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

ObjectiveSevere 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. Design and SettingWe 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). PatientsAdults (age [≥]18 years) hospitalized with severe febrile illness InterventionsNone Measurements and Main ResultsAcross both cohorts, severe HIV-associated TB was common, affecting 18% of participants in the discovery cohort and 21% in the validation cohort. Overall mortality was significant (30-day mortality of 22% in the discovery cohort & 60-day mortality of 26% in the validation cohort). 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. In both cohorts, PLWH with microbiologically diagnosed TB were at highest risk of critical illness and death (30-day mortality of 42% in the discovery cohort & 60-day mortality of 52% in the validation cohort). 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). ConclusionsWe 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. Key PointsO_ST_ABSQuestionC_ST_ABSWhat host-response patterns characterize severe HIV-associated tuberculosis among adults hospitalized with severe febrile illness in sub-Saharan Africa? FindingsIn two prospective cohorts of adults hospitalized with severe febrile illness in Uganda, severe HIV-associated tuberculosis accounted for 18-21% of cases and was associated with higher rates of physiological instability and mortality. An eight-protein host-response signature reproducibly distinguished this high-risk phenotype, reflecting immune activation, tissue injury, extracellular matrix remodeling, and dysregulated coagulation. MeaningSevere HIV-associated tuberculosis is associated with a distinct, high-risk clinical phenotype characterized by reproducible host-response patterns that may inform risk stratification and host-directed therapeutic strategies.