Mechanisms of systemic low-grade inflammation in HIV patients on long-term suppressive antiretroviral therapy: the inflammasome hypothesis

Objective: We aimed to determine the contribution of inflammasome activation in chronic low-grade systemic inflammation observed in patients with HIV (PWH) on long-term suppressive antiretroviral therapy (ART) and to explore mechanisms of such activation. Design: Forty-two PWH on long-term suppressive ART (HIV-RNA < 40 copies/ml) were compared with 10 HIV-negative healthy controls (HC). Methods: Inflammasome activation was measured by dosing mature interleukin (IL)-1 beta and IL-18 cytokines in patient serum. We explored inflammasome pathways through ex vivo stimulation of PWH primary monocytes with inflammasome activators; expression of inflammasome components by transcriptomic analysis; and metabolomics analysis of patient sera. Results: Median (Q1; Q3) age, ART and viral suppression duration in PWH were 54 (48; 60), 15 (9; 20) and 7.5 (5; 12) years, respectively. Higher serum IL-18 was measured in PWH than in HC (61 (42; 77) vs. 36 (27- 48 pg/ml), P = 0.009); IL-1 beta was detected in 10/42 PWH (0.5 (0.34; 0.80) pg/ml) but not in HC. Monocytes from PWH did not produce more inflammatory cytokines in vitro, but secretion of IL-1 beta in response to NOD like receptor family, pyrin domain containing 3 (NLRP3) inflammasome stimulation was higher than in HC. This was not explained at the transcriptional level. We found an oxidative stress molecular profile in PWH sera. Conclusion: HIV infection with long-term effective ART is associated with a serum inflammatory signature, including markers of inflammasome activation, and an increased activation of monocytes upon inflammasome stimulation. Other cells should be investigated as sources of inflammatory cytokines in PWH. Oxidative stress might contribute to this chronic low-grade inflammation. Copyright (c) 2023 Wolters Kluwer Health, Inc. All rights reserved.

Automated summary

The objective of this study was to determine the contribution of inflammasome activation in chronic low-grade systemic inflammation observed in patients with HIV on long-term suppressive antiretroviral therapy. Inflammasome activation was measured by cytokine analysis in patient serum and ex vivo stimulation of primary monocytes. The results showed higher levels of IL-18 in HIV-positive patients compared to HIV-negative controls, along with increased secretion of IL-1 beta in response to inflammasome stimulation. Oxidative stress was also observed in patient sera. In conclusion, HIV infection with long-term effective ART is associated with inflammasome activation and increased monocyte activation, possibly mediated by oxidative stress.