Université de Strasbourg, CNRS, Architecture et Réactivité de l'ARN, UPR 9002, IBMC-15 rue René Descartes, F-67000, Strasbourg, France.
Université de Strasbourg, INSERM, UMR 1109, Laboratoire d'ImmunoRhumatologie Moléculaire, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Institut de Virologie, 3 rue Koeberlé, F-67000 Strasbourg, France.
Sci Rep. 2016 Dec 20;6:39507. doi: 10.1038/srep39507.
The essential HIV-1 viral infectivity factor (Vif) allows productive infection of non-permissive cells expressing cytidine deaminases APOBEC3G (A3G) and A3F by decreasing their cellular level, and preventing their incorporation into virions. Unlike the Vif-induced degradation of A3G, the functional role of the inhibition of A3G translation by Vif remained unclear. Here, we show that two stem-loop structures within the 5'-untranslated region of A3G mRNA are crucial for translation inhibition by Vif in cells, and most Vif alleles neutralize A3G translation efficiently. Interestingly, K26R mutation in Vif abolishes degradation of A3G by the proteasome but has no effect at the translational level, indicating these two pathways are independent. These two mechanisms, proteasomal degradation and translational inhibition, similarly contribute to decrease the cellular level of A3G by Vif and to prevent its incorporation into virions. Importantly, inhibition of A3G translation is sufficient to partially restore viral infectivity in the absence of proteosomal degradation. These findings demonstrate that HIV-1 has evolved redundant mechanisms to specifically inhibit the potent antiviral activity of A3G.
HIV-1 病毒必需的感染因子（Vif）通过降低细胞内 APOBEC3G（A3G）和 A3F 的水平，并阻止它们被包装到病毒颗粒中，从而允许非允许细胞进行有效的感染。与 Vif 诱导的 A3G 降解不同，Vif 抑制 A3G 翻译的功能作用仍不清楚。在这里，我们显示 A3G mRNA 5'-非翻译区中的两个茎环结构对于 Vif 在细胞中抑制翻译至关重要，并且大多数 Vif 等位基因有效地中和 A3G 翻译。有趣的是，Vif 中的 K26R 突变消除了 A3G 被蛋白酶体降解，但在翻译水平上没有影响，表明这两种途径是独立的。这两种机制，蛋白酶体降解和翻译抑制，同样有助于通过 Vif 降低 A3G 的细胞水平，并阻止其被包装到病毒颗粒中。重要的是，抑制 A3G 翻译足以在没有蛋白酶体降解的情况下部分恢复病毒感染性。这些发现表明，HIV-1 已经进化出冗余的机制来专门抑制 A3G 的强大抗病毒活性。
