Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 6068507, Japan.
Institute of Industrial Sciences, The University of Tokyo, Tokyo 1538505, Japan; PRESTO, Japan Science and Technology Agency, Saitama 3320012, Japan.
Cell Host Microbe. 2018 Jan 10;23(1):110-120.e7. doi: 10.1016/j.chom.2017.12.009.
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 发挥了几种免疫调节功能，包括拮抗宿主限制因子 tetherin、下调 CD4 表达和抑制 NF-κB 活性，从而促进 HIV-1 感染。然而，个别 Vpu 功能对 HIV-1 在体内感染的相对贡献仍不清楚。在这里，我们使用了人源化小鼠模型和 Vpu 选择性突变的 HIV-1 株，证明了 Vpu 的抗 tetherin 活性是感染早期病毒有效传播的前提。SIVcpz（大流行性 HIV-1 的灵长类前体）中的数学建模和功能获得性突变证实了这一发现。干扰素信号阻断结合转录组分析表明，基础 tetherin 水平足以控制病毒复制。这些结果将 tetherin 确立为固有免疫防御 HIV-1 的关键效应因子，并表明 Vpu 介导的 tetherin 拮抗作用对于 HIV-1 复制的初始阶段病毒的有效传播至关重要。
