Abstract
Pattern-recognition receptors (PRRs) elicit antiviral immune responses to human immunodeficiency virus type 1 (HIV-1). Here we show that HIV-1 required signaling by the PRRs Toll-like receptor 8 (TLR8) and DC-SIGN for replication in dendritic cells (DCs). HIV-1 activated the transcription factor NF-kappaB through TLR8 to initiate the transcription of integrated provirus by RNA polymerase II (RNAPII). However, DC-SIGN signaling was required for the generation of full-length viral transcripts. Binding of the HIV-1 envelope glycoprotein gp120 to DC-SIGN induced kinase Raf-1-dependent phosphorylation of the NF-kappaB subunit p65 at Ser276, which recruited the transcription-elongation factor pTEF-b to nascent transcripts. Transcription elongation and generation of full-length viral transcripts was dependent on pTEF-b-mediated phosphorylation of RNAPII at Ser2. Inhibition of either pathway abrogated replication and prevented HIV-1 transmission. Thus, HIV-1 subverts crucial components of the immune system for replication that might be targeted to prevent infection and dissemination.
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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Cell Adhesion Molecules / immunology
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Cell Adhesion Molecules / metabolism
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Cells, Cultured
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Dendritic Cells / immunology
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Dendritic Cells / metabolism*
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Dendritic Cells / pathology
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Dendritic Cells / virology
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HIV Envelope Protein gp120 / genetics
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HIV Envelope Protein gp120 / metabolism
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HIV Infections / genetics
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HIV Infections / immunology*
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HIV Infections / metabolism
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HIV Infections / virology
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HIV-1 / pathogenicity
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HIV-1 / physiology*
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Humans
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Immunity, Innate*
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Lectins, C-Type / immunology
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Lectins, C-Type / metabolism
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Phosphorylation
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Positive Transcriptional Elongation Factor B / metabolism
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Protein Binding / genetics
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Protein Engineering
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Proto-Oncogene Proteins c-raf / metabolism
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RNA Polymerase II / metabolism
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Receptors, Cell Surface / immunology
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Receptors, Cell Surface / metabolism
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Second Messenger Systems / genetics
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Second Messenger Systems / immunology
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Sequence Deletion / genetics
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Toll-Like Receptor 8 / immunology
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Toll-Like Receptor 8 / metabolism*
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Transcriptional Activation / genetics
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Transcriptional Activation / immunology
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Virus Replication / drug effects
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Virus Replication / genetics
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Virus Replication / immunology
Substances
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Cell Adhesion Molecules
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DC-specific ICAM-3 grabbing nonintegrin
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HIV Envelope Protein gp120
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Lectins, C-Type
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NF-kappa B
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Receptors, Cell Surface
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Toll-Like Receptor 8
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gp120 protein, Human immunodeficiency virus 1
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Positive Transcriptional Elongation Factor B
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Proto-Oncogene Proteins c-raf
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RNA Polymerase II