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The cellular protein APOBEC3G disrupts HIV replication when incorporated into new virions (shown budding from a macrophage).
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Interferon (IFN)-
gives macrophages the upper hand against HIV, according to a study on page 41. Peng and colleagues show that the cytokine IFN- enhances the expression of the RNA-editing enzyme APOBEC3G, which mutates HIV DNA, thus triggering its degradation.
APOBEC3G is a close relative of the B cell–specific protein AID (activation-induced cytidine deaminase), which mutates immunoglobulin DNA to generate high affinity antibodies. APOBEC3G—which may have evolved as a regulator of endogenous retroviruses—recently emerged as an inhibitor of HIV replication in T cells, owing to its propensity to mutate retrotranscribed viral DNA. But HIV effectively counters this defense with the Vif protein, which binds to APOBEC3G and targets it for proteasomal degradation.
Boosting cellular levels of APOBEC3G might be an effective way to combat the destructive effects of Vif, but no APOBEC3G-inducing factors had been identified. Now, Peng and colleagues show that IFN—a known inhibitor of HIV replication—activates an IFN-responsive element in the APOBEC3G promoter in macrophages, thus driving APOBEC3G synthesis and overwhelming Vif's capacity to degrade the protein.
But endogenous IFN-, which is produced during viral infection, does not curtail HIV infection in vivo. This finding might be explained by the fact that T cells—the other major cell type targeted by HIV—do not appear to induce APOBEC3G expression in response to IFN-. Besides investigating why the signal doesn't get through to T cells (which express IFN receptors), the authors are now examining whether APOBEC3G expression or activity differs in myeloid cells that are resistant to HIV infection. Indeed, a recent study showed that the enzyme restricts HIV replication in resting T cells but becomes mired in an enzymatically inactive protein–RNA complex upon T cell activation, possibly explaining why HIV preferentially replicates in activated T cells.
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