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

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. 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. 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. 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.