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

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.