Impact of virus subtype and host IFNL4 genotype on large-scale RNA structure formation in the genome of hepatitis C virus
- Peter Simmonds1,
- Lize Cuypers2,
- Will L. Irving3,
- John McLauchlan4,
- Graham S. Cooke5,
- Ellie Barnes1,
- STOP-HCV Consortium6 and
- M. Azim Ansari1
- 1Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, OX1 3SY, Oxford, United Kingdom
- 2University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Research, BE 3000, Leuven, Belgium
- 3Faculty of Medicine and Health Sciences, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, NG7 2UH, United Kingdom
- 4MRC-University of Glasgow Centre for Virus Research, Glasgow, G61 1QH, United Kingdom
- 5Imperial College London, London, W2 1PG, United Kingdom
- 7University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom
- 8University of Oxford, Peter Medawar Building for Pathogen Research, Oxford OX1 3SY, United Kingdom
- 9Gilead Sciences, Inc., Foster City, California 94404, USA
- 10Conatus Pharmaceuticals, Inc., San Diego, California 92127, USA
- 11University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom
- 12Queen Mary's University of London, London E1 4AT, United Kingdom
- 13Hepatitis C Trust, London SE1 3YD, United Kingdom
- 14University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom
- 15Hepatitis C Trust, London SE1 3YD, United Kingdom
- 16Gilead Sciences, Inc., Uxbridge, Middlesex UB11 1AF, United Kingdom
- 17University of Oxford, Oxford OX1 3LB, United Kingdom
- 18BC Centre for Excellence in HIV/AIDS, St Paul's Hospital, Vancouver, British Columbia, Canada V6Z 1Y6
- 19University of Oxford, Peter Medawar Building for Pathogen Research, Oxford OX1 3SY, United Kingdom
- 20Glasgow Caledonian University, Glasgow G4 0BA, Scotland, United Kingdom
- 21University of Southampton, Southampton SO17 1BJ, United Kingdom
- 22University of Oxford, Peter Medawar Building for Pathogen Research, Oxford OX1 3SY, United Kingdom
- 23UC San Diego, La Jolla, California 92093-0507, USA
- 24Gilead Sciences, Inc., Foster City, California 94404, USA
- 25Public Health England, London NW9 5EQ, United Kingdom
- 26Gilead Sciences, Inc., Foster City, California 94404, USA
- 27University of Birmingham, Centre for Human Virology, Edgbaston, Birmingham B15 2TT, United Kingdom
- 28London School of Hygiene and Tropical Medicine, London WC1H 9SH, United Kingdom
- 29OncImmune Limited, Clinical Sciences Building, Nottingham City Hospital, Nottingham NG5 1PB, United Kingdom
- 30Merck & Co., Inc., Kenilworth, New Jersey 07033, USA
- 31University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom
- 32University of Glasgow, MRC-CVR, Glasgow G61 1QH, United Kingdom
- 33University of Bristol, Clifton BS8 2BN, United Kingdom
- 34University of Oxford, Oxford OX1 3QU, United Kingdom
- Corresponding author: Peter.simmonds{at}ndm.ox.ac.uk
Abstract
Mechanisms underlying the ability of hepatitis C virus (HCV) to establish persistent infections and induce progressive liver disease remain poorly understood. HCV is one of several positive-stranded RNA viruses capable of establishing persistence in their immunocompetent vertebrate hosts, an attribute previously associated with formation of large-scale RNA structure in their genomic RNA. We developed novel methods to analyze and visualize genome-scale ordered RNA structure (GORS) predicted from the increasingly large data sets of complete genome sequences of HCV. Structurally conserved RNA secondary structure in coding regions of HCV localized exclusively to polyprotein ends (core, NS5B). Coding regions elsewhere were also intensely structured based on elevated minimum folding energy difference (MFED) values, but the actual stem–loop elements involved in genome folding were structurally poorly conserved, even between subtypes 1a and 1b. Dynamic remodeling was further evident from comparison of HCV strains in different host genetic backgrounds. Significantly higher MFED values, greater suppression of UpA dinucleotide frequencies, and restricted diversification were found in subjects with the TT genotype of the rs12979860 SNP in the IFNL4 gene compared to the CC (nonexpressing) allele. These structural and compositional associations with expression of interferon-λ4 were recapitulated on a larger scale by higher MFED values and greater UpA suppression of genotype 1 compared to genotype 3a, associated with previously reported HCV genotype-associated differences in hepatic interferon-stimulated gene induction. Associations between innate cellular responses with HCV structure and further evolutionary constraints represent an important new element in RNA virus evolution and the adaptive interplay between virus and host.
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Footnotes
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Article is online at http://www.rnajournal.org/cgi/doi/10.1261/rna.075465.120.
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Freely available online through the RNA Open Access option.
- Received March 28, 2020.
- Accepted July 29, 2020.
This article, published in RNA, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.