Macropinosomes are a site of HIV-1 entry into primary CD4+T cells

Tomoyuki Murakami, Ricardo de Souza Cardoso, Praveen Manivannan, Ya-Ting Chang, Eric Rentchler, Kai-Neng Chou, Yipei Tang, Joel A Swanson, Philip D King, Akira Ono
2025 · doi:10.1101/2025.03.07.642068
preprint OA: closed CC-BY-NC-4.0
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Abstract

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. Significance statement HIV-1 entry is an important therapeutic target. However, the exact subcellular location of HIV-1 entry into primary CD4 + T cells, a major in vivo host for HIV-1, remains undetermined. The current study shows that macropinosomes serve as a site for productive HIV-1 entry into the cytoplasm of primary CD4+ T cells. Supporting the role for macropinosomes, inhibition of macropinocytosis prevents HIV-1 internalization into, fusion with, and infection of primary CD4 + T cells. By contrast, HIV-1 infection of a CD4 + T cell line commonly used in HIV-1 research is insensitive to macropinocytosis inhibition. Altogether, this study highlights the primary-T-cell-specific dependence of HIV-1 on macropinocytosis for productive entry and therefore suggests the macropinosome-mediated HIV-1 entry as a potential target for antiviral strategies.

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License: CC-BY-NC-4.0