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 (Universidad Autónoma de Madrid)
Sánchez-Cerrillo, Ildefonso (Universidad Autónoma de Madrid)
Martín-Cófreces, Noa (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Martínez-Fleta, Pedro (Hospital Universitario de la Princesa (Madrid))
de la Fuente, Hortensia (Hospital Universitario de la Princesa (Madrid))
Tsukalov, Ilya (Universidad Autónoma de Madrid)
Delgado-Arévalo, Cristina (Universidad Autónoma de Madrid)
Calzada, María José (Universidad Autónoma de Madrid)
de los Santos Gil, Ignacio (Hospital Universitario de la Princesa (Madrid))
Sanz, Jesús (Hospital Universitario de la Princesa (Madrid))
García-Fraile, Lucio (Hospital Universitario de la Princesa (Madrid))
Sánchez-Madrid, Francisco (Universidad Autónoma de Madrid)
Alfranca, Arantzazu (Hospital Universitario de la Princesa (Madrid))
Muñoz-Fernández, María Ángeles (Hospital General Universitario Gregorio Marañón)
Buzón, Maria José (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Martín-Gayo, Enrique (Hospital Universitario de la Princesa (Madrid))

Date:	2022
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. 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.
Grants:	Agencia Estatal de Investigación RTI2018-097485-A-I00
Rights:	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.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	HIV ; CD8 + T cell ; Dendritic cell ; Immunotherapy ; Immune exhaustion ; Metabolism
Published in:	EBioMedicine, Vol. 81 (june 2022) , ISSN 2352-3964

DOI: 10.1016/j.ebiom.2022.104090
PMID: 35665682

18 p, 1.5 MB

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