NLRP3 inflammasome induces [CD4.sup.+] T cell loss in chronically HIV-1-infected patients

Introduction Human immunodeficiency virus type 1 (HIV-1) infection leads to a progressive loss of [CD4.sup.+] T cells, which has long been recognized as central to HIV-1 pathogenesis but remains to [...]
Chronic HIV-1 infection is generally characterized by progressive [CD4.sup.+] T cell depletion due to direct and bystander death that is closely associated with persistent HIV-1 replication and an inflammatory environment in vivo. The mechanisms underlying the loss of [CD4.sup.+] T cells in patients with chronic HIV-1 infection are incompletely understood. In this study, we simultaneously monitored caspase-1 and caspase-3 activation in circulating [CD4.sup.+] T cells, which revealed that pyroptotic and apoptotic [CD4.sup.+] T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in [CD4.sup.+] T cells were significantly elevated during chronic HIV-1 infection, and decreased following effective antiretroviral therapy. Notably, the occurrence of pyroptosis was further confirmed by elevated gasdermin D activation in lymph nodes of HIV-1-infected individuals. Mechanistically, caspase-1 activation closely correlated with the inflammatory marker expression and was shown to occur through NLRP3 inflammasome activation driven by virus-dependent and/or -independent ROS production, while caspase-3 activation in [CD4.sup.+] T cells was more closely related to T cell activation status. Hence, our findings show that NLRP3-dependent pyroptosis plays an essential role in [CD4.sup.+] T cell loss in HIV-1-infected patients and implicate pyroptosis signaling as a target for anti-HIV-1 treatment.