NLRP3 inflammasome induces CD4+ T cell loss in chronically HIV-1-infected patients

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...

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Published in:The Journal of clinical investigation 2021-03, Vol.131 (6), p.1-12
Main Authors: Zhang, Chao, Song, Jin-Wen, Huang, Hui-Huang, Fan, Xing, Huang, Lei, Deng, Jian-Ning, Tu, Bo, Wang, Kun, Li, Jing, Zhou, Ming-Ju, Yang, Cui-Xian, Zhao, Qi-Wen, Yang, Tao, Wang, Li-Feng, Zhang, Ji-Yuan, Xu, Ruo-Nan, Jiao, Yan-Mei, Shi, Ming, Shao, Feng, Sékaly, Rafick-Pierre, Wang, Fu-Sheng
Format: Article
Language:English
Subjects:
Antiretroviral therapy
Antiviral agents
Apoptosis
Biomedical research
Caspase-1
Caspase-3
CD4 antigen
Cell activation
Chronic infection
Drug therapy
Flow cytometry
HIV
Human immunodeficiency virus
Infections
Inflammasomes
Inflammation
Lymph nodes
Lymphatic system
Lymphocytes
Lymphocytes T
Pyroptosis
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI138861