{"doi":"10.1101/2022.01.14.476403","title":"ART duration and immunometabolic state determine efficacy of DC-based treatment restoring functional HIV- specific CD8+ T cells in PLWH","abstract":"ABSTRACT Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated in detail. Here, we studied the association of ART duration with memory subsets, exhaustion and metabolic profiles of CD8+ T cells from PLWH and improvement of polyfunctional and effector HIV-1 specific responses after stimulation with Gag-adjuvant-primed DC. HIV-1-specific CD8+ T cell responses from a larger proportion PLWH on ART for more than 10 years (LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro . In contrast, CD8+ T cells from PLWH on ART for less than a decade (ST-ARTp) were less responsive to DC treatment and functional improvement was limited in this group. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolytic induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+PD1-cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells. Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":302507,"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":0.9529,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":244375,"name":"Ildefonso Sánchez‐Cerrillo","orcid":"0000-0001-7262-1234","position":1,"is_corresponding":false},{"id":890824,"name":"Noa B. Martín‐Cófreces","orcid":"0000-0003-0439-8979","position":2,"is_corresponding":false},{"id":244387,"name":"Hortensia de la Fuente","orcid":"0000-0001-8708-753X","position":3,"is_corresponding":false},{"id":913440,"name":"Ilya Tsukalov","orcid":"0000-0002-2162-917X","position":4,"is_corresponding":false},{"id":474400,"name":"Cristina Delgado‐Arévalo","orcid":null,"position":5,"is_corresponding":false},{"id":244388,"name":"Marı́a J. Calzada","orcid":"0000-0001-8615-960X","position":6,"is_corresponding":false},{"id":244382,"name":"Ignacio de los Santos","orcid":"0000-0001-7073-5211","position":7,"is_corresponding":false},{"id":747139,"name":"Jesús Sanz","orcid":"0000-0001-8740-0063","position":8,"is_corresponding":false},{"id":747140,"name":"Lucio García‐Fraile","orcid":"0000-0002-2512-6107","position":9,"is_corresponding":false},{"id":244391,"name":"Francisco Sánchez‐Madrid","orcid":"0000-0001-5303-0762","position":10,"is_corresponding":false},{"id":244390,"name":"Arántzazu Alfranca","orcid":"0000-0002-3732-5816","position":11,"is_corresponding":false},{"id":441508,"name":"María Ángeles Muñoz‐Fernández","orcid":"0000-0002-0813-4500","position":12,"is_corresponding":false},{"id":263029,"name":"María J. Buzón","orcid":"0000-0003-4427-9413","position":13,"is_corresponding":false},{"id":244393,"name":"Enrique Martín‐Gayo","orcid":"0000-0002-2619-6086","position":14,"is_corresponding":false},{"id":747136,"name":"Marta Calvet‐Mirabent","orcid":"0000-0002-9134-0849","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T00:32:16.279991Z","pmid":null,"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":[]}