independently of other viral proteins and to be associated with the depletion of APOBEC3G protein from the cell, although APOBEC3G messenger RNA levels were not reduced.

Pulse-chase radiolabelling studies carried out by all three groups showed that in the presence of Vif, the half-life of APOBEC3G was markedly reduced. This decrease in APOBEC3G protein levels was abrogated in the presence of proteasome inhibitors, indicating that Vif either targets APOBEC3G to the proteasome for degradation or enhances the natural turnover of the protein. In addition, using immunofluorescence, Marin et al. showed that APOBEC3G and Vif expression was restricted to separate cells in cultures co-transfected with APOBEC3G and Vif DNA, and that in the presence of protease inhibitors cells could express both proteins. These data provide further evidence to indicate that APOBEC3G is eliminated in a proteasome-dependent manner from cells co-expressing APOBEC3G and Vif.

Sheehy et al. and Marin et al. then showed that ubiquitylated APOBEC3G accumulates in the presence of Vif, implying that Vif enhances APOBEC3G turnover by inducing its ubiquitylation and thereby targeting it to the proteasome for degradation. By designing a series of Vif deletion mutants, Marin et al. determined that Vif contains two regions that are important for its effect on APOBEC3G, one of which has amino-acid sequence similarities with other molecules that target proteins for ubiquitylation and degradation, such as human suppressor of cytokine signalling 6 (SOCS6), and therefore this motif probably directs the ubiquitylation of APOBEC3G and its subsequent destruction. The other region of Vif that is crucial for APOBEC3G elimination was found to mediate the association of Vif with APOBEC3G.

Stopak et al. observed that levels of APOBEC3G were diminished in the presence of Vif even at the early time points of the pulse-chase radiolabelling studies, indicating that Vif might impair translation of APOBEC3G mRNA. They were able to confirm this in both in vitro translation assays and additional short-term radiolabelling studies, in which Vif had a dose-dependent inhibitory effect on APOBEC3G translation.

These studies have identified two mechanisms — inhibition of APOBEC3G mRNA translation and enhanced proteasomal degradation of APOBEC3G protein — by which the HIV-1 virulence factor Vif overcomes the anti-viral host defence provided by APOBEC3G. The combined effect of this bimodal action is that APOBEC3G protein is depleted from the host cell and therefore is absent from the virion particles generated. Further understanding of the molecular mechanisms by which Vif mediates these effects could lead to the generation of a new class of anti-viral drug that impedes Vif function.