PSGL-1 has recently been identified as an HIV restriction factor that inhibits HIV DNA synthesis and more potently, virion infectivity. But the underlying mechanisms of these inhibitions are unknown. Here we show that PSGL-1 directly binds to cellular actin filaments (F-actin) to restrict actin dynamics, which leads to inhibition of HIV DNA synthesis. PSGL-1 is incorporated into nascent virions and restricts actin dynamics in the virions, which partially accounts for the inhibition of virion infectivity. More potently, PSGL-1 inhibits incorporation of Env proteins into nascent virions, causing a loss of envelope spikes on the virions as shown by Cryo-electron microscopy and super-resolution imaging. This loss is associated with a profound defect in viral entry. Mechanistically, PSGL-1 binds gp41 and sequesters gp41 at the plasma membrane, explaining the inhibition of Env incorporation in nascent virions. PSGL-1’s dual anti-HIV mechanisms represent novel strategies of human cells to defend against HIV infection.

PSGL-1 最近被确定为一种 HIV 限制因子，可抑制 HIV DNA 合成，更有效地抑制病毒体传染性。但这些抑制的潜在机制尚不清楚。在这里，我们表明 PSGL-1 直接与细胞肌动蛋白丝（F-肌动蛋白）结合以限制肌动蛋白动力学，从而抑制 HIV DNA 合成。PSGL-1 被纳入新生病毒粒子并限制病毒粒子中的肌动蛋白动力学，这部分解释了病毒粒子传染性的抑制。更有效的是，PSGL-1 抑制 Env 蛋白掺入新生病毒粒子，导致病毒粒子上的包膜尖峰丢失，如冷冻电子显微镜和超分辨率成像所示。这种损失与病毒进入的严重缺陷有关。从机制上讲，PSGL-1 结合 gp41 并在质膜上隔离 gp41，解释了对新生病毒体中 Env 掺入的抑制。PSGL-1 的双重抗 HIV 机制代表了人类细胞抵御 HIV 感染的新策略。