title: HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells.
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.
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. s.i.gringhuis@amc.uva.nl
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Gringhuis
authors.forename: Michiel
authors.initials: M
authors.lastname: van der Vlist
authors.forename: Linda M
authors.initials: LM
authors.lastname: van den Berg
authors.forename: Jeroen
authors.initials: J
authors.lastname: den Dunnen
authors.forename: Manja
authors.initials: M
authors.lastname: Litjens
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
mesh_terms: D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D015202:Protein Engineering; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D015290:Second Messenger Systems / Q000235:genetics / Q000276:immunology; D017384:Sequence Deletion / Q000235:genetics; D051200:Toll-Like Receptor 8 / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D016328:NF-kappa B; D042925:Positive Transcriptional Elongation Factor B; D019908:Proto-Oncogene Proteins c-raf; D012319:RNA Polymerase II; D011956:Receptors, Cell Surface; D051200:Toll-Like Receptor 8; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C514793:gp120 protein, Human immunodeficiency virus 1