Trained Immunity in People Living with HIV

Background: Trained immunity (TRIM) enhances innate immune responses through epigenetic and metabolic reprogramming but can become maladaptive, contributing to chronic inflammation. In people living with HIV (PLWH), maladaptive TRIM has been proposed but remains insufficiently defined. Methods: We examined inflammatory cytokine production in monocyte-derived macrophages (MDMs) obtained from PLWH and age-matched individuals without HIV infection. Baseline cytokine output and responses to Toll-like receptor (TLR) stimulation were measured. We also assessed whether TRIM influenced susceptibility of MDMs to HIV infection. Results: Unstimulated MDMs from male, but not female, PLWH produced significantly higher levels of IL-6 compared with uninfected controls. IL-6 production positively correlated with duration of HIV infection, suggesting cumulative TRIM imprinting. TLR engagement markedly amplified cytokine responses in PLWH-derived MDMs, consistent with a trained phenotype. Despite enhanced inflammatory responsiveness, TRIM did not confer protection from HIV infection of MDMs, indicating functional maladaptation rather than beneficial priming. Conclusions: These findings provide evidence of maladaptive TRIM in PLWH, characterized by persistent inflammation and heightened cytokine responsiveness. The observed sex-specific differences suggest distinct TRIM programming in male and female PLWH. Further studies are needed to elucidate mechanisms driving these disparities and to determine their impact on HIV-associated inflammation and clinical outcomes.