Abstract
People living with HIV (PLWH) have an increased risk for developing tuberculosis (TB) after infection with Mycobacterium tuberculosis (Mtb), despite anti-retroviral therapy (ART). To delineate the underlying mechanisms, we conducted single cell transcriptomics on bronchoalveolar lavage (BAL) cells from PLWH on ART and HIV uninfected healthy controls (HC) infected with Mtb ex vivo. We identified an M1-like proinflammatory alveolar macrophage (AM) subset that sequentially acquired TNF signaling capacity in HC but not in PLWH. Cell-cell communication analyses revealed robust interactions between M1-like AMs and effector memory T cells within TNF superfamily, chemokine, and costimulatory networks in the airways of HC. These interaction networks were lacking in PLWH infected with Mtb, where anti-inflammatory M2-like AMs and T regulatory cells dominated along with dysregulated T cell signatures. Our data support a model in which impaired TNF-TNFR signaling, and aberrant AM-T cell crosstalk, lead to ineffective immunity to Mtb in PLWH on ART.