Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF

Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2992-7. doi: 10.1073/pnas.0408824102. Epub 2005 Feb 14.


Toll-like receptors (TLRs) bind pathogen-specific ligands early in infection, initiating signaling pathways that lead to expression of multiple protective cellular genes. Many viruses have evolved strategies that block the effector mechanisms induced through these signaling pathways, but viral interference with critical proximal receptor interactions has not been described. We show here that the NS3/4A serine protease of hepatitis C virus (HCV), a virus notorious for its ability to establish persistent intrahepatic infection, causes specific proteolysis of Toll-IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF or TICAM-1), an adaptor protein linking TLR3 to kinases responsible for activating IFN regulatory factor 3 (IRF-3) and NF-kappaB, transcription factors controlling a multiplicity of antiviral defenses. NS3/4A-mediated cleavage of TRIF reduces its abundance and inhibits polyI:C-activated signaling through the TLR3 pathway before its bifurcation to IRF-3 and NF-kappaB. This uniquely broad mechanism of immune evasion potentially limits expression of multiple host defense genes, thereby promoting persistent infections with this medically important virus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Amino Acid Sequence
  • Cells, Cultured
  • DNA-Binding Proteins / physiology
  • Hepacivirus / immunology*
  • Humans
  • Interferon Regulatory Factor-3
  • Membrane Glycoproteins / physiology
  • Molecular Sequence Data
  • Receptors, Cell Surface / physiology
  • Signal Transduction
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • Transcription Factors / physiology
  • Viral Nonstructural Proteins / physiology*


  • Adaptor Proteins, Vesicular Transport
  • DNA-Binding Proteins
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Membrane Glycoproteins
  • NS3 protein, hepatitis C virus
  • NS4 protein, hepatitis C virus
  • Receptors, Cell Surface
  • TICAM1 protein, human
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • Transcription Factors
  • Viral Nonstructural Proteins