Herpes simplex virus type 2 virion host shutoff protein suppresses innate dsRNA antiviral pathways in human vaginal epithelial cells

J Gen Virol. 2011 Sep;92(Pt 9):1981-1993. doi: 10.1099/vir.0.030296-0. Epub 2011 Jun 1.


Viruses that establish persistent infections have evolved numerous strategies to evade host innate antiviral responses. We functionally assessed the role of herpes simplex virus type 2 (HSV-2) virion host shutoff (vhs) protein on innate immune sensing pathways in human vaginal epithelial cells (VK2 ECs). Infection of cells with wild-type (WT) HSV-2 significantly decreased expression of innate immune sensors of viral infection, Toll-like receptor (TLR)2, TLR3, retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda-5), relative to cells infected with a mutant that lacks vhs (vhsB) or mock-infected cells. Transfection with HSV-2 vhs similarly decreased expression of TLR2, TLR3, RIG-I and Mda-5, which was also confirmed in human embryonic kidney (HEK) 293 cells. vhsB infection of VK2 cells caused robust increases in the active form of interferon regulatory factor (IRF)3 and its translocation to the nucleus compared with the WT. Additionally, IRF3 activation by Sendai virus and polyinosinic : polycytidylic acid-induced stimulation of beta interferon (IFN-β) was significantly inhibited in vhs-transfected cells. Overall, our findings provide the first evidence that HSV-2 vhs plays roles in selectively inhibiting TLR3 and RIG-I/Mda-5, as well as TLR2-mediated antiviral pathways for sensing dsRNA and effectively suppresses IFN-β antiviral responses in human vaginal ECs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / antagonists & inhibitors
  • Epithelial Cells / immunology*
  • Epithelial Cells / virology*
  • Herpesvirus 2, Human / immunology*
  • Herpesvirus 2, Human / pathogenicity*
  • Humans
  • Immune Evasion
  • Immunity, Innate*
  • Interferon-Induced Helicase, IFIH1
  • Interferon-beta / antagonists & inhibitors
  • Receptors, Immunologic
  • Toll-Like Receptor 2 / antagonists & inhibitors
  • Toll-Like Receptor 3 / antagonists & inhibitors
  • Viral Proteins / immunology*
  • Viral Proteins / metabolism
  • Virulence Factors / immunology*
  • Virulence Factors / metabolism


  • Receptors, Immunologic
  • TLR2 protein, human
  • TLR3 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 3
  • Viral Proteins
  • Virulence Factors
  • herpes simplex virus type 2 protein UL41
  • Interferon-beta
  • RIGI protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1