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.
HIV-1 infected individuals become increasingly immunocompromised and susceptible to opportunistic infection during disease progression, which is associated with significant reduction of the dendritic cell number in the peripheral blood or secondary lymphoid tissues. Because dendritic cells are the most powerful antigen-presenting cells, their survival is critical for host defence and inadequate dendritic cell number will fail to induce effective host immune responses. Here we describe a mechanism that may at least partly explain why dendritic cells become significantly depleted in chronic HIV-1 infection. We found that after binding of the HIV-1 envelope protein gp120 to the dendritic cell surface protein DC-SIGN, the subsequent activation by CD40 ligation, or by exposure to bacterial product lipopolysaccharide or pro-inflammatory cytokines such as TNF-α and IL-1β, will lead to overexpression of pro-apoptotic molecule ASK-1, resulting in excessive dendritic cell death. We also confirmed that DC-SIGN(+) dendritic cells in the blood of HIV-1 infected individuals have actually been pre-sensitized by viral gp120, which exists in vast amount in the blood, for activation-induced exorbitant death. Our study thus reveals a previously unknown pathway for dendritic cell depletion and provides clues for potential therapeutic approaches to prevent DC depletion in chronic HIV infection.