HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells

Nat Immunol. 2010 May;11(5):419-26. doi: 10.1038/ni.1858. Epub 2010 Apr 4.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion Molecules / immunology
  • Cell Adhesion Molecules / metabolism
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Dendritic Cells / pathology
  • Dendritic Cells / virology
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / metabolism
  • HIV Infections / genetics
  • HIV Infections / immunology*
  • HIV Infections / metabolism
  • HIV Infections / virology
  • HIV-1 / pathogenicity
  • HIV-1 / physiology*
  • Humans
  • Immunity, Innate*
  • Lectins, C-Type / immunology
  • Lectins, C-Type / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Phosphorylation
  • Positive Transcriptional Elongation Factor B / metabolism
  • Protein Binding / genetics
  • Protein Engineering
  • Proto-Oncogene Proteins c-raf / metabolism
  • RNA Polymerase II / metabolism
  • Receptors, Cell Surface / immunology
  • Receptors, Cell Surface / metabolism
  • Second Messenger Systems / genetics
  • Second Messenger Systems / immunology
  • Sequence Deletion / genetics
  • Toll-Like Receptor 8 / immunology
  • Toll-Like Receptor 8 / metabolism*
  • Transcriptional Activation / genetics
  • Transcriptional Activation / immunology
  • Virus Replication / drug effects
  • Virus Replication / genetics
  • Virus Replication / immunology

Substances

  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • HIV Envelope Protein gp120
  • Lectins, C-Type
  • NF-kappa B
  • Receptors, Cell Surface
  • Toll-Like Receptor 8
  • gp120 protein, Human immunodeficiency virus 1
  • Positive Transcriptional Elongation Factor B
  • Proto-Oncogene Proteins c-raf
  • RNA Polymerase II