Proteomic Immune Signatures of Severe HIV-Associated Tuberculosis in Sub-Saharan Africa: A Prospective, Multicenter Analysis from Uganda.

Background: Severe tuberculosis (TB) is a major cause of critical illness and death in people living with HIV (PLWH) worldwide. Despite this, the immunopathology of severe HIV-associated TB (HIV/TB) is poorly understood. We aimed to identify an immunopathologic signature of severe HIV/TB in sub-Saharan Africa. Setting: We analyzed proteomic data from two prospective observational cohorts of adults hospitalized with severe undifferentiated infection in Uganda: an urban discovery cohort (Entebbe, N=241) and a rural validation cohort (Tororo, N=253). Methods: Soluble immune-related proteins were quantified in serum using Olink proteomics. Participants were stratified into three HIV/TB phenotypes: HIV-negative without TB, PLWH without TB, and PLWH with microbiologically diagnosed TB. We applied ordinal random forest models in the discovery cohort to identify proteins strongly predictive of progressive HIV/TB phenotype. The top 10 ranked proteins were then analyzed using multivariable linear regression models in both the discovery and validation cohorts to quantify their associations with HIV/TB phenotype. Results: In both cohorts, PLWH with microbiologically diagnosed TB were at highest risk of physiological instability and death. An eight-protein signature reliably distinguished this phenotype, reflecting mediators of macrophage/dendritic cell activation (LAMP3), NK-and T-cell stimulation and cytotoxicity (CD70, CRTAM), B-cell activation (IGLC2), protease-mediated tissue injury (PRSS2), dysregulated coagulation (SERPINA5), extracellular matrix remodeling (EFEMP1), and GH/IGF axis dysregulation (IGFBP3). Conclusions: We identified an immunologic signature of severe HIV-associated TB defined by mediators of macrophage/dendritic cell and cytotoxic lymphocyte activation, extracellular matrix remodeling, and dysregulated coagulation. These findings offer new insight into HIV/TB pathobiology and highlight potential targets for host-directed therapies in this high-risk population.