title: 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 HIV type 1 (HIV-1). pDCs produce substantial quantities of type I IFN and proinflammatory cytokines upon stimulation via TLRs, specifically TLR7 or TLR9. The HIV-1 envelope glycoproteins, 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, IFN regulatory factor 7, and BAFF. Receptor-blocking and cross-linking studies showed that these inhibitory effects of gp120 were mediated by interactions with CD4 and mannose-binding C-type lectin receptors, 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 envelope glycoprotein vaccines.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Nancy P Y
authors.initials: NP
authors.lastname: Chung
authors.forename: Katie
authors.initials: K
authors.lastname: Matthews
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D061251:Primary Cell Culture; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*
chemical_list: D053264:B-Cell Activating Factor; D015704:CD4 Antigens; C513201:CpG-B 2006; D015699:HIV Envelope Protein gp120; C508600:IL6 protein, human; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; C495348:TLR7 protein, human; C495371:TLR9 protein, human; C505719:TNFSF13B protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C514793:gp120 protein, Human immunodeficiency virus 1