NLRP1 and NLRP3 trigger inflammasome activation in CD8+ T cells of ART-treated HIV patients and contribute differently to their chronic activation

Abstract Chronic HIV infection leads to persistent immune activation and inflammation, which can impair the function of CD8+ T cells and their immune competence against infections and tumours. Independently from anti-retroviral treatment, in HIV patients, circulating leukocytes exhibit heightened expression of exhaustion markers and inflammasome-related genes. This study delves into the dysregulation of the inflammasome in CD8+ T lymphocytes of HIV-infected individuals and explores its impact on cell functionality, contributing to persistent inflammation. Our findings demonstrate that HIV CD8+ cells present a basal moderate activation of caspase-1, further increased by DPP-8/9 inhibition and TCR stimulation through activating the NLRP1/ASC and NLRP3/ASC pathways, respectively. Due to inflammasome activation, the HIV CD8+ T cells undergo GSDMD-induced pyroptosis. Compared with healthy donors’ CD8+ T cells, we observed resistance to NLRP1/caspase-1/GSDMD pyroptosis in HIV cells, compatible with the constitutive activation state of those cells. Moreover, the activation of the inflammasome is directly correlated with IFN-Ɣ secretion and with the expression of exhaustion markers on CD8+ T cells. Genotype-guided assays confirmed the presence of NLRP1 and NLRP3 inflammasomes in CD8+ T cells and revealed differential activation in HIV patients. In summary, we confirmed the presence of NLRP1 and NLRP3 inflammasomes in CD8+ T cells. We addressed how they are differentially activated in HIV patients, suggesting the inflammasome as a potential novel therapeutic target for HIV-related chronic inflammation. Keywords: HIV, CD8+ lymphocytes, inflammasome, pyroptosis, NLRP3, NLRP1, CARD8.