{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T04:02:44Z","timestamp":1770350564206,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,2]]},"group-title":"HIV\/AIDS","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T00:00:00Z","timestamp":1767312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design and Setting<\/jats:title>\n                  <jats:p>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).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Patients<\/jats:title>\n                  <jats:p>Adults (age \u226518 years) hospitalized with severe febrile illness<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interventions<\/jats:title>\n                  <jats:p>None<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Measurements and Main Results<\/jats:title>\n                  <jats:p>Across 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 &amp; 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 &amp; 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).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Question<\/jats:title>\n                    <jats:p>What host-response patterns characterize severe HIV-associated tuberculosis among adults hospitalized with severe febrile illness in sub-Saharan Africa?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>In 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Meaning<\/jats:title>\n                    <jats:p>Severe 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.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.31.25343299","type":"posted-content","created":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T00:50:14Z","timestamp":1767401414000},"source":"Crossref","is-referenced-by-count":0,"title":["Proteomic Immune Signatures of Severe HIV-Associated Tuberculosis in Sub-Saharan Africa: A Prospective, Multicenter Analysis from Uganda"],"prefix":"10.64898","author":[{"given":"Jesse E.","family":"Ross","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Immunology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alin S.","family":"Tomoiaga","sequence":"additional","affiliation":[{"name":"Department of Accounting, Business Analytics, Computer Information Systems, and Law, Manhattan College, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Owor","sequence":"additional","affiliation":[{"name":"Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, 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