HIV-1 gp120 Impairs the Induction of B Cell Responses by TLR9-Activated Plasmacytoid Dendritic Cells

Abstract

Plasmacytoid dendritic cells (pDCs) play a central role in innate and adaptive immune responses to viral infections, including human immunodeficiency virus type 1 (HIV-1). pDCs produce substantial quantities of type I interferon (IFN) and proinflammatory cytokines upon stimulation via Toll-like receptors (TLRs), specifically TLR7 or TLR9. The HIV-1 envelope glycoproteins (Env), exemplified by the gp120 monomer, are the focus of vaccines aimed at inducing B cell responses. We have studied how the interactions of gp120 with various receptors on human pDCs affect the activation of these cells via TLR9, and their subsequent ability to stimulate B cells. We observed that IFN-α production by pDCs in response to TLR9, but not TLR7 stimulation, was reduced by exposure to gp120. Specifically, gp120 inhibited the CpG-induced maturation of pDCs and their expression of TNF-α, IL-6, TLR9, IRF-7 and B cell-activating factor of the TNF family (BAFF). Receptor-blocking and cross-linking studies showed that these inhibitory effects of gp120 were mediated by interactions with CD4 and MCLRs, but not with the chemokine receptors CCR5 and CXCR4. Of note is that gp120 inhibited the activation of B cells by TLR9-stimulated pDCs. Taken together, our data show that HIV-1 gp120 impairs pDC functions, including activation of B cell responses, and imply that TLR9 ligands may not be good adjuvants to use in combination with Env vaccines.

Dendritic Cell Interactions with HIV-1 Envelope Glycoprotein: Implications for Preventing Transmission

“…As mentioned above, exposure to Env also sensitized DCs to undergo extensive apoptosis upon activation by various stimuli that would normally promote DC function, including CD40 ligand, TLR ligands, and proinflammatory cytokines both in vitro and in vivo (Chen et al 2013). These immunosuppressive effects have all been shown to be dependent on Env interactions with mannose-binding CLRs, such as DC-SIGN and MR (Shan et al 2007;Chung et al 2012;Chen et al 2013). In line with these observations, immunization of humanized mice with Env glycoproteins where the mannose moieties were occluded or removed, thus preventing binding to CLRs and presumably circumventing this route of DC dysfunction, resulted in enhanced Env-specific Ab titers and T cell responses (Banerjee et al 2009(Banerjee et al , 2012.…”

“…Exposure to certain strains of Env results in defective maturation of DCs in response to classical maturation stimuli (Shan et al 2007), as well as impaired production of effector cytokines such as TNF, IL-12, and IFNa (Fantuzzi Encyclopedia 2004;Martinelli et al 2007;Chung et al 2012) and the induction of anti-inflammatory IL-10 ( Shan et al 2007;Sarkar et al 2013). Furthermore, Env exposure can lead to a decreased capacity to stimulate T cell proliferation (Fantuzzi et al 2004;Fernando et al 2007;Shan et al 2007;Hu et al 2008) and B cell activation ).…”

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.…”

Impact of in vitro Costimulation with TLR2, TLR4 and TLR9 Agonists and HIV-1 on Antigen-Presenting Cell Activation

“…Recently it was demonstrated that HIV-1 gp120 inhibits the CpG-induced maturation of plasmacytoid DCs (pDCs) and the expression of TNF-α, IL-6, TLR9 and IFN-regulatory factor 7. These effects were mediated by interaction of gp120 with CD4 and mannose-binding C-type lectin [16,17]. …”