NLRP3 inflammasome induces CD4+ T cell loss in chronically HIV-1–infected patients
Chao Zhang, Jin‐Wen Song, Hui-Huang Huang, Xing Fan, Lei Huang, Jianning Deng, Bo Tu, Kun Wang, Jing Li, Ming‐Ju Zhou, Cuixian Yang, Qiwen Zhao, Tao Yang, Lifeng Wang, Jiyuan Zhang, XU Ruonan, Yan‐Mei Jiao, Ming Shi, Feng Shao, Rafick‐Pierre Sékaly, Fu‐Sheng Wang
Abstract
Chronic HIV-1 infection is generally characterized by progressive CD4+ 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+ 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+ T cells, which revealed that pyroptotic and apoptotic CD4+ T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in CD4+ 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+ 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+ T cell loss in HIV-1-infected patients and implicate pyroptosis signaling as a target for anti-HIV-1 treatment.