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.

HIV-1 gp120 Glycoprotein Interacting with Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN) Down-Regulates Tight Junction Proteins to Disrupt the Blood Retinal Barrier and Increase Its Permeability

“…This finding partially explains the DC depletion in chronically infected HIV-1 patients (36). On the other hand, HIV-1 replication in DCs requires DC-SIGN signaling triggered by gp120 and binding of gp120 to DC-SIGN-induced kinase Raf1-dependent phosphorylation of the NF-B subunit p65, which could recruit the transcription elongation factor pTEF-b, demonstrating that DC-SIGN signaling triggered by gp120 is essential for HIV-1 transcription elongation (37).…”

HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

“…So far, to the best of our knowledge, HIV-1 has not been shown to activate DCs, although a previous study suggested that recognition of HIV-1 viral ssRNA by TLR7/8 on plasmacytoid DCs and monocytes may partially contribute to immune activation seen in HIV-infected individuals (43). Other studies have shown that binding of gp120 by DC-specific ICAM-3-grabbing nonintegrin can lead to suppression of IFN-a and apoptosis signal-regulating kinase 1-dependent cell death (46,47). A recent report by Manel and colleagues (48) found that monocyte-derived DCs were unable to respond to HIV-1 in the absence of a productive infection, but when replication could be artificially induced, type I IFN responses were produced.…”

Modulation of apoptosis and viral latency – an axis to be well understood for successful cure of human immunodeficiency virus

“…During later stages of HIV infection, binding of membrane-bound or soluble gp120 with CD4 leads to the apoptosis of HIV-infected and uninfected bystander CD4 + T-cells (Li & Pauza, 2013). In addition, soluble gp120 has been reported to induce apoptosis in a variety of cells such as CD8 + T-cells, neurons, human vascular endothelial cells, cardiomyocytes, oral keratinocytes and renal tubular cells (Chen et al, 2013;Février et al, 2011;Green et al, 2014;Vashistha et al, 2009) through several mechanisms as depicted in Fig. 1(b).…”