Abstract
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.
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Acknowledgements
Dr. John Browne, Professor Steven Gordon, and the University College Dublin NanoString laboratory staff. We acknowledge the key contributions of The Irish Blood Transfusion Services. The following reagent was obtained through BEI Resources, NIAID, NIH: Mycobacterium tuberculosis, Strain H37Rv, Gamma-Irradiated Whole Cells, NR-49098Bei Resources, NIAID, NIH.
Funding
This work was funded by the Royal Hospital of Dublin City Trust and the Health Research Board (EIA-2019-010, ILP-POR-2019-106). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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Brown, K., Walsh, A., Yennemadi, A.S. et al. HIV inhibits Warburg metabolism in human macrophages infected with Mycobacterium tuberculosis. Sci Rep (2026). https://doi.org/10.1038/s41598-026-50059-3
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DOI: https://doi.org/10.1038/s41598-026-50059-3
