Murakami Tomoyuki, Cardoso Ricardo de Souza, Manivannan Praveen, Chang Ya-Ting, Rentchler Eric, Chou Kai-Neng, Tang Yipei, Swanson Joel A, King Philip D, Ono Akira
Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
Microscopy core, Biomedical Research Core Facilities, Office of Research, University of Michigan Medical School, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A. 2025 Jun 10;122(23):e2417676122. doi: 10.1073/pnas.2417676122. Epub 2025 Jun 4.
HIV-1 has been observed to enter target cells at both the plasma membrane and endosomes. However, which pathways mediate its entry into primary CD4 T cells, the major targets of this virus, remains unclear. Here, we show that HIV-1 can enter primary CD4 T cells through macropinocytosis, a form of endocytosis. We found that HIV-1 can enter primary CD4 T cells at both the plasma membrane and internal compartments, while entry into common T cell lines occurred primarily at the plasma membrane. Inhibition of macropinocytosis suppressed HIV-1 internalization into and subsequent fusion with primary CD4 T cells regardless of the viral coreceptor usage. Microscopic analysis of viral contents exposed to the cytosol confirmed that HIV-1 fusion occurs at the macropinosomal membrane. Finally, the inhibition of macropinocytosis blocked HIV-1 infection of primary CD4 T cells. Altogether, this study identifies macropinocytosis as one pathway for HIV-1 entry into primary CD4 T cells.
据观察，HIV-1可在质膜和内体处进入靶细胞。然而，介导其进入该病毒主要靶标——原代CD4 T细胞的是哪些途径，仍不清楚。在此，我们表明HIV-1可通过巨胞饮作用（一种内吞作用形式）进入原代CD4 T细胞。我们发现HIV-1可在质膜和内部区室进入原代CD4 T细胞，而进入常见T细胞系主要发生在质膜处。抑制巨胞饮作用可抑制HIV-1内化进入原代CD4 T细胞以及随后与原代CD4 T细胞的融合，而与病毒共受体的使用情况无关。对暴露于胞质溶胶的病毒内容物进行显微镜分析证实，HIV-1融合发生在巨胞饮体膜处。最后，抑制巨胞饮作用可阻断HIV-1对原代CD4 T细胞的感染。总之，本研究确定巨胞饮作用是HIV-1进入原代CD4 T细胞的一种途径。
