Touro University Nevada College of Osteopathic Medicine, Henderson, NV, USA.
Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany.
Nat Commun. 2023 Aug 10;14(1):4588. doi: 10.1038/s41467-023-40227-8.
The mechanism of human immunodeficiency virus 1 (HIV-1) nuclear entry, required for productive infection, is not fully understood. Here, we report that in HeLa cells and activated CD4 T cells infected with HIV-1 pseudotyped with VSV-G and native Env protein, respectively, Rab7 late endosomes containing endocytosed HIV-1 promote the formation of nuclear envelope invaginations (NEIs) by a molecular mechanism involving the VOR complex, composed of the outer nuclear membrane protein VAP-A, hyperphosphorylated ORP3 and Rab7. Silencing VAP-A or ORP3 and drug-mediated impairment of Rab7 binding to ORP3-VAP-A inhibited the nuclear transfer of the HIV-1 components and productive infection. In HIV-1-resistant quiescent CD4 T cells, ORP3 was not hyperphosphorylated and neither VOR complex nor NEIs were formed. This new cellular pathway and its molecular players are potential therapeutic targets, perhaps shared by other viruses that require nuclear entry to complete their life cycle.
人类免疫缺陷病毒 1（HIV-1）的核进入机制是病毒感染所必需的，但尚未完全阐明。在这里，我们报告称，在分别感染了用 VSV-G 假型化的 HIV-1 以及天然 Env 蛋白的 HeLa 细胞和激活的 CD4 T 细胞中，含有内吞的 HIV-1 的 Rab7 晚期内涵体通过一种分子机制促进核膜内陷（NEIs）的形成，该机制涉及由核外膜蛋白 VAP-A、过度磷酸化的 ORP3 和 Rab7 组成的 VOR 复合物。沉默 VAP-A 或 ORP3 以及药物介导的 Rab7 与 ORP3-VAP-A 的结合抑制了 HIV-1 成分的核转移和有效的感染。在 HIV-1 抗性静止 CD4 T 细胞中，ORP3 没有过度磷酸化，也没有形成 VOR 复合物或 NEIs。这条新的细胞途径及其分子组成可能是其他需要核进入以完成生命周期的病毒的潜在治疗靶点。
