The HIV-1-encoded accessory protein Vpu exerts several immunomodulatory functions, including counteraction of the host restriction factor tetherin, downmodulation of CD4, and inhibition of NF-κB activity to facilitate HIV-1 infection. However, the relative contribution of individual Vpu functions to HIV-1 infection in vivo remained unclear. Here, we used a humanized mouse model and HIV-1 strains with selective mutations in vpu to demonstrate that the anti-tetherin activity of Vpu is a prerequisite for efficient viral spread during the early phase of infection. Mathematical modeling and gain-of-function mutations in SIVcpz, the simian precursor of pandemic HIV-1, corroborate this finding. Blockage of interferon signaling combined with transcriptome analyses revealed that basal tetherin levels are sufficient to control viral replication. These results establish tetherin as a key effector of the intrinsic immune defense against HIV-1, and they demonstrate that Vpu-mediated tetherin antagonism is critical for efficient viral spread during the initial phase of HIV-1 replication.

HIV-1编码的辅助蛋白Vpu具有多种免疫调节功能，包括宿主限制因子tetherin的反作用，CD4的下调和对NF-κB活性的抑制，以促进HIV-1感染。但是，尚不清楚个体Vpu功能对体内HIV-1感染的相对贡献。在这里，我们使用了人性化的小鼠模型和在vpu中具有选择性突变的HIV-1毒株证明Vpu的抗Tetherin活性是在感染早期有效传播病毒的先决条件。大流行HIV-1的猿猴前体SIVcpz的数学建模和功能获得突变证实了这一发现。干扰素信号传导的阻断与转录组分析相结合，表明基础系氨酸水平足以控制病毒复制。这些结果确立了系链素是针对HIV-1的内在免疫防御的关键作用，并且它们表明Vpu介导的系链素拮抗作用对于在HIV-1复制的初始阶段有效传播病毒至关重要。