HIV blocks macrophage energy switch linked to TB vulnerability

Tuberculosis (TB) remains a leading cause of death among people living with HIV (PLWH), and researchers are trying to understand why HIV undermines the body’s ability to fight Mycobacterium tuberculosis (Mtb). Gina Leisching and colleagues focused on macrophages, the immune cells that first take up Mtb and are crucial for controlling infection. Prior work has pointed to macrophage dysfunction as a key reason PLWH have worse TB outcomes, so the team set out to map how HIV changes macrophage metabolism during Mtb infection. To do this they used a chronically HIV-infected macrophage cell line model called U1, and primary human monocyte-derived macrophages (MDMs) treated with HIV-1 gp120, a viral protein that signals to host cells. The researchers systematically characterized immunometabolic changes during Mtb infection to see whether HIV shifts the cellular energy programs that underlie immune responses. Their goal was to link specific metabolic patterns to the macrophage’s ability to respond to Mtb, and to explore whether HIV-related signals persist in conditions similar to those found in people on antiretroviral therapy (ART).

The team combined molecular profiling and functional metabolic tests to compare responses to Mtb alone, HIV-related signals alone, and coinfection. Using Nanostring RNA analysis, they found that Mtb monoinfection upregulated glycolytic genes and repressed oxidative phosphorylation (OXPHOS) transcripts — a pattern consistent with a Warburg-type metabolic shift toward glycolysis. By contrast, HIV altered that program: HIV infection downregulated glycolytic enzymes and enhanced mitochondrial respiratory chain components. Coinfection experiments showed that HIV suppressed the glycolytic reprogramming normally induced by Mtb. Functional readouts using Extracellular flux analysis confirmed the effect: exposure to HIV-1 gp120 increased basal oxygen consumption rate but impaired spare respiratory capacity in Mtb-infected MDMs, effectively blocking the Warburg transition. Importantly, gp120 concentrations equivalent to those seen in ART-treated PLWH significantly disrupted metabolic plasticity, and high-dose gp120 reduced Mtb-induced TNF-α secretion. These results link specific transcriptional changes to altered cellular respiration in macrophages exposed to HIV signals.

The findings point to a clear mechanism by which HIV may weaken macrophage defenses against Mtb: by preventing the shift to glycolysis that normally supports antimicrobial activity. Because the effect was driven by gp120-mediated signaling and was observed at gp120 levels comparable to those in ART-treated PLWH, the study suggests a persistent immunological vulnerability even when viral replication is controlled. This metabolic reprogramming could help explain the persistently elevated TB risk among people on ART and highlights macrophage immunometabolism as a potential target for host-directed therapies in HIV/TB coinfection. The dissociation the authors observed between metabolic changes and cytokine responses — for example, altered metabolism without parallel cytokine patterns — underscores that the relationship between cellular metabolism and immune effector functions is complex. Further work will be needed to map the molecular pathways linking metabolic states to antimicrobial activity and to test whether correcting metabolic defects can restore macrophage control of Mtb.