Innate Immunity Induced by Composition-Dependent RIG-I Recognition of Hepatitis C Virus RNA

Nature. 2008 Jul 24;454(7203):523-7. doi: 10.1038/nature07106. Epub 2008 Jun 11.

Abstract

Innate immune defences are essential for the control of virus infection and are triggered through host recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs). Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million people worldwide. Infection is regulated by hepatic immune defences triggered by the cellular RIG-I helicase. RIG-I binds PAMP RNA and signals interferon regulatory factor 3 activation to induce the expression of interferon-alpha/beta and antiviral/interferon-stimulated genes (ISGs) that limit infection. Here we identify the polyuridine motif of the HCV genome 3' non-translated region and its replication intermediate as the PAMP substrate of RIG-I, and show that this and similar homopolyuridine or homopolyriboadenine motifs present in the genomes of RNA viruses are the chief feature of RIG-I recognition and immune triggering in human and murine cells. 5' terminal triphosphate on the PAMP RNA was necessary but not sufficient for RIG-I binding, which was primarily dependent on homopolymeric ribonucleotide composition, linear structure and length. The HCV PAMP RNA stimulated RIG-I-dependent signalling to induce a hepatic innate immune response in vivo, and triggered interferon and ISG expression to suppress HCV infection in vitro. These results provide a conceptual advance by defining specific homopolymeric RNA motifs within the genome of HCV and other RNA viruses as the PAMP substrate of RIG-I, and demonstrate immunogenic features of the PAMP-RIG-I interaction that could be used as an immune adjuvant for vaccine and immunotherapy approaches.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / immunology
  • Adenine / metabolism
  • Animals
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / deficiency
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Genome, Viral / genetics
  • Hepacivirus / genetics*
  • Hepacivirus / immunology*
  • Hepacivirus / pathogenicity
  • Humans
  • Immunity, Innate / immunology*
  • Interferon-beta / biosynthesis
  • Interferon-beta / genetics
  • Interferon-beta / immunology
  • Ligands
  • Liver / immunology
  • Liver / virology
  • Mice
  • RNA, Viral / genetics*
  • RNA, Viral / immunology*
  • Uridine / genetics
  • Uridine / immunology
  • Uridine / metabolism
  • Virus Replication / genetics

Substances

  • Ligands
  • RNA, Viral
  • Interferon-beta
  • Ddx58 protein, mouse
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Adenine
  • Uridine