Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA

• Published in: Nature 2008-07, Vol.454 (7203), p.523-527
• Main Authors: Gale Jr, Michael, Saito, Takeshi, Owen, David M, Jiang, Fuguo, Marcotrigiano, Joseph
• Format: Article
• Language: English
• Subjects: Adenine - immunology; Adenine - metabolism; Animals; Biological and medical sciences; Cell Line; Cellular biology; DEAD Box Protein 58; DEAD-box RNA Helicases - deficiency; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic aspects; Genome, Viral - genetics; Genomics; Health aspects; Hepacivirus - genetics; Hepacivirus - immunology; Hepacivirus - pathogenicity; Hepatitis; Hepatitis C virus; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunity, Innate - immunology; Immunotherapy; Interferon-beta - biosynthesis; Interferon-beta - genetics; Interferon-beta - immunology; letter; Ligands; Liver - immunology; Liver - virology; Methods; Mice; Microbiology; multidisciplinary; Physiological aspects; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; RNA sequencing; RNA, Viral - genetics; RNA, Viral - immunology; Science; Uridine - genetics; Uridine - immunology; Uridine - metabolism; Virology; Virus Replication - genetics
• ISSN: 0028-0836; 1476-4687; 1476-4687; 1476-4679
• DOI: 10.1038/nature07106

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- / 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.