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
Author
Calvet-Mirabent, Marta; Sánchez-Cerrillo, Ildefonso; Martín-Cófreces, Noa; Martínez-Fleta, Pedro; de la Fuente, Hortensia; Tsukalov, Ilya; Delgado-Arevalo, Cristina; Calzada García, María Josefa; Santos Gil, Ignacio de los; Sanz Sanz, Jesús; García-Fraile, Lucio; Sánchez Madrid, Francisco; Alfranca González, Arantzazu; Muñoz Fernández, María Angeles; Buzón, Maria J.; Martín-Gayo, EnriquePublisher
ElsevierDate
2022-06-02Citation
10.1016/j.ebiom.2022.104090
eBioMedicine 81 (2022):104090
ISSN
2352-3964 (online)DOI
10.1016/j.ebiom.2022.104090Funded by
NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grantsProject
Gobierno de España. RTI2018-097485-A-I00Editor's Version
https://doi.org/10.1016/j.ebiom.2022.104090Subjects
CD8 T cell +; Dendritic cell; HIV; Immune exhaustion; Immunotherapy; Metabolism; MedicinaRights
© 2022 The AuthorsEsta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Background: 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. Methods: 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. Findings: 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. Interpretation: Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines. Funding: NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants
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Google Scholar:Calvet-Mirabent, Marta
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Sánchez-Cerrillo, Ildefonso
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Martín-Cófreces, Noa
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Martínez-Fleta, Pedro
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de la Fuente, Hortensia
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Tsukalov, Ilya
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Delgado-Arevalo, Cristina
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Calzada García, María Josefa
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Santos Gil, Ignacio de los
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Sanz Sanz, Jesús
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García-Fraile, Lucio
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Sánchez Madrid, Francisco
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Alfranca González, Arantzazu
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Muñoz Fernández, María Angeles
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Buzón, Maria J.
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Martín-Gayo, Enrique
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