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. Macrophage metabolic switching has emerged as a paradigm of host success, yet the influence of HIV on this 'Warburg' response in the context of Mtb infection has not been studied. 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 transcriptomic and 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 OXPHOS. 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 attenuated Mtb-induced TNF-α secretion and impaired macrophage control of Mtb growth. This study reveals that HIV gp120 blocks the protective Warburg response to Mtb and highlights the potential of host-directed therapies that boost glycolysis or its downstream effectors (e.g. TNF-α) as adjunctive strategies in TB/HIV co-infection.