Retroviral restriction by APOBEC proteins

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Abstract
At least two human DNA-cytosine deaminases, APOBEC3F and APOBEC3G, are capable of inhibiting the infection of retroviruses such as HIV-1. This occurs by the high-frequency conversion of retroviral cDNA (minus strand) cytosines to uracils, lesions that, when replicated, result in lethal retroviral plus-strand G to A hypermutations. HIV-1 and many other vertebrate lentiviruses have a counterdefence protein known as Vif (virion infectivity factor), which is able to mediate the proteasomal destruction of these APOBEC3 proteins. HIV-1 Vif is not always effective, as retroviral plus-strand G to A hypermutations are commonly found in patient-derived samples. These observations indicate that the in vivo balance between HIV-1 Vif and the APOBEC3 proteins might be amenable to therapeutic intervention. At least nine other APOBEC3-related cytosine deaminases are encoded by the human genome, and only two of these have well-known functions. APOBEC1 edits C6666 in APOB mRNA, which results in a premature stop codon and a novel protein, whereas AID uses DNA-cytosine deamination to trigger three types of immunoglobulin-gene diversification — somatic hypermutation, gene conversion and class-switch recombination. Parallels between the innate APOBEC3-dependent restriction mechanism and the adaptive AID-dependent antibody response are striking and will probably contribute to future advances in this field. Many of the other APOBEC-family cytosine deaminases probably have as-yet-unappreciated physiological roles. They might target DNA and/or RNA substrates and have important innate immune functions. An examination of other vertebrate genomes shows that the APOBEC3 proteins are specific to mammals and have undergone a relatively recent evolutionary expansion (rodents have one, whereas humans and chimpanzees have eight APOBEC3 genes). We speculate that a protective role in reproduction might constitute a significant part of the selective pressure that drove this gene expansion.