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