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. 2026 Feb;177(2):413-431.
doi: 10.1111/imm.70054. Epub 2025 Oct 28.

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

Yee Teng Chan  1 , Kar Min Loh  1 , Zhi Ying Phong  1 , Ting Fang Tang  1 , Chun Howe Ng  1 , Alireza Saeidi  1 , Heng Choon Cheong  1 , Yi Ying Cheok  1 , Rong Xiang Ng  2   3 , Raja Iskandar Shah Raja Azwa  2   3 , Kian-Kai Cheng  4 , Chung Yeng Looi  5 , Adeeba Kamarulzaman  6 , Reena Rajasuriar  2   3 , Won Fen Wong  1
Affiliations

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

Yee Teng Chan et al. Immunology. 2026 Feb.

Abstract

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 TEMRA 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.

Keywords: CD8+ T cell; HIV; T cell exhaustion; metabolic pathways; mitochondria; people living with HIV (PLWH).

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