Title Binding of HIV-1 gp 120 to DC-SIGN promotes ASK-1-dependentactivation-induced apoptosis of human dendritic cells

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 TNFa and IL-1b. 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 proapoptotic 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. Citation: Chen Y, Hwang S-L, Chan VSF, Chung NPY, Wang S-R, et al. (2013) Binding of HIV-1 gp120 to DC-SIGN Promotes ASK-1-Dependent Activation-Induced Apoptosis of Human Dendritic Cells. PLoS Pathog 9(1): e1003100. doi:10.1371/journal.ppat. 1003100 Editor: Susan R. Ross, University of Pennsylvania School of Medicine, United States of America Received July 1, 2012; Accepted October 23, 2012; Published January 31, 2013 Copyright: 2013 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by RGC/CERG HKU7242/02M, HKU Grant Council Matching Grant 20600436, the AIDS Trust Fund, Hong Kong, SAR, China; the National Natural Science Foundation of China No. 81070075 and the Natural Science Foundation of Fujian Province, China No. 2010J01237; the Excellence for Cancer Research Center grant, NSC99-2314-B-037-043-MY3 from the National Science council, Taiwan, NHRI-EX100-10036BI from the National Health Research Institute, Taiwan, and DOH99-TD-C-111-002 from the Department of Health, Executive Yuan, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: jon.austyn@nds.ox. ac.uk (JMA); stevelin@kmu.edu. tw (CLSL) . These authors contributed equally to this work.