title: HIV Blocks Interferon Induction in Human Dendritic Cells and Macrophages by Dysregulation of TBK1.
abstract: Dendritic cells (DCs) and macrophages are present in the tissues of the anogenital tract, where HIV-1 transmission occurs in almost all cases. These cells are both target cells for HIV-1 and represent the first opportunity for the virus to interfere with innate recognition. Previously we have shown that both cell types fail to produce type I interferons (IFNs) in response to HIV-1 but that, unlike T cells, the virus does not block IFN induction by targeting IFN regulatory factor 3 (IRF3) for cellular degradation. Thus, either HIV-1 inhibits IFN induction by an alternate mechanism or, less likely, these cells fail to sense HIV-1. Here we show that HIV-1 (but not herpes simplex virus 2 [HSV-2] or Sendai virus)-exposed DCs and macrophages fail to induce the expression of all known type I and III IFN genes. These cells do sense the virus, and pattern recognition receptor (PRR)-induced signaling pathways are triggered. The precise stage in the IFN-inducing signaling pathway that HIV-1 targets to block IFN induction was identified; phosphorylation but not K63 polyubiquitination of TANK-binding kinase 1 (TBK1) was completely inhibited. Two HIV-1 accessory proteins, Vpr and Vif, were shown to bind to TBK1, and their individual deletion partly restored IFN-β expression. Thus, the inhibition of TBK1 autophosphorylation by binding of these proteins appears to be the principal mechanism by which HIV-1 blocks type I and III IFN induction in myeloid cells.
  
  
  OBJECTIVE
  Dendritic cells (DCs) and macrophages are key HIV target cells. Therefore, definition of how HIV impairs innate immune responses to initially establish infection is essential to design preventative interventions, especially by restoring initial interferon production. Here we demonstrate how HIV-1 blocks interferon induction by inhibiting the function of a key kinase in the interferon signaling pathway, TBK1, via two different viral accessory proteins. Other viral proteins have been shown to target the general effects of TBK1, but this precise targeting between ubiquitination and phosphorylation of TBK1 is novel.
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Andrew N
authors: AN
authors: Harman
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Najla
authors: N
authors: Nasr
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Alexandra
authors: A
authors: Feetham
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Ani
authors: A
authors: Galoyan
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Abdullateef A
authors: AA
authors: Alshehri
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Dharshini
authors: D
authors: Rambukwelle
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Rachel A
authors: RA
authors: Botting
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Bonnie M
authors: BM
authors: Hiener
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Eve
authors: E
authors: Diefenbach
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Russell J
authors: RJ
authors: Diefenbach
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors: Min
authors: M
authors: Kim
authors: Centre for Innate Immunity and Infectious Diseases, Monash Institute for Medical Research, Clayton, Victoria, Australia.
authors: Ashley
authors: A
authors: Mansell
authors: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia tony.cunningham@sydney.edu.au.
authors: Anthony L
authors: AL
authors: Cunningham
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007372:Interferons / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D054875:Ubiquitination; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; D007372:Interferons; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human