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Here, we report that genetically anchoring the short-peptide fusion inhibitor 2P23 to the cell membrane can fully prevent infections from divergent HIV-1, HIV-2, and SIV isolates as well as a panel of enfuvirtide-resistant mutants. Membrane-bound 2P23 also effectively blocks HIV-1 Env-mediated cell-cell fusion and cell-associated virion-mediated cell-cell transmission, renders CD4<jats:sup>+<\/jats:sup>T cells nonpermissive to infection, and confers a robust survival advantage over unmodified cells. Thus, our studies verify a powerful strategy to generate resistant cells for gene therapy of both the HIV-1 and HIV-2 infections.<\/jats:p>","DOI":"10.1128\/jvi.01177-19","type":"journal-article","created":{"date-parts":[[2019,8,29]],"date-time":"2019-08-29T09:50:16Z","timestamp":1567072216000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["A Membrane-Anchored Short-Peptide Fusion Inhibitor Fully Protects Target Cells from Infections of Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus"],"prefix":"10.1128","volume":"93","author":[{"given":"Xiaoran","family":"Tang","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical 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