{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:22:42Z","timestamp":1790356962703,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,25]],"date-time":"2022-06-25T00:00:00Z","timestamp":1656115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GBM","award":["NIH R37 AI150453"],"award-info":[{"award-number":["NIH R37 AI150453"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>SERINC5 incorporates into HIV-1 particles and inhibits the ability of Env glycoprotein to mediate virus-cell fusion. SERINC5-resistance maps to Env, with primary isolates generally showing greater resistance than laboratory-adapted strains. Here, we examined a relationship between the inhibition of HIV-1 infectivity and the rate of Env inactivation using a panel of SERINC5-resistant and -sensitive HIV-1 Envs. SERINC5 incorporation into pseudoviruses resulted in a faster inactivation of sensitive compared to resistant Env strains. A correlation between fold reduction in infectivity and the rate of inactivation was also observed for multiple Env mutants known to stabilize and destabilize the closed Env structure. Unexpectedly, most mutations disfavoring the closed Env conformation rendered HIV-1 less sensitive to SERINC5. In contrast, functional inactivation of SERINC5-containing viruses was significantly accelerated in the presence of a CD4-mimetic compound, suggesting that CD4 binding sensitizes Env to SERINC5. Using a small molecule inhibitor that selectively targets the closed Env structure, we found that, surprisingly, SERINC5 increases the potency of this compound against a laboratory-adapted Env which prefers a partially open conformation, indicating that SERINC5 may stabilize the closed trimeric Env structure. Our results reveal a complex effect of SERINC5 on Env conformational dynamics that promotes Env inactivation and is likely responsible for the observed restriction phenotype.<\/jats:p>","DOI":"10.3390\/v14071388","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T22:50:23Z","timestamp":1656283823000},"page":"1388","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["SERINC5 Restricts HIV-1 Infectivity by Promoting Conformational Changes and Accelerating Functional Inactivation of Env"],"prefix":"10.3390","volume":"14","author":[{"given":"Junghwa","family":"Kirschman","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Marin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University, Atlanta, GA 30322, USA"},{"name":"Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Cheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University, Atlanta, GA 30322, USA"},{"name":"Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alon","family":"Herschhorn","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1712-8567","authenticated-orcid":false,"suffix":"III","given":"Amos B.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5385-3013","authenticated-orcid":false,"given":"Gregory B.","family":"Melikyan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University, Atlanta, GA 30322, USA"},{"name":"Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nature15399","article-title":"HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation","volume":"526","author":"Rosa","year":"2015","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/nature15400","article-title":"SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef","volume":"526","author":"Usami","year":"2015","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6014","DOI":"10.1074\/jbc.M117.777714","article-title":"SERINC5 protein inhibits HIV-1 fusion pore formation by promoting functional inactivation of envelope glycoproteins","volume":"292","author":"Sood","year":"2017","journal-title":"J. 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