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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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B-Cell Activating Factor / genetics
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B-Cell Activating Factor / immunology
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology*
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B-Lymphocytes / virology
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CD4 Antigens / genetics
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CD4 Antigens / immunology
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Cell Communication / drug effects
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Coculture Techniques
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Dendritic Cells / virology
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Gene Expression / drug effects
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Gene Expression / immunology
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HIV Envelope Protein gp120 / pharmacology*
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HIV-1 / immunology*
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Humans
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Interferon Regulatory Factor-7 / genetics
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Interferon Regulatory Factor-7 / immunology
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Interferon-alpha / biosynthesis
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Interferon-alpha / immunology
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Interleukin-6 / biosynthesis
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Interleukin-6 / immunology
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Lymphocyte Activation
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Oligodeoxyribonucleotides / pharmacology*
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Primary Cell Culture
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Recombinant Proteins / pharmacology
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Signal Transduction / drug effects
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Toll-Like Receptor 7 / genetics
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Toll-Like Receptor 7 / immunology
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Toll-Like Receptor 9 / genetics
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Toll-Like Receptor 9 / immunology*
Substances
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B-Cell Activating Factor
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CD4 Antigens
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CpG-B 2006
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HIV Envelope Protein gp120
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IL6 protein, human
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Interferon Regulatory Factor-7
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Interferon-alpha
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Interleukin-6
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Oligodeoxyribonucleotides
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Recombinant Proteins
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TLR7 protein, human
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TLR9 protein, human
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TNFSF13B protein, human
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Toll-Like Receptor 7
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Toll-Like Receptor 9
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gp120 protein, Human immunodeficiency virus 1