Since the identification of APOBEC3G (A3G) as a potent restriction factor of HIV-1, a tremendous amount of effort has led to a broadened understanding of both A3G and the APOBEC3 (A3) family to which it belongs. In spite of the fine-tuned viral counterattack to A3 activity, in the form of the HIV-1 Vif protein, enthusiasm for leveraging the Vif？:？A3G axis as a point of clinical intervention remains high. In an impressive explosion of information over the last decade, additional A3 family members have been identified as antiviral proteins, mechanistic details of the restrictive capacity of these proteins have been elucidated, structure-function studies have revealed important molecular details of the Vif？:？A3G interaction, and clinical cohorts have been scrutinized for correlations between A3 expression and function and viral pathogenesis. In the last year, novel and unexpected findings regarding the role of A3G in immunity have refocused efforts on exploring the potential of harnessing the natural power of this immune defense. These most recent reports allude to functions of the A3 proteins that extend beyond their well-characterized designation as restriction factors. The emerging story implicates the A3 family as not only defense proteins, but also as participants in the broader innate immune response. 1. Introduction In 2002, the cloning of APOBEC3G (A3G; then called CEM15) and the identification of the protein product of this gene as the first cellular protein capable of restricting HIV-1 infection revealed a novel direction for chemotherapeutic intervention and ignited the search for additional defense proteins capable of counteracting viral invasion [1]. The report of this cloning solved a long-standing enigma in the field of HIV-1 pathogenesis. Early work examining and comparing the pathogenesis of wild-type and Vif-deficient HIV-1 had yielded conflicting results with some laboratories concluding that Vif was dispensable for productive infection while other groups maintained that Vif expression was essential [2–4]. Ultimately, it was decisively shown that the requirement for Vif was cell-type dependent; permissive cells supported the growth of HIV-1Δvif while nonpermissive cells limited such viral replication [5, 6]. Most interesting and relevant was the inability of Vif-deficient HIV to productively infect primary CD4+ T cells, one of the critical natural targets of HIV-1 infection [2, 3, 5, 7, 8]. The molecular explanation for the “Vif phenotype” remained unexplained for the subsequent decade. Proffered in this early work was the idea that
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