The cytidine deaminase APOBEC3G is a host protein that becomes packaged into HIV virions, where its enzymatic activity induces the degradation of HIV DNA. HIV counters this form of host defence through virion infectivity factor (Vif), which targets APOBEC3G for proteasomal degradation. However, in a report published in The Journal of Experimental Medicine, it has now been shown that interferon-α (IFNα) can increase the expression of APOBEC3G by macrophages to such an extent that the effects of Vif are overcome and HIV replication is markedly decreased.

IFNα can inhibit the infection of macrophages by HIV in many ways. So, because IFNα has been shown to induce the expression of an RNA-specific adenosine deaminase, Peng et al. set out to determine whether IFNα could limit HIV infection of macrophages by inducing the expression of cytidine deaminases that can target HIV DNA. Indeed, IFNα was found to increase the amount of APOBEC3G (both mRNA and protein) expressed by human primary monocyte-derived macrophages, and this increase correlated with a decrease in viral replication. IFNα was also shown to induce the expression of several other members of the APOBEC3 family: APOBEC3A and APOBEC3F. The promoters of the genes encoding these three APOBEC3 proteins were found to contain IFN-stimulated response elements (ISREs), indicating that IFNα regulates the amount of these APOBEC3 proteins that are expressed by macrophages by inducing transcription. Because APOBEC3F has similar anti-HIV activity to APOBEC3G, the induction of these two APOBEC3 proteins is likely to provide another mechanism by which IFNα inhibits the infection of macrophages by HIV. Consistent with this notion, knockdown of Apobec3G expression by small interfering RNA markedly reduced the ability of low doses of IFNα to inhibit the infection of macrophages by HIV, although at high doses of IFNα, inhibition of infection was still observed, probably because other IFNα-induced antiviral mechanisms were activated.

These data indicate that IFNα induction of APOBEC3G expression by macrophages tips the delicate balance between APOBEC3G and Vif in favour of APOBEC3G, and that this is one mechanism by which IFNα mediates its anti-HIV effects in macrophages. Because APOBEC3G has also recently been shown to inhibit the replication of hepatitis B virus, the authors suggest that IFNα-mediated induction of APOBEC3G expression by macrophages might be a widely used antiviral host-defence mechanism.