{"doi":"10.1128/jvi.01667-25","title":"Conformational dynamics of the HIV-1 envelope glycoprotein from CRF01_AE is associated with susceptibility to antibody-dependent cellular cytotoxicity","abstract":"ABSTRACT The HIV-1 envelope glycoprotein (Env) is expressed at the surface of infected cells and, as such, can be targeted by non-neutralizing antibodies (nnAbs) that mediate antibody-dependent cellular cytotoxicity (ADCC). Previous single-molecule Förster resonance energy transfer (smFRET) studies demonstrated that Envs from clinical isolates predominantly adopt a “closed” 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 “open” 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 JR-FL , 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. IMPORTANCE 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 “open” 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.","journal":"Journal of Virology","year":2025,"id":584686,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":241571,"name":"Mehdi Benlarbi","orcid":"0000-0001-9966-3784","position":1,"is_corresponding":false},{"id":846329,"name":"Debashree Chatterjee","orcid":"0000-0003-0276-9262","position":2,"is_corresponding":false},{"id":623260,"name":"Manon Nayrac","orcid":"0000-0001-5717-6232","position":3,"is_corresponding":false},{"id":1498221,"name":"Megane Robidas","orcid":null,"position":4,"is_corresponding":false},{"id":398187,"name":"Suteeraporn Pinyakorn","orcid":"0000-0003-3880-4381","position":5,"is_corresponding":false},{"id":399563,"name":"Nittaya Phanuphak","orcid":"0000-0002-0036-3165","position":6,"is_corresponding":false},{"id":347967,"name":"Carlo Sacdalan","orcid":"0000-0002-5839-4837","position":7,"is_corresponding":false},{"id":243836,"name":"Halima Medjahed","orcid":null,"position":8,"is_corresponding":false},{"id":241563,"name":"Jérémie Prévost","orcid":"0000-0002-5260-5154","position":9,"is_corresponding":false},{"id":369630,"name":"Lydie Trautmann","orcid":"0000-0002-3012-0009","position":10,"is_corresponding":false},{"id":335148,"name":"Marzena Pazgier","orcid":"0000-0003-0594-5057","position":11,"is_corresponding":false},{"id":241588,"name":"Andrés Finzi","orcid":"0000-0002-4992-5288","position":12,"is_corresponding":false},{"id":284591,"name":"James B. Munro","orcid":"0000-0001-7634-4633","position":13,"is_corresponding":false},{"id":850068,"name":"Marco A Díaz-Salinas","orcid":"0000-0003-2983-0123","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:59:16.166424Z","pmid":"41363844","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}