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Antiretroviral therapy duration and immunometabolic state determine efficacy of ex vivo dendritic cell-based treatment restoring functional HIV-specific CD8+ T cells in people living with HIV Calvet-Mirabent, Marta Sánchez-Cerrillo, Ildefonso Martín-Cófreces, Noa Martínez-Fleta, Pedro de la Fuente, Hortensia Tsukalov, Ilya Delgado-Arévalo, Cristina Calzada, María José de los Santos Gil, Ignacio Sanz, Jesús García-Fraile, Lucio Sánchez-Madrid, Francisco Alfranca, Arantzazu Muñoz-Fernández, María Ángeles Buzón, Maria José Martín-Gayo, Enrique HIV CD8 + T cell Dendritic cell Immunotherapy Immune exhaustion Metabolism 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. We studied association of restoration of functional HIV-1-specific CD8 + T cell responses after stimulation with Gag-adjuvant-primed DC with ART duration, exhaustion, metabolic and memory cell subsets profiles. HIV-1-specific CD8 + T cell responses from a larger proportion of PLWH on long-term ART (more than 10 years; LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24 + infected CD4 + T cells in vitro. In contrast, functional improvement of CD8 + T cells from PLWH on short-term ART (less than a decade; ST-ARTp) after DC treatment was limited. This was associated with lower frequencies of central memory CD8 + T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolysis 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. NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants. 2022 Article https://ddd.uab.cat/record/292204 urn:10.1016/j.ebiom.2022.104090 urn:oai:ddd.uab.cat:292204 urn:pmcid:PMC9301875 urn:pmc-uid:9301875 urn:oai:pubmedcentral.nih.gov:9301875 urn:pmid:35665682 eng Agencia Estatal de Investigación RTI2018-097485-A-I00 EBioMedicine ; Vol. 81 (june 2022) open access Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades. https://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf