Department of Microbiology, Mount Sinai School of Medicine, New York, New York, USA.
J Virol. 2012 Jan;86(1):49-59. doi: 10.1128/JVI.06082-11. Epub 2011 Oct 19.
The APOBEC3 family comprises seven cytidine deaminases (APOBEC3A [A3A] to A3H), which are expressed to various degrees in HIV-1 susceptible cells. The HIV-1 Vif protein counteracts APOBEC3 restriction by mediating its degradation by the proteasome. We hypothesized that Vif proteins from various HIV-1 subtypes differ in their abilities to counteract different APOBEC3 proteins. Seventeen Vif alleles from seven HIV-1 subtypes were tested for their abilities to degrade and counteract A3G, A3F, and A3H haplotype II (hapII). We show that most Vif alleles neutralize A3G and A3F efficiently but display differences with respect to the inhibition of A3H hapII. The majority of non-subtype B Vif alleles tested presented some activity against A3H hapII, with two subtype F Vif variants being highly effective in counteracting A3H hapII. The residues required for activity were mapped to two residues in the amino-terminal region of Vif (positions 39F and 48H). Coimmunoprecipitations showed that these two amino acids were necessary for association of Vif with A3H hapII. These findings suggest that the A3H hapII binding site in Vif is distinct from the regions important for A3G and A3F recognition and that it requires specific amino acids at positions 39 and 48. The differential Vif activity spectra, especially against A3H hapII, suggest adaptation to APOBEC3 repertoires representative of different human ancestries. Phenotypic assessment of anti-APOBEC3 activity of Vif variants against several cytidine deaminases will help reveal the requirement for successful replication in vivo and ultimately point to interventions targeting the Vif-APOBEC3 interface.
APOBEC3 家族包含七种胞嘧啶脱氨酶（APOBEC3A [A3A] 至 A3H），它们在 HIV-1 易感细胞中以不同程度表达。HIV-1 的 Vif 蛋白通过介导其被蛋白酶体降解来拮抗 APOBEC3 的限制。我们假设来自不同 HIV-1 亚型的 Vif 蛋白在拮抗不同的 APOBEC3 蛋白方面的能力存在差异。我们测试了来自七种 HIV-1 亚型的 17 种 Vif 等位基因，以确定它们降解和拮抗 A3G、A3F 和 A3H 单倍型 II（hapII）的能力。我们表明，大多数 Vif 等位基因能够有效地中和 A3G 和 A3F，但在抑制 A3H hapII 方面存在差异。测试的大多数非 B 亚型 Vif 等位基因对 A3H hapII 具有一定的活性，两种 F 亚型 Vif 变体在拮抗 A3H hapII 方面非常有效。活性所需的残基被映射到 Vif 氨基末端区域的两个残基（位置 39F 和 48H）。共免疫沉淀表明，这两个氨基酸对于 Vif 与 A3H hapII 的结合是必需的。这些发现表明，Vif 中 A3H hapII 的结合位点与识别 A3G 和 A3F 重要的区域不同，并且它需要在位置 39 和 48 处具有特定的氨基酸。Vif 的不同活性谱，特别是针对 A3H hapII 的活性谱，表明它适应了不同人类祖源的 APOBEC3 库。对 Vif 变体针对几种胞嘧啶脱氨酶的抗 APOBEC3 活性的表型评估将有助于揭示体内成功复制的要求，并最终指向针对 Vif-APOBEC3 界面的干预措施。
