INFLAMMASOME AND PYROPTOSIS ARE INVOLVED IN THE LACK OF IMMUNE RESPONSE DURING CART

Inflammasome-mediated activation of caspase-1 regulates inflammatory responses and pyroptosis. Pyroptosis was recently shown to play a major role in CD4 T lymphocyte loss and to contribute to immune activation in HIV infection¹.The possible role of inflammasomes and pyroptosis in the lack of immune reconstitution seen in a percentage of ART-treated HIV patients has nevertheless not been investigated. We analyzed possible associations between inflammasome activity, caspase-1 activation, pyroptosis and immune reconstitution in HIV+ ART treated patients¹Doitsh G et al., 2014

Cross-sectional, single-site study. HIV-infected patients on antiretroviral therapy for≥24 months and plasma HIV-RNA<50 cp/mL for≥12 months, matched for nadir CD4 T cell count were enrolled. Presence of opportunistic AIDS-related diseases, HBV or HCV coinfection, chronic inflammatory disorders, ongoing immunosuppressive therapy were exclusion criteria. Patients were classified as immunological responders (IR) or non responders (INR) if CD4 count was ≥500 or ≤350 cells/μL, respectively. Expression of inflammasome, caspases 1, 3, 4, and 5, pro-inflammatory cytokines and of IFI16 genes was measured in unstimulated and in AT2-HIV-1 stimulated cells of all IRs and INRs

39 patients (22 IR; 17 INR, 77% M, medians: age 47 years, time from HIV diagnosis 10 years, time with HIV-RNA<50cp/mL 57 months) were enrolled. INR patients were older (median 60vs.43 years, p<0.001) and had a higher prevalence of past AIDS-defining illnesses (76%vs.18%, p<0.001). Median CD4 count was 840 (IQR 718-1131) cells/µL in IR vs. 295 (IQR 256-343) cells/µL in INR. AT2 stimulation induced NLRP3 gene expression in both IR and INR; NLRP3 and IL-18 expression were nevertheless significantly increased in INR compared to IR (p=0.009 and p=0.004). Significant higher caspase-1 expression was seen as well in both unstimulated (p=0.02) and AT2-stimulated cells of INR (p=0.003), whereas caspase 3, 4 and 5 expression was similar in both groups. Finally, IFI16 expression as well plasma concentration of caspase-1 and IL-1β were higher in INR compared to IR patients

Increased inflammasome and caspase-1 activation is observed in INR patients. The upregulation of these proinflammatory mechanisms plausibly contributes to the persistent immune activation that characterize INRs. Notably, caspase-1 activation is likely to induce CD4 T cell loss via pyroptosis, contributing to the unsatisfactory CD4 recovery seen in INRs