HIV-1 virion infectivity factor (Vif) promotes degradation of the antiviral APOBEC3 (A3) proteins through the host ubiquitin-proteasome pathway to enable viral immune evasion. Disrupting Vif-A3 interactions to reinstate the A3-catalyzed suppression of human immunodeficiency virus type 1 (HIV-1) replication is a potential approach for antiviral therapeutics. However, the molecular mechanisms by which Vif recognizes A3 proteins remain elusive. Here we report a cryo-EM structure of the Vif-targeted C-terminal domain of human A3F in complex with HIV-1 Vif and the cellular cofactor core-binding factor beta (CBFβ) at 3.9-Å resolution. The structure shows that Vif and CBFβ form a platform to recruit A3F, revealing a direct A3F-recruiting role of CBFβ beyond Vif stabilization, and captures multiple independent A3F-Vif interfaces. Together with our biochemical and cellular studies, our structural findings establish the molecular determinants that are critical for Vif-mediated neutralization of A3F and provide a comprehensive framework of how HIV-1 Vif hijacks the host protein degradation machinery to counteract viral restriction by A3F.

中文翻译：

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HIV-1 Vif拮抗人APOBEC3F的结构基础。

HIV-1病毒粒子感染因子（Vif）通过宿主泛素-蛋白酶体途径促进抗病毒APOBEC3（A3）蛋白的降解，从而实现病毒免疫逃避。破坏 Vif-A3 相互作用以恢复 A3 催化的人类免疫缺陷病毒 1 型 (HIV-1) 复制的抑制是抗病毒治疗的一种潜在方法。然而，Vif 识别 A3 蛋白的分子机制仍然难以捉摸。在这里，我们报告了人类 A3F 的 Vif 靶向 C 末端结构域与 HIV-1 Vif 和细胞辅因子核心结合因子β (CBFβ) 复合的低温 EM 结构，分辨率为 3.9-Å。该结构表明，Vif 和 CBFβ 形成了一个招募 A3F 的平台，揭示了 CBFβ 在 Vif 稳定之外的直接 A3F 招募作用，并捕获了多个独立的 A3F-Vif 界面。