HIV inhibits Warburg metabolism in human macrophages infected with Mycobacterium tuberculosis.
Tuberculosis (TB)-associated mortality remains disproportionately high among people living with HIV (PLWH), with macrophage dysfunction representing a key mechanism of impaired host defence against Mycobacterium tuberculosis (Mtb) infection. Using the U1 chronically HIV-infected macrophage cell line model coupled with primary human monocyte-derived macrophages (MDMs) exposed to HIV-1 gp120, we systematically characterized immunometabolic perturbations during Mtb infection. Nanostring RNA analysis revealed that Mtb monoinfection upregulated glycolytic genes while suppressing oxidative phosphorylation (OXPHOS) transcripts, consistent with a Warburg-type metabolic shift. Conversely, HIV infection downregulated glycolytic enzymes and enhanced mitochondrial respiratory chain components. Coinfection studies demonstrated HIV-mediated suppression of Mtb-induced glycolytic reprogramming. Extracellular flux analysis demonstrated that gp120 exposure increased basal oxygen consumption rate while impairing spare respiratory capacity in Mtb-infected MDMs, effectively blocking the Warburg metabolic transition. Notably, gp120 concentrations equivalent to those observed in antiretroviral therapy (ART)-treated PLWH significantly disrupted metabolic plasticity and high-dose gp120 attenuated Mtb-induced TNF- secretion. ImportanceThis study provides mechanistic insight into HIV-associated susceptibility to TB by demonstrating that HIV-1 infection fundamentally alters macrophage immunometabolic responses to Mtb. We establish that HIV-1, through gp120-mediated signaling, subverts the critical glycolytic induction required for effective antimicrobial responses against Mtb. The persistence of this metabolic dysregulation at clinically relevant gp120 concentrations, comparable to those observed in virologically suppressed PLWH, suggests ongoing immunological vulnerability despite ART. These findings identify HIV-induced metabolic reprogramming as a potential contributor to the persistently elevated TB risk in ART-treated individuals and highlight macrophage immunometabolism as a promising therapeutic target for host-directed therapies in HIV/TB coinfection. The dissociation between metabolic and cytokine responses suggests complex, multifactorial mechanisms underlying HIV-associated impairment of anti-mycobacterial immunity, warranting further investigation into the molecular pathways connecting cellular metabolism and immune effector functions.