期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 6, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI138861
关键词
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资金
- Innovation Groups of the National Natural Science Foundation of China [81721002]
- National Natural Science and Technology Major Project [2018ZX10302104-002]
- National Natural Science Foundation of China [81772185, 81901617]
Chronic HIV-1 infection leads to CD4(+) T cell loss, with distinct mechanisms affecting pyroptotic and apoptotic CD4(+) T cells. Pyroptosis is closely associated with inflammation and driven by NLRP3 inflammasome activation, while apoptosis is more related to T cell activation status.
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.
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