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

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.

• Authors: Chao Zhang, Jin-Wen Song, Hui-Huang Huang, Xing Fan, Lei Huang, Jian-Ning Deng, Bo Tu, Kun Wang, Jing Li, Ming-Ju Zhou, Cui-Xian Yang, Qi-Wen Zhao, Tao Yang, Li-Feng Wang, Ji-Yuan Zhang, Ruo-Nan Xu, Yan-Mei Jiao, Ming Shi, Feng Shao, Rafick-Pierre Sékaly, Fu-Sheng Wang
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 6 (03 15 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 33720048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Reactive Oxygen Species
• CASP3 protein, human
• Caspase 3
• Caspase 1

Topics

• Adolescent
• Adult
• Apoptosis (immunology)
• CD4-Positive T-Lymphocytes (immunology, metabolism, pathology)
• Case-Control Studies
• Caspase 1 (metabolism)
• Caspase 3 (metabolism)
• Female
• HIV Infections (immunology, metabolism, pathology)
• HIV-1
• Humans
• Inflammasomes (immunology, metabolism)
• Lymphocyte Activation
• Male
• Middle Aged
• Models, Immunological
• NLR Family, Pyrin Domain-Containing 3 Protein (immunology)
• Pyroptosis (immunology)
• Reactive Oxygen Species (metabolism)
• Viral Load
• Young Adult