A comparison of inflammasome markers in people living with HIV, with and without polysubstance use

Abstract

Despite the widespread use of antiretroviral therapy, systemic inflammation remains a hallmark of HIV-1 infection. This not only affects brain function, but may also promote immune cell exhaustion and persistence of HIV reservoirs, among other effects. Inflammasomes, key regulators of the innate immune response, are central to this inflammatory process. Polysubstance use, prevalent among people living with HIV (PLWH), can exacerbate HIV-induced inflammation. This study compared inflammasome marker levels in PLWH, with and without polysubstance use. To determine and compare the median of selected inflammasome markers (IL-1β, IL-18, IL-33, IL-6, IL-8, IL-15, TNF-α) in plasma between people living with HIV, with and without polysubstance use. To determine the factors (CD4+ T cell count, time on ART, Age, and sex) that are associated with statistically significant inflammasome markers in PLWH, with and without polysubstance use. Inflammasome marker levels in plasma were measured using Luminex assays. Median plasma concentrations of inflammasome markers were higher among PLWH with polysubstance use compared to non-users. Notably, IL-15 levels were 106.5 pg/mL (IQR: 82-118.3) in users vs. 78.4 pg/mL (IQR: 63.7-103) in non-users (p = 0.015), and IL-18 levels were 1573.8 pg/mL (IQR: 1136.1-1722.3) vs. 1195.1 pg/mL (IQR: 881.7-1573.4), respectively (p = 0.029).Multivariate analysis revealed that male sex was associated with a 30% higher IL-15 concentration relative to females (GMR = 1.30; 95% CI: 1.00–1.67; FDR = 0.095), suggesting a sex-specific pattern of immune activation in the context of polysubstance use. Altogether,this study demonstrates that elevated levels of inflammasome markers are associated with polysubstance use among PLWH,with IL-15 and IL-18 being significantly associated. Notably, multivariate analysis revealed that male polysubstance users exhibit disproportionately high IL-15 levels, suggesting a sex-specific immune activation pattern. These findings underscore the complex interplay between substance use, sex, and immune dysregulation in HIV-positive populations. IL-15 may serve as a potential biomarker for chronic immune stimulation in this subgroup, warranting further investigation into targeted interventions and sex-sensitive immunomodulatory strategies.