Abstract

In 2024, over 40 million people were living with HIV (PWH), and 31.6 million were on antiviral therapy (ART). Emerging evidence shows that lung immune cells, especially alveolar macrophages (AMs), from ART-treated PWH exhibit impaired antimicrobial responses to Mycobacterium tuberculosis (Mtb), the bacterium that causes TB, which is the leading cause of death among PWH. Because AMs shape early immune defense, we hypothesize that HIV causes lasting impairment in lung macrophages that persists despite ART, impairing cellular metabolism and diminishing macrophage–T cell communication, which are critical to control Mtb. Using a humanized mouse model, we will define how HIV/ART alters early immune responses to Mtb by measuring viral and bacterial burdens in diverse lung cell populations, and lung pathology. These studies will illuminate mechanisms of HIV-driven susceptibility to TB and guide future host-directed therapeutic strategies.