title: Binding of HIV-1 gp120 to DC-SIGN promotes ASK-1-dependent activation-induced apoptosis of human dendritic cells.
abstract: 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.
authors: The Eye Institute, Faculty of Medicine, Xiamen University, Xiamen, Fujian, China.
authors: Yongxiong
authors: Y
authors: Chen
authors: Shiuh-Lin
authors: SL
authors: Hwang
authors: Vera S F
authors: VS
authors: Chan
authors: Nancy P Y
authors: NP
authors: Chung
authors: Shu-Rong
authors: SR
authors: Wang
authors: Zhongye
authors: Z
authors: Li
authors: Jing
authors: J
authors: Ma
authors: Chia-Wei
authors: CW
authors: Lin
authors: Ya-Ju
authors: YJ
authors: Hsieh
authors: Kao-Ping
authors: KP
authors: Chang
authors: Sui-Sum
authors: SS
authors: Kung
authors: Yi-Chia
authors: YC
authors: Wu
authors: Cheng-Wei
authors: CW
authors: Chu
authors: Hsiao-Ting
authors: HT
authors: Tai
authors: George F
authors: GF
authors: Gao
authors: Bojian
authors: B
authors: Zheng
authors: Kazunari K
authors: KK
authors: Yokoyama
authors: Jonathan M
authors: JM
authors: Austyn
authors: Chen-Lung S
authors: CL
authors: Lin
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020868:Gene Silencing; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism*; D015658:HIV Infections / Q000097:blood / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5 / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D014162:Transfection; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D019013:CD40 Antigens; D015815:Cell Adhesion Molecules; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D048848:MAP Kinase Kinase Kinase 5; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C482858:MAP3K5 protein, human
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