1. 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
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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, Enrique, Institut Català de la Salut, [Calvet-Mirabent M, Sánchez-Cerrillo I] Immunology Unit from Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa, Madrid, Spain. Universidad Autónoma de Madrid, Madrid, Spain. [Martín-Cófreces N] Immunology Unit from Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa, Madrid, Spain. Universidad Autónoma de Madrid, Madrid, Spain. Centro de Investigación Biomédica en Red Cardiovascular, CIBERCV, Madrid, Spain. [Martínez-Fleta P] Immunology Unit from Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa, Madrid, Spain. [de la Fuente H] Immunology Unit from Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa, Madrid, Spain. Centro de Investigación Biomédica en Red Cardiovascular, CIBERCV, Madrid, Spain. [Tsukalov I] Universidad Autónoma de Madrid, Madrid, Spain. [Buzón MJ] Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Ministerio de Ciencia y Competitividad (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Comunidad de Madrid (España), Gilead Sciences (Spain), Fundación La Caixa, Instituto de Salud Carlos III, and Ministerio de Ciencia e Innovación (España)
- Subjects
CD4-Positive T-Lymphocytes ,CD8 T cell + ,virosis::infecciones por virus ARN::infecciones por Retroviridae::infecciones por Lentivirus::infecciones por VIH [ENFERMEDADES] ,Medicina ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,HIV Infections ,CD8-Positive T-Lymphocytes ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,General Biochemistry, Genetics and Molecular Biology ,Humans ,Antiretrovirals - Ús terapèutic ,Virus Diseases::RNA Virus Infections::Retroviridae Infections::Lentivirus Infections::HIV Infections [DISEASES] ,sistemas sanguíneo e inmunológico::sistema inmunológico::células presentadoras de antígenos::sistemas sanguíneo e inmunológico::sistema inmunológico::células dendríticas [ANATOMÍA] ,Immune exhaustion ,HIV ,acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antiinfecciosos::antivíricos::antirretrovirales [COMPUESTOS QUÍMICOS Y DROGAS] ,Dendritic Cells ,General Medicine ,Hemic and Immune Systems::Immune System::Antigen-Presenting Cells::Hemic and Immune Systems::Immune System::Dendritic Cells [ANATOMY] ,Infeccions per VIH - Tractament ,Metabolism ,Anti-Retroviral Agents ,Cèl·lules dendrítiques ,HIV-1 ,Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents::Anti-Retroviral Agents [CHEMICALS AND DRUGS] ,Immunotherapy ,Dendritic cell - 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, NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants
- Published
- 2022
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