Glycolysis inhibition in tuberculosis-driven metabolic rewiring reduces HIV-1 spread in macrophages

The study shows that tuberculosis-driven glycolysis in macrophages promotes tunneling nanotube formation, thereby enhancing HIV-1 spread, highlighting metabolism as a target to limit viral dissemination. Tuberculosis (TB) is a significant aggravating factor in individuals living with HIV-1, the causative agent for AIDS. Both Mycobacterium tuberculosis (Mtb), the bacterium responsible for TB, and HIV-1 target macrophages. Understanding how Mtb subverts these cells may facilitate the identification of new druggable targets. Here, we explored how TB can induce macrophages to form tunneling nanotubes (TNT), promoting HIV-1 spread. We found that TB triggers metabolic rewiring of macrophages, increasing their glycolytic ATP production. Using several pharmacological inhibitors, glucose deprivation, and glucose or galactose supplementation, we discovered that disrupting aerobic glycolysis significantly reduces HIV-1 infection in these macrophages. Glycolysis is essential for tunneling nanotubes formation, which facilitates viral transfer and cell-to-cell fusion. Importantly, HIF-1α activation contributes to these processes. Overall, these data might facilitate the development of targeted therapies aimed at inhibiting HIF-1α–dependent glycolytic activity in TB-induced immunomodulatory macrophages to ultimately halt HIV-1 dissemination in coinfected patients. Graphical Abstract lsa;9/5/e202503333/GA F1 GA