The Activity Spectrum of Vif from Multiple HIV-1 Subtypes against APOBEC3G, APOBEC3F, and APOBEC3H
The Activity Spectrum of Vif from Multiple HIV-1 Subtypes against APOBEC3G, APOBEC3F, and APOBEC3H
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DOI：
10.1128/jvi.06082-11
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发表时间：
2012-01-01
影响因子：
5.4
通讯作者：
Simon, Viviana
中科院分区：
文献类型：
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作者：
Binka, Mawuena;Ooms, Marcel;Simon, Viviana
APOBEC 3家族包含7种胞苷脱氨酶（APOBEC 3A [A3 A]至A3 H），其在HIV-1易感细胞中以不同程度表达。HIV-1 Vif蛋白通过介导蛋白酶体降解APOBEC 3来抵消APOBEC 3限制。我们假设来自不同HIV-1亚型的Vif蛋白对抗不同APOBEC 3蛋白的能力不同。测试了来自7种HIV-1亚型的17个Vif等位基因降解和抵消A3 G、A3 F和A3 H单倍型II（hapII）的能力。我们发现，大多数Vif等位基因有效地中和A3 G和A3 F，但显示A3 H hapII抑制方面的差异。测试的大多数非亚型B Vif等位基因对A3 H hapII表现出一定的活性，其中两种亚型F Vif变体在抵消A3 H hapII方面非常有效。活性所需的残基被定位到Vif的氨基末端区域中的两个残基（位置39 F和48 H）。免疫共沉淀表明，这两个氨基酸是必要的协会的Vif与A3 H hapII。这些研究结果表明，A3 H hapII结合位点Vif是从A3 G和A3 F识别的重要区域不同，它需要在位置39和48的特定氨基酸。差异Vif活性谱，特别是针对A3 H hapII的活性谱，表明适应于代表不同人类祖先的APOBEC 3库。Vif变体对几种胞苷脱氨酶的抗APOBEC 3活性的表型评估将有助于揭示体内成功复制的要求，并最终指向靶向Vif-APOBEC 3界面的干预措施。
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.