{"doi":"10.1073/pnas.2517311122","title":"Exceptionally broad HIV-1 neutralization via bispecific antibody–mediated prepositioning","abstract":"Antibodies that recognize the conserved prehairpin intermediate (PHI) of class I viral membrane-fusion proteins typically show limited neutralization and have not been considered promising therapeutic agents. We previously developed a bispecific antibody (bsAb), iMab/D5_AR, directed toward both the gp41 N-heptad repeat (NHR) that is exposed within the HIV-1 PHI and toward CD4, the HIV-1 receptor on T cells. CD4-binding led to prepositioning of the bsAb at the site of viral fusion, enhancing its neutralization potency and achieving 95% breadth (IC80 < 5 μg/mL) against a panel of 119 pseudotyped, multiclade HIV-1 viruses. In the current study, we engineered a bsAb against NHR that also targets CCR5, one of two HIV-1 coreceptors on T cells. This optimized bsAb design further improves neutralization potency and achieves 100% neutralization breadth against the 119-member pseudotyped virus panel, including those resistant to CD4-binding iMab/D5_AR. Considering that nearly all initial HIV-1 infections occur via CCR5-tropic viruses, we expect our redesigned bsAb targeting CCR5 to be an effective prophylactic agent. These findings further support the rationale for pursuing the NHR as a therapeutic target for HIV-1 and lay the groundwork for a new class of engineered broadly neutralizing antibodies.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":528968,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"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":1392062,"name":"Katie A. Travisano","orcid":null,"position":1,"is_corresponding":false},{"id":1392063,"name":"B. J. Wilder","orcid":null,"position":2,"is_corresponding":false},{"id":1380123,"name":"Martina Palomares","orcid":null,"position":3,"is_corresponding":false},{"id":1407212,"name":"Zheng Cao","orcid":"0000-0002-1849-1720","position":4,"is_corresponding":false},{"id":16991,"name":"Michael S. Seaman","orcid":"0000-0001-6444-3562","position":5,"is_corresponding":false},{"id":226842,"name":"Peter S. Kim","orcid":"0000-0001-6503-4541","position":6,"is_corresponding":false},{"id":974961,"name":"Soohyun Kim","orcid":"0000-0002-5584-5073","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T02:50:52.565868Z","pmid":"41026814","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":[]}