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Persistent IFN-I signaling inhibits mitochondrial oxidative metabolism in CD8+ T cells during HIV-1 infection under cART

Cellular & Molecular Immunology (2026)Cite this article

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Abstract

Persistent type I interferon (IFN-I) signaling contributes to immune exhaustion and promotes HIV-1 persistence. While we and others have demonstrated that blocking IFN-I signaling in vivo restores anti-HIV-1 T-cell function and reduces viral reservoirs, the underlying mechanism remains unclear. Here, we showed that in humanized mice (hu-mice) and cells from people living with HIV-1 (PLWH), IFN-I signaling impaired mitochondrial activity in CD8+ T cells during chronic HIV-1 infection with effective antiretroviral therapy. Reprogramming immunometabolism by transient inhibition of glycolysis with 2-deoxy-D-glucose (2-DG) rescued mitochondrial activity, reversed aberrant immune activation, and enhanced CD8+ T-cell activity in HIV-infected hosts, both ex vivo and in vivo. When combined with an HIV-1 reservoir-activating agent, 2-DG reduced the viral reservoir size in hu-mice and suppressed HIV-1 amplification in cells from PLWH. These findings indicate that 2-DG-mediated immunometabolic reprogramming represents a novel strategy to restore host immunity and control HIV-1 reservoirs.

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Fig. 1: IFNAR blockade reduces HIV-1 reservoirs in a CD8+ T-cell-dependent manner.
Fig. 2: IFNAR blockade enhances mitochondrial oxidative phosphorylation in CD8+ T cells from HIV-1-infected hu-mice with cART.
Fig. 3: Persistent IFN-I directly impairs CD8+ T-cell function and mitochondrial metabolism.
Fig. 4: Reprogramming metabolism by 2-DG ex vivo enhances the function of CD8+ T cells.
Fig. 5: In vivo 2-DG treatment enhances mitochondrial membrane potential, improves T-cell recovery, and reduces HIV-1 reservoirs.
Fig. 6: 2-DG treatment enhances CD8+ T-cell functions and reduces HIV-1 replication from HIV-1 reservoirs in PBMCs from PLWH.

Data availability

All the data are available in the manuscript or supplementary materials. The RNA-seq data will be deposited according to the guidelines of the journal.

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Acknowledgements

We wish to thank Ourania Tsahouridis, Yaxu Wu and Weirong Yuan for their technical support. We also acknowledge the scientific cores at the following centers for their assistance: the Center for AIDS Research and Lineberger Comprehensive Cancer at the University of North Carolina at Chapel Hill; the Institute of Human Virology and the Greenbaum Comprehensive Cancer Center at the University of Maryland School of Medicine; and the core facilities of the Medical Research Institute at Wuhan University. We thank the Supercomputing Center of Wuhan University for supporting the bioinformatics analysis. We also thank Dr. Edward Pearce for discussions and critical reading of the manuscript. This work was supported by the National Key R&D Program 2024YFA1306500 (LC), the National Natural Science Foundation of China 82071784 (LC), the Natural Science Foundation of Wuhan 2024040701010031 (LC), the Fundamental Research Funds for the Central Universities 2042022dx0003 (LC), PTPP2023002 (LC), the National Institutes of Health grant AI136990 (LS), and the National Institutes of Health grant CA228172 (LS).

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Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Liang Cheng, Guangming Li, Wenwen Bi, Jianping Ma, Haisheng Yu, Nilu Goonetilleke & Lishan Su

  2. Department of Infectious Diseases, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, State Key Laboratory of Virology and Biosafety, Wuhan University, Wuhan, China

    Liang Cheng, Fei Luo, Mengmeng Lu, Na Liu, Qiuchen Zhao, Runpeng Han, Hongyu Wang, Hao Yang, Wenjia Hu & Yong Xiong

  3. Center for AIDS Research, Wuhan University, Wuhan, China

    Liang Cheng, Wenjia Hu & Yong Xiong

  4. Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA

    Guangming Li & Lishan Su

  5. State Key Laboratory of Virology and Biosafety, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China

    Wei Hou

  6. Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    R. Brad Jones

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  1. Liang Cheng
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Contributions

Conceptualization: LC, LS. Methodology: LC, LS, QZ, and RH. Investigation: GL, FL, WB, ML, NL, HW, HY, JM, WH, HYu, WHou, YX, NG, and RBJ. Visualization: LC, LS, FL, QZ, and RH. Funding acquisition: LC, LS. Project administration: LC, LS. Supervision: LC, LS. Writing – original draft: LC, LS. Writing – review & editing: LC, LS, RH

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Correspondence to Liang Cheng or Lishan Su.

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The authors declare that they have no competing interests. LS is an editorial board member of Cellular & Molecular Immunology, but he has not been involved in peer review or decision-making related to the article.

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Cheng, L., Li, G., Luo, F. et al. Persistent IFN-I signaling inhibits mitochondrial oxidative metabolism in CD8+ T cells during HIV-1 infection under cART. Cell Mol Immunol (2026). https://doi.org/10.1038/s41423-026-01398-8

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