{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:38:12Z","timestamp":1792798692233,"version":"4.5.0"},"reference-count":73,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"40","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,10,3]]},"abstract":"<jats:p>The viral accessory protein Nef is a major determinant of HIV-1 pathogenicity in vivo. Nef is a multifunctional, immunomodulatory protein that downmodulates cell surface proteins, including CD4 and MHC class I (MHC-I), which are important for T cell\u2013mediated immunity. In addition, Nef also regulates cell-intrinsic immunity\u2014Nef boosts the infectivity of virions produced and released from HIV-infected cells, at least in part, by counteracting the antiviral activity of transmembrane proteins SERINC3 and SERINC5. Here, we show that Nef proteins derived from many primary isolates of HIV-1 restore infectivity in interferon-treated cells and confer resistance to the antiviral protein interferon-induced transmembrane protein 3 (IFITM3) in a SERINC3\/5-independent manner. Using Nef derived from primary HIV-1 clade C infection, we found that Nef interacts with IFITM3 in membranes, reduces IFITM3 incorporation into HIV-1 virions, and restores HIV-1 fusion with target cells. Our findings reveal a previously unrecognized immunomodulatory role for Nef in the setting of the interferon-induced antiviral state during HIV-1 infection.<\/jats:p>","DOI":"10.1126\/sciadv.adz7083","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T17:58:40Z","timestamp":1759341520000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["Restriction of HIV-1 infectivity by interferon and IFITM3 is counteracted by Nef"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1988-1629","authenticated-orcid":true,"given":"Mahesh","family":"Agarwal","sequence":"first","affiliation":[{"name":"Center for Cancer Research, National Cancer Institute, Frederick, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2694-6243","authenticated-orcid":true,"given":"Kin 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