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<p>Persistent type&#xa0;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<sup>+</sup> 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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年4月2日

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  • Liang Cheng,
  • Guangming Li,
  • Fei Luo,
  • Wenwen Bi,
  • Mengmeng Lu,
  • Na Liu,
  • Qiuchen Zhao,
  • Runpeng Han,
  • Hongyu Wang,
  • Hao Yang,
  • Jianping Ma,
  • Wenjia Hu,
  • Haisheng Yu,
  • Wei Hou,
  • Yong Xiong,
  • Nilu Goonetilleke,
  • R. Brad Jones,
  • Lishan Su

摘要

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.