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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.
- Source :
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EBioMedicine [EBioMedicine] 2022 Jul; Vol. 81, pp. 104090. Date of Electronic Publication: 2022 Jun 02. - Publication Year :
- 2022
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Abstract
- Background: Dysfunction of CD8 <superscript>+</superscript> 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 <superscript>+</superscript> T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8 <superscript>+</superscript> T cells after DC treatment have not been investigated.<br />Methods: We studied association of restoration of functional HIV-1-specific CD8 <superscript>+</superscript> T cell responses after stimulation with Gag-adjuvant-primed DC with ART duration, exhaustion, metabolic and memory cell subsets profiles.<br />Findings: HIV-1-specific CD8 <superscript>+</superscript> 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 <superscript>+</superscript> infected CD4 <superscript>+</superscript> T cells in vitro. In contrast, functional improvement of CD8 <superscript>+</superscript> 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 <superscript>+</superscript> T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolysis induction upon TCR activation. In contrast, CD8 <superscript>+</superscript> T cells from LT-ARTp showed increased frequencies of TIM3 <superscript>+</superscript> PD1 <superscript>-</superscript> cells and preserved induction of glycolysis. Treatment of dysfunctional CD8 <superscript>+</superscript> 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 <superscript>+</superscript> T cells.<br />Interpretation: Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines.<br />Funding: NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants.<br />Competing Interests: Declaration of interests The authors have declared that no conflict of interest exists.<br /> (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 2352-3964
- Volume :
- 81
- Database :
- MEDLINE
- Journal :
- EBioMedicine
- Publication Type :
- Academic Journal
- Accession number :
- 35665682
- Full Text :
- https://doi.org/10.1016/j.ebiom.2022.104090