HIV-1 entry into host cells starts with interactions between the viral envelope glycoprotein (Env) and cellular CD4 receptors and coreceptors. Previous work has suggested that efficient HIV entry also depends on intracellular signaling, but this remains controversial. Here we report that formation of the pre-fusion Env-CD4-coreceptor complexes triggers non-apoptotic cell surface exposure of the membrane lipid phosphatidylserine (PS). HIV-1-induced PS redistribution depends on Ca²⁺ signaling triggered by Env-coreceptor interactions and involves the lipid scramblase TMEM16F. Externalized PS strongly promotes Env-mediated membrane fusion and HIV-1 infection. Blocking externalized PS or suppressing TMEM16F inhibited Env-mediated fusion. Exogenously added PS promoted fusion, with fusion dependence on PS being especially strong for cells with low surface density of coreceptors. These findings suggest that cell-surface PS acts as an important cofactor that promotes the fusogenic restructuring of pre-fusion complexes and likely focuses the infection on cells conducive to PS signaling.

HIV-1 进入宿主细胞始于病毒包膜糖蛋白 (Env) 与细胞 CD4 受体和辅助受体之间的相互作用。先前的研究表明，艾滋病毒的有效进入也取决于细胞内信号传导，但这仍然存在争议。在这里，我们报告融合前 Env-CD4-辅助受体复合物的形成触发膜脂磷脂酰丝氨酸 (PS) 的非凋亡细胞表面暴露。 HIV-1 诱导的 PS 重新分布取决于 Env-辅助受体相互作用触发的 Ca ²⁺信号传导，并涉及脂质扰乱酶 TMEM16F。外化的 PS 强烈促进 Env 介导的膜融合和 HIV-1 感染。阻断外化 PS 或抑制 TMEM16F 会抑制 Env 介导的融合。外源添加的 PS 促进融合，对于辅助受体表面密度较低的细胞，融合对 PS 的依赖性尤其强。这些发现表明，细胞表面 PS 作为重要的辅助因子，促进融合前复合物的融合重组，并可能将感染集中在有利于 PS 信号传导的细胞上。