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.
Highlights
HIV-1 envelope protein gp120 binds to CD4 and chemokine receptors CCR5 or CXCR4 which are expressed by dendritic cells (DC) and which facilitate viral entry into the cells [1]
We found that after binding of the HIV-1 envelope protein gp120 to the dendritic cell surface protein DC-specific ICAM-grabbing non-integrin (DC-SIGN), the subsequent activation by CD40 ligation, or by exposure to bacterial product lipopolysaccharide or pro-inflammatory cytokines such as TNF-a and IL-1b, will lead to overexpression of pro-apoptotic molecule apoptosis signal regulating kinase-1 (ASK-1), resulting in excessive dendritic cell death
We confirmed that DC-SIGN(+) dendritic cells in the blood of HIV-1 infected individuals have been presensitized by viral gp120, which exists in vast amount in the blood, for activation-induced exorbitant death
Summary
HIV-1 envelope protein gp120 binds to CD4 and chemokine receptors CCR5 or CXCR4 which are expressed by dendritic cells (DC) and which facilitate viral entry into the cells [1]. HIV-1 gp120 binds to DC-specific ICAM-grabbing non-integrin (DC-SIGN), initiating an intracellular signalling cascade that promotes viral infection and dissemination to T cells [7,8]. A subset of CD14(+)DC-SIGN(+) DC has been identified in blood, which can bind HIV-1 and to transmit infectious virus to T cells [9]. During progression to AIDS, HIV(+) individuals become increasingly immunosuppressed and susceptible to opportunistic infections and some cancers. This is accompanied by progressive depletion of DC from different anatomical compartments, but the reasons for this remain largely unknown.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
