Protein clues reveal why HIV-linked TB becomes deadly

Severe tuberculosis (TB) remains one of the deadliest complications for people living with HIV (PLWH) worldwide, yet the immune processes that drive critical illness in this group are not well described. To close that gap, Jesse Ross and collaborators conducted a prospective, multicenter analysis in Uganda to search for a reproducible immune signature tied to severe HIV-associated TB (HIV/TB). They used proteomic data from two independent groups of adults hospitalized with severe febrile illness: an urban “discovery” cohort in Entebbe (N=241) and a rural “validation” cohort in Tororo (N=253). All participants were adults (age ≥18 years) admitted with undifferentiated, severe infection; there were no experimental interventions. The team focused on real-world hospitalized patients to capture the biology of serious disease, then compared people across three clinical phenotypes: HIV-negative without TB, PLWH without TB, and PLWH with microbiologically diagnosed TB. By studying blood protein patterns in these clearly defined groups, the researchers hoped to reveal immune processes linked to the most dangerous forms of HIV/TB that could guide diagnosis, prognosis, and new treatment approaches.

The investigators analyzed proteomic measurements and applied ordinal random forest models in the Entebbe discovery cohort to pinpoint proteins most strongly associated with progressive HIV/TB phenotype, then tested those findings in the Tororo validation cohort. Severe HIV-associated TB was common in both cohorts (18% in Entebbe, 21% in Tororo) and overall mortality was high (30-day mortality 22% in the discovery cohort; 60-day mortality 26% in the validation cohort). When participants were stratified, PLWH with microbiologically diagnosed TB had the worst outcomes: 30-day mortality of 42% in the discovery cohort and 60-day mortality of 52% in the validation cohort. From the proteomic analysis the team identified an eight-protein signature that reliably distinguished this high-risk phenotype. The proteins were LAMP3, CD70, CRTAM, IGLC2, PRSS2, SERPINA5, EFEMP1, and IGFBP3 — representing 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).

These findings point to a distinct immunologic pattern underlying severe HIV-associated TB — one that combines hyperactivation of innate antigen-presenting cells, heightened cytotoxic lymphocyte activity, B-cell involvement, tissue-damaging proteases, altered coagulation, and remodeling of the extracellular matrix. By describing a reproducible host-response signature across urban and rural cohorts in Uganda, the study offers new biological insight into why some PLWH develop life-threatening TB while others do not. Practically, an eight-protein profile like this could be developed into a prognostic test to help clinicians identify patients at highest short-term risk and prioritize monitoring or adjunctive treatments. The specific pathways highlighted — for example, macrophage/dendritic cell activation and coagulation dysregulation — also suggest targets for host-directed therapies aimed at reducing organ damage and death in this high-risk population. Further work will be needed to translate these proteomic markers into clinical tests and interventions, and to test whether modifying the implicated pathways improves patient outcomes.