Exhausted <scp>CD8</scp> ⁺ T Cell in <scp>HIV</scp> Infection Exhibits an Impaired Bioenergetic Metabolism Driven by Mitochondrial Dysfunction

In people living with HIV (PLWH), persistent viral replication and antiretroviral therapy (ART)-associated toxicity contribute to T cell exhaustion, characterised by significant metabolic reprogramming that negatively impacts cellular function and longevity. Understanding the metabolic dysregulation in exhausted T cells could unveil novel therapeutic strategies to rejuvenate immune responses in PLWH. This study investigated the prevalence and metabolic gene expression profiles of exhausted CD8⁺ T cells across three PLWH cohorts: viremic treatment-naïve (TN), viremic treatment-failure (TF) and aviremic treatment-responders (TR). Our analysis revealed that the proportion of exhausted CD8⁺ T cells (PD1⁺CD107a^-) was markedly higher in viremic TN (5.1%) and TF (4.2%) groups compared to the aviremic TR cohort (2.2%, p < 0.05). Similarly, the percentage of terminally differentiated T_EMRA cells (CCR7^-CD45RA⁺) was elevated in TN (38.0%) and TF (44.7%) compared with TR (21.5%, p < 0.05), indicating a higher prevalence of late-stage differentiation and exhaustion in viremic individuals. NanoString analysis revealed a broad downregulation of metabolic genes in exhausted CD8⁺ T cells from viremic individuals, suggesting a shift toward a metabolically quiescent state akin to naïve T cells. Seahorse analysis revealed impaired mitochondrial respiration in CD8⁺ T cells from viremic PLWH, characterised by reductions in both ATP-linked respiration and proton leak. Furthermore, we reported that combined treatment with MitoTEMPO and N-acetyl-l-cysteine (NAC) improved mitochondrial function but failed to restore the effector capacity of CD8⁺ T cells. In summary, this study highlights the defective metabolic programming of exhausted CD8⁺ T cells in viremic PLWH, underscoring potential metabolic targets for therapeutic intervention.