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Thus, immunogen design aims to mimic the closed Env conformation as preferred target for eliciting broadly neutralizing antibodies (bnAbs). Here we identify incompletely closed Env conformations of 6 out of 13 transmitted\/founder (T\/F) strains that are sensitive to antibodies that recognize internal epitopes typically exposed on open Envs. A 3.6\u2009\u00c5 cryo-electron microscopy structure of unliganded, incompletely closed T\/F Envs (1059-SOSIP) reveals protomer motion that increased sampling of states with incompletely closed trimer apex. We reconstruct de novo the post-transmission evolutionary pathway of a second T\/F. Evolved viruses exhibit increased Env resistance to cold, soluble CD4 and 19b, all of which correlate with closing of the adapted Env trimer. Lastly, we show that the ultra-broad N6 bnAb efficiently recognizes different Env conformations and exhibits improved antiviral breadth against VRC01-resistant Envs isolated during the first-in-humans antibody-mediated-prevention trial.<\/jats:p>","DOI":"10.1038\/s41467-024-51656-4","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T10:03:19Z","timestamp":1724666599000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Conformational flexibility of HIV-1 envelope glycoproteins modulates transmitted\/founder sensitivity to broadly neutralizing antibodies"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6105-1192","authenticated-orcid":false,"given":"Durgadevi","family":"Parthasarathy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karunakar Reddy","family":"Pothula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sneha","family":"Ratnapriya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor","family":"Cervera Benet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2630-2344","authenticated-orcid":false,"given":"Ruth","family":"Parsons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salam","family":"Sammour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Janowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9750-1615","authenticated-orcid":false,"given":"Joseph","family":"Sodroski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0089-277X","authenticated-orcid":false,"given":"Priyamvada","family":"Acharya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9323-4820","authenticated-orcid":false,"given":"Alon","family":"Herschhorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,26]]},"reference":[{"key":"51656_CR1","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1126\/science.2986290","volume":"228","author":"JS Allan","year":"1985","unstructured":"Allan, J. 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