Binding of HIV-1 gp120 to DC-SIGN Promotes ASK-1-Dependent Activation-Induced Apoptosis of Human Dendritic Cells

PLoS Pathogens

Kazunari K. Yokoyama¹  George F. Gao²  Ya-Ju Hsieh²  Kao-Ping Chang²  Hsiao-Ting Tai²  Vera S. F. Chan²  Sui-Sum Kung²  Yi-Chia Wu²  Cheng-Wei Chu²  Zhongye Li²  Nancy P. Y. Chung³  Shiuh-Lin Hwang³  Shu-Rong Wang³  Jonathan M. Austyn⁴  Bojian Zheng⁵  Chen-Lung S. Lin⁶  Chia-Wei Lin⁷  Jing Ma⁷  Yongxiong Chen⁷ 

[1] Department of Microbiology, The University of Hong Kong Medical Center, Hong Kong, SAR, China;Department of Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Surgery, The University of Hong Kong Medical Center, Hong Kong, SAR, China;Graduate School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Institute of Microbiology, Chinese Academy of Science, Beijing, China;Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom;The Eye Institute, Faculty of Medicine, Xiamen University, Xiamen, Fujian, China

关键词: Apoptosis;    HIV-1;    T helper cells;    Blood;    Opportunistic infections;    Dendritic cells;    Flow cytometry;    T cells;   

DOI  :  10.1371/journal.ppat.1003100

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

During disease progression to AIDS, HIV-1 infected individuals become increasingly immunosuppressed and susceptible to opportunistic infections. It has also been demonstrated that multiple subsets of dendritic cells (DC), including DC-SIGN(+) cells, become significantly depleted in the blood and lymphoid tissues of AIDS patients, which may contribute to the failure in initiating effective host immune responses. The mechanism for DC depletion, however, is unclear. It is also known that vast quantities of viral envelope protein gp120 are shed from maturing HIV-1 virions and form circulating immune complexes in the serum of HIV-1-infected individuals, but the pathological role of gp120 in HIV-1 pathogenesis remains elusive. Here we describe a previously unrecognized mechanism of DC death in chronic HIV-1 infection, in which ligation of DC-SIGN by gp120 sensitizes DC to undergo accelerated apoptosis in response to a variety of activation stimuli. The cultured monocyte-derived DC and also freshly-isolated DC-SIGN(+) blood DC that were exposed to either cross-linked recombinant gp120 or immune-complex gp120 in HIV(+) serum underwent considerable apoptosis after CD40 ligation or exposure to bacterial lipopolysaccharide (LPS) or pro-inflammatory cytokines such as TNFα and IL-1β. Furthermore, circulating DC-SIGN(+) DC that were isolated directly from HIV-1(+) individuals had actually been pre-sensitized by serum gp120 for activation-induced exorbitant apoptosis. In all cases the DC apoptosis was substantially inhibited by DC-SIGN blockade. Finally, we showed that accelerated DC apoptosis was a direct consequence of excessive activation of the pro-apoptotic molecule ASK-1 and transfection of siRNA against ASK-1 significantly prevented the activation-induced excessive DC death. Our study discloses a previously unknown mechanism of immune modulation by envelope protein gp120, provides new insights into HIV immunopathogenesis, and suggests potential therapeutic approaches to prevent DC depletion in chronic HIV infection.

【 授权许可】

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