{"doi":"10.4049/jimmunol.2100367","title":"Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy","abstract":"Abstract In people with HIV (PWH) on antiretroviral therapy (ART), immune dysfunction persists, including elevated expression of immune checkpoint (IC) proteins on total and HIV-specific T cells. Reversing immune exhaustion is one strategy to enhance the elimination of HIV-infected cells that persist in PWH on ART. We aimed to evaluate whether blocking CTL-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), T cell Ig domain and mucin domain 3 (TIM-3), T cell Ig and ITIM domain (TIGIT) and lymphocyte activation gene-3 (LAG-3) alone or in combination would enhance HIV-specific CD4+ and CD8+ T cell function ex vivo. Intracellular cytokine staining was performed using human PBMCs from PWH on ART (n = 11) and expression of CD107a, IFN-γ, TNF-α, and IL-2 was quantified with HIV peptides and Abs to IC. We found the following: 1) IC blockade enhanced the induction of CD107a and IL-2 but not IFN-γ and TNF-α in response to Gag and Nef peptides; 2) the induction of CD107a and IL-2 was greatest with multiple combinations of two Abs; and 3) Abs to LAG-3, CTLA-4, and TIGIT in combinations showed synergistic induction of IL-2 in HIV-specific CD8+ and CD107a and IL-2 production in HIV-specific CD4+ and CD8+ T cells. These results demonstrate that the combination of Abs to LAG-3, CTLA-4, or TIGIT can increase the frequency of cells expressing CD107a and IL-2 that associated with cytotoxicity and survival of HIV-specific CD4+ and CD8+ T cells in PWH on ART. These combinations should be further explored for an HIV cure.","journal":"The Journal of Immunology","year":2021,"id":165983,"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":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9615,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":350100,"name":"Judy Chang","orcid":"0000-0001-5785-3643","position":1,"is_corresponding":false},{"id":352012,"name":"Ashanti Dantanarayana","orcid":null,"position":2,"is_corresponding":false},{"id":352011,"name":"Ajantha Solomon","orcid":null,"position":3,"is_corresponding":false},{"id":350101,"name":"Vanessa A. Evans","orcid":"0000-0001-9462-0662","position":4,"is_corresponding":false},{"id":350095,"name":"Rachel D. Pascoe","orcid":"0000-0001-7707-1972","position":5,"is_corresponding":false},{"id":690606,"name":"Céline Gubser","orcid":"0000-0002-3588-3814","position":6,"is_corresponding":false},{"id":691521,"name":"Lydie Trautman","orcid":null,"position":7,"is_corresponding":false},{"id":342350,"name":"Rémi Fromentin","orcid":"0000-0002-8153-1799","position":8,"is_corresponding":false},{"id":235294,"name":"Nicolas Chomont","orcid":"0000-0001-9747-5018","position":9,"is_corresponding":false},{"id":350099,"name":"James McMahon","orcid":"0000-0003-1460-5572","position":10,"is_corresponding":false},{"id":350105,"name":"Paul Cameron","orcid":"0000-0002-1906-6945","position":11,"is_corresponding":false},{"id":522125,"name":"Thomas A. Rasmussen","orcid":"0000-0001-5354-2442","position":12,"is_corresponding":false},{"id":299394,"name":"Sharon R. Lewin","orcid":"0000-0002-0330-8241","position":13,"is_corresponding":false},{"id":690605,"name":"Chris Chiu","orcid":"0000-0002-5380-1114","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-18T23:45:45.220559Z","pmid":"34853078","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":[]}