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Previous single-molecule F\u00f6rster resonance energy transfer (smFRET) studies demonstrated that Envs from clinical isolates predominantly adopt a \u201cclosed\u201d conformation (State 1), which is resistant to nnAbs. After interacting with the cellular receptor CD4, the conformational equilibrium of Env shifts toward States 2 and 3, exposing the coreceptor-binding site (CoRBS) and permitting targeting by CD4-induced (CD4i) antibodies. We showed that the binding of anti-CoRBS Abs enables the engagement of other nnAbs that target the cluster A epitopes on Env. Anti-cluster A nnAbs stabilize an asymmetric Env conformation, State 2A, and have potent ADCC activity. CRF01_AE strains were suggested to be intrinsically susceptible to ADCC mediated by nnAbs. This may be due to the presence of a histidine at position 375, known to shift Env toward more \u201copen\u201d conformations. In this work, through adaptation of an established smFRET imaging approach, we report that native, unliganded CRF01_AE HIV-1 Envs frequently sample the State 2A conformation. This is in striking contrast with Envs from clades A and B, for example HIV-1\n                      <jats:sub>JR-FL<\/jats:sub>\n                      , which do not transition to State 2A in the absence of ligands. These findings inform on the conformational dynamics of CRF01_AE Env, which are relevant for structure-based design of both synthetic inhibitors of receptor binding and enhancers of ADCC as therapeutic alternatives.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>A concerning increase in infections with HIV-1 from CRF01_AE has occurred globally and regionally in recent years, especially in Southeast Asia. Despite the advances made in understanding HIV-1 envelope glycoprotein (Env) conformational dynamics, the knowledge about Env from CRF01_AE HIV-1 is limited. Here, we demonstrate that the unliganded CRF01_AE Env readily samples an \u201copen\u201d conformation (State 2A), which is susceptible to antibody-dependent cellular cytotoxicity (ADCC). This is in contrast with the subtypes previously studied from HIV-1 group M that rely on anti-cluster A antibodies to adopt State 2A. These findings are relevant for the structure-based design of novel synthetic inhibitors of CD4 binding and enhancers of ADCC for the elimination of infected cells.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01667-25","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T14:00:11Z","timestamp":1765288811000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Conformational dynamics of the HIV-1 envelope glycoprotein from CRF01_AE is associated with susceptibility to antibody-dependent cellular cytotoxicity"],"prefix":"10.1128","volume":"100","author":[{"given":"Marco A.","family":"D\u00edaz-Salinas","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, University of Massachusetts Chan Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9966-3784","authenticated-orcid":false,"given":"Mehdi","family":"Benlarbi","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHUM","place":["Montr\u00e9al, Canada"]},{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al","place":["Montr\u00e9al, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debashree","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHUM","place":["Montr\u00e9al, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Nayrac","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHUM","place":["Montr\u00e9al, Canada"]},{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al","place":["Montr\u00e9al, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megane","family":"Robidas","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHUM","place":["Montr\u00e9al, Canada"]},{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al","place":["Montr\u00e9al, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suteeraporn","family":"Pinyakorn","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0145znz58","id-type":"ROR","asserted-by":"publisher"}],"name":"U.S. Military HIV Research Program, Walter Reed Army Institute of Research","place":["Silver Spring, USA"]},{"name":"Henry M. 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