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Increased Mitochondrial Mass Leads to Heightened Pyroptosis that Drives CD4+ T Cell Depletion in Patients with HIV-1 Infection

28 Pages Posted: 13 Nov 2019

See all articles by Fengting Yu

Fengting Yu

Capital Medical University - Clinical and Research Center of Infectious Diseases

Chengjie Ma

Capital Medical University - Beijing Ditan Hospital

Xia Jin

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Molecular Virology & Immunology

Hongxin Zhao

Capital Medical University - Clinical and Research Center of Infectious Disease

Jiang Xiao

Capital Medical University - Beijing Ditan Hospital

Li Li

Capital Medical University - Beijing Ditan Hospital

Shujing Song

Capital Medical University - Beijing Ditan Hospital

Xia Zhang

Capital Medical University - Beijing Ditan Hospital

Xiaohui Xie

Capital Medical University - Beijing Ditan Hospital

Siyuan Yang

Capital Medical University - Beijing Ditan Hospital

Yunxia Tang

Capital Medical University - Beijing Ditan Hospital

Linghang Wang

Capital Medical University - Clinical and Research Center of Infectious Disease

Fujie Zhang

Capital Medical University - Clinical and Research Center of Infectious Disease

More...

Abstract

In HIV-1 infection, over 90% CD4+ T cells have died of caspase-1 mediated pyroptosis. What governs the increased susceptibility of CD4+ T cells to pyroptosis is poorly understood. Here, we examined the involvement of mitochondria in pyroptosis. Mitochondrial mass (MM) levels are significantly higher in CD4+ T cells from HIV-infected patients than that in healthy controls, and cells with the MMhigh phenotype manifest greater sensitivity to caspase-1 mediated pyroptosis. Moreover, the increased MM is more pronounced in the early differentiated and inactivated CD4+ T cells. However, higher MM is not intrinsically linked to T cell differentiation disorder or excessive activation of CD4+ T cells. Mechanistically, the increased MM is significantly correlated with an elevated expression of the mitochondrial fusion gene Mfn1. Additionally, MM increase in CD4+ T cells is associated with heightened sensitivity of these cells to pyroptosis in HIV-1 infected patients whom were either treated with antiretroviral drugs or not. These results reveal a previously unknown mechanism that links mitochondrial change to pyroptosis, and suggest that modulation of this interaction may help to prevent CD4+ T cell loss in HIV infection.

Funding Statement: This work was funded in part by The National 13th Five-Year Plan’s Grand Program on Key Infectious Disease Control (2018ZX10302-102 to F.Z., 2018ZX10715-005 to H.Z.), the National Natural Science Foundation of China (NSFC81672000 to H.Z.), the Culture Project of Beijing Municipal Commission of Health and Family Planning (215-3-109 to L.W.), the Science and technology innovation service capacity building (1192070325 to F.Z.).

Declaration of Interests: The authors have no conflicts of interest to declare.

Ethics Approval Statement: Written informed consent was obtained from each subject. The local human research subject review board (RSRB) approved the study.

Keywords: HIV/AIDS; CD4+ T cell; Pyroptosis; Mitochondrial mass; Mfn1

Suggested Citation

Yu, Fengting and Ma, Chengjie and Jin, Xia and Zhao, Hongxin and Xiao, Jiang and Li, Li and Song, Shujing and Zhang, Xia and Xie, Xiaohui and Yang, Siyuan and Tang, Yunxia and Wang, Linghang and Zhang, Fujie, Increased Mitochondrial Mass Leads to Heightened Pyroptosis that Drives CD4+ T Cell Depletion in Patients with HIV-1 Infection (10/23/2019 11:25:43). Available at SSRN: https://ssrn.com/abstract=3475569 or http://dx.doi.org/10.2139/ssrn.3475569

Fengting Yu

Capital Medical University - Clinical and Research Center of Infectious Diseases

Beijing
China

Chengjie Ma

Capital Medical University - Beijing Ditan Hospital

Beijing
China

Xia Jin

Chinese Academy of Sciences (CAS) - CAS Key Laboratory of Molecular Virology & Immunology

Shanghai
China

Hongxin Zhao

Capital Medical University - Clinical and Research Center of Infectious Disease

Beijing, 100015
China

Jiang Xiao

Capital Medical University - Beijing Ditan Hospital

Beijing
China

Li Li

Capital Medical University - Beijing Ditan Hospital

Beijing
China

Shujing Song

Capital Medical University - Beijing Ditan Hospital

Beijing
China

Xia Zhang

Capital Medical University - Beijing Ditan Hospital

Beijing
China

Xiaohui Xie

Capital Medical University - Beijing Ditan Hospital

Beijing
China

Siyuan Yang

Capital Medical University - Beijing Ditan Hospital

Beijing
China

Yunxia Tang

Capital Medical University - Beijing Ditan Hospital

Beijing
China

Linghang Wang

Capital Medical University - Clinical and Research Center of Infectious Disease ( email )

Beijing, 100015
China

Fujie Zhang (Contact Author)

Capital Medical University - Clinical and Research Center of Infectious Disease ( email )

Beijing, 100015
China