Dissecting the Impact of HIV-Induced Immunometabolic Perturbation on Tuberculosis Control

About This Grant

SUMMARY HIV and Mycobacterium tuberculosis (Mtb) are among the world’s deadliest infections, and co-infection is particularly devastating because each pathogen accelerates the progression and severity of the other. Notably, for reasons that are not well understood, people living with HIV (PLWH) remain at elevated TB risk despite effective antiretroviral therapy (ART) and viral suppression. Our goal is to define how HIV-TB co-infection, even with virologic control, impairs Mtb immunity. Macrophages and CD4+ T cells are central to the pathogenesis of both diseases; Mtb infects lung macrophages and depends to CD4+ T cells to prevent disease progression, while HIV infects both macrophages and CD4+ T cells. Macrophages can harbor latent HIV proviruses, which persist despite treatment. Both pathogens reprogram macrophage metabolism, which is intimately linked to antimicrobial functions. However, the impact of co-infection on macrophage immunometabolism and Mtb control remains unclear. In addition, although antiretroviral treatment (ART) can restore CD4+ T cell counts to normal ranges, the T cells often remain dysfunctional and exhibit signs of exhaustion. We unite leading HIV and TB investigators and leverage unique cellular and animal models of HIV latency. We hypothesize that, despite ART and virologic suppression, PLWH experience macrophage immunometabolic reprogramming that enhances TB susceptibility and that ART-restored CD4+ T cells are dysfunctional and fail to enhance microbicidal properties of macrophages. Using dual-reporter human macrophage models and ex vivo studies of PLWH and controls, we will profile antimicrobial and immunometabolic responses of Mtb-infected macrophages, and we will test the contribution of exhausted CD4+ T cells to macrophage dysfunction. A long-standing obstacle to studying HIV- TB coinfection has been the absence of a small animal model. We will use a novel humanized mouse model that recapitulates human lung immune cell populations and HIV infection dynamics, including active viral replication, latency establishment, and viral suppression with ART. We will assess how untreated and treated HIV infection affects Mtb pathogenesis, assessing pathogen burden, immunometabolic responses, and cellular infection patterns, using spectral flow cytometry, scRNAseq and metabolic profiling. These studies will clarify the molecular basis of immune dysfunction during HIV-TB co-infection and inform on host-directed therapies to restore immune function and improve outcomes.