{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:25:01Z","timestamp":1785403501925,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,28]]},"group-title":"Microbiology","reference-count":107,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01 AI65381"],"award-info":[{"award-number":["R01 AI65381"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,28]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>Macropinocytosis is a large-scale, actin-driven, fluid-phase form of endocytosis that can be exploited by HIV-1 for entry into primary CD4+ T cells. Herein, we show that HIV-1 actively induces macropinocytosis in resting and activated primary CD4+ T cells. HIV-1-induced T cell macropinocytosis is triggered by the interaction of soluble gp120 Env with cell surface CD4, is clathrin-independent and actin-dependent, and does not require CXCR4 or any other known HIV-1 coreceptors. Notably, Env-induced macropinocytosis requires calcium-independent phospholipase A2 (iPLA2) activity, identifying a role for a lipid-signaling axis downstream of Env\u2013CD4 engagement. Across a gp120 panel, multiple HIV-1 clade B gp120 Envs can induce CD4+ T cell macropinocytosis. However, the magnitude of macropinocytosis does not correlate with CD4-binding strength alone and instead aligns with Env-driven changes in CD4 epitope exposure in CD4 domains distal to the Env-binding domain. Importantly, inhibitors of Env-induced macropinocytosis block HIV-1 infection of resting CD4+ T cells. Therefore, Env-induced macropinocytosis is a functionally important mechanism that promotes HIV-1 infection of this cell type.<\/jats:p>","DOI":"10.64898\/2026.04.27.721102","type":"posted-content","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T03:45:18Z","timestamp":1777434318000},"source":"Crossref","is-referenced-by-count":0,"title":["The gp120 Envelope Glycoprotein of HIV-1 Triggers Macropinocytosis in Primary CD4+ T Cells to Promote HIV-1 Infection"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2679-8626","authenticated-orcid":false,"given":"Praveen","family":"Manivannan","sequence":"first","affiliation":[{"name":"The Department of Microbiology and Immunology The University of Michigan Medical School Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Santos da Costa","sequence":"additional","affiliation":[{"name":"The Department of Microbiology and Immunology The University of 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