1. Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98195-7650, USA
2. Department of Microbiology, UT Southwestern Medical Center, Dallas, Texas 75235-9048, USA
3. Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA

Correspondence to: Michael Gale Jr.¹ Correspondence and requests for materials should be addressed to M.G. (Email: mgale@u.washington.edu).

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)¹. Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million people worldwide². 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^{3, 4, 5, 6, 7, 8, 9, 10}. 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 cells⁸. 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.

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