{"doi":"10.1172/jci.insight.189909","title":"CD8+ T cells cross-restricted by HLA-B*57 and HLA-E*01 recognize HIV Gag with different functional profiles","abstract":"Few HIV-specific epitopes restricted by non-classical HLA-E have been described, and even less is known about the functional profile of responding CD8+ T cells (CD8s). This study evaluates the functional characteristics of CD8s targeting the Gag epitope KF11 (KAFSPEVIPMF) restricted by either HLA-E (E-CD8s) or HLA-B57 (B57-CD8s). CD8s from 8 people with HIV (PWH) were cocultured with KF11 peptide presented by cell lines expressing HLA-B*57:01, HLA-E*01:01, or HLA-E*01:03. CD8 responses were analyzed using single-cell RNA and TCR sequencing. Supernatants were also assessed for soluble protein profiling. HLA-I multimers were developed to identify CD8s restricted by HLA-B57 and/or HLA-E ex vivo. B57-CD8s secreted higher levels of cytotoxic cytokines such as IFN-γ, whereas E-CD8s produced more chemotactic cytokines, including RANTES, CXCL10 (IP-10), and IL-27, findings that were corroborated through single-cell RNA sequencing. TCR clonotypes stimulated by KF11 were cross-restricted by HLA-B*57 and HLA-E*01:03 as demonstrated by in vitro T cell reporter assays and ex vivo multimer screening. Ex vivo CD8s were singly restricted by HLA-B57 and HLA-E, with dual restriction only observed in PWH with lower viral load. These findings demonstrate that certain HIV-specific CD8s in PWH exhibit dual restriction by HLA-B*57 and HLA-E*01:03, leading to functionally distinct immune responses depending on the restricting allele(s).","journal":"JCI Insight","year":2025,"id":537597,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9623,"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":1423394,"name":"Michael Rose","orcid":"0000-0002-7182-0474","position":1,"is_corresponding":false},{"id":999541,"name":"Allisa K. Oman","orcid":null,"position":2,"is_corresponding":false},{"id":499245,"name":"Abha Chopra","orcid":"0000-0001-5008-9080","position":3,"is_corresponding":false},{"id":1004707,"name":"Hua-Shiuan A. Hsieh","orcid":null,"position":4,"is_corresponding":false},{"id":1423819,"name":"Zerufael Derza","orcid":null,"position":5,"is_corresponding":false},{"id":1423820,"name":"Rachel Waterworth","orcid":null,"position":6,"is_corresponding":false},{"id":440232,"name":"Mark A. Brockman","orcid":"0000-0001-6432-1426","position":7,"is_corresponding":false},{"id":331744,"name":"Spyros A. Kalams","orcid":"0000-0003-0098-7995","position":8,"is_corresponding":false},{"id":385016,"name":"Anju Bansal","orcid":"0000-0002-8142-0386","position":9,"is_corresponding":false},{"id":240555,"name":"Paul Goepfert","orcid":"0000-0001-8441-5737","position":10,"is_corresponding":false},{"id":742064,"name":"Kevin J. Maroney","orcid":"0000-0002-6758-5256","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:52:12.997494Z","pmid":"41411059","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":[]}