Immunometabolic and RAAS determinants of circulating interferon gamma in an HIV and TB Zambian cohort.

BACKGROUND: Tuberculosis (TB) and human immunodeficiency virus (HIV) remain major global health challenges, particularly in sub-Saharan Africa where co-infection and chronic immune activation are highly prevalent. Interferon-gamma (IFN-γ) plays a central role in host defense against Mycobacterium tuberculosis, yet its determinants in real-world, high-burden populations especially in the context of metabolic and systemic inflammation are not fully understood. This study investigated clinical, inflammatory, and metabolic factors associated with circulating IFN-γ levels in adults in a high HIV/TB burden setting. METHODS: This was a cross-sectional study of 227 adults attending medical clinic at Livingstone University Teaching Hospital, Zambia. Circulating IFN-γ and a panel of inflammatory, metabolic, and renin-angiotensin-aldosterone system (RAAS) biomarkers were measured. Associations were assessed using simple and multivariable linear regression models, with log transformation applied to skewed variables. Statistical significance was defined as p < 0.05. RESULTS: Among participants (median age 50 years; 64.3% living with HIV), several variables were associated with IFN-γ in unadjusted analyses, including inflammatory cytokines, hs-CRP, angiotensin II, and fasting glucose. However, in multivariable analysis, only female sex (β = -0.440, p = 0.023), fasting glucose (β = 0.153, p = 0.042), angiotensin II (log-transformed) (β = 0.688, p = 0.022), and IL-17 A (log-transformed) (β = 0.332, p = 0.019) remained independently associated with IFN-γ levels. Notably, HIV status, prior tuberculosis infection, hs-CRP, and other inflammatory markers were not independently associated after adjustment. CONCLUSION: In this high HIV/TB burden population, circulating IFN-γ levels were independently associated with metabolic (fasting glucose), vascular-hormonal (angiotensin II), and immune (IL-17 A) factors, but not with HIV infection or prior TB after adjustment. These findings suggest that IFN-γ may reflect broader immunometabolic and inflammatory processes rather than infection-specific immune activation in treated populations. Longitudinal studies are needed to clarify the prognostic and clinical utility of IFN-γ in integrated chronic disease management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1186/s12982-026-02839-5.