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Elife. 2019 Sep 3;8. pii: e42463. doi: 10.7554/eLife.42463.

Interferon lambda 4 impacts the genetic diversity of hepatitis C virus.

Author information

1
Wellcome Centre Human Genetics, University of Oxford, Oxford, United Kingdom.
2
MRC-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, Glasgow, United Kingdom.
3
Nuffield Department of Medicine and the Oxford NIHR BRC, University of Oxford, Oxford, United Kingdom.
4
University of Nottingham.
5
University of Oxford.
6
Conatus Pharmaceuticals.
7
Imperial College London.
8
University of Dundee.
9
Queen Mary University of London.
10
The Hepatitis C Trust.
11
Glasgow Caledonian University.
12
University of Southampton.
13
University of Bristol.
14
Public Health England.
15
University of Glasgow.
16
London School of Hygiene and Tropical Medicine.
17
OncImmune.
18
Merck.
19
Gilead Sciences.
20
Blizard Institute, Queen Mary University, London, United Kingdom.
21
National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom.
22
Institute of Liver Studies, King's College Hospital, London, United Kingdom.
23
Department of Statistics, University of Oxford, Oxford, United Kingdom.
24
Laboratoire MIVEGEC (UMR CNRS 5290, IRD, UM), Montpellier, France.
#
Contributed equally

Abstract

Hepatitis C virus (HCV) is a highly variable pathogen that frequently establishes chronic infection. This genetic variability is affected by the adaptive immune response but the contribution of other host factors is unclear. Here, we examined the role played by interferon lambda-4 (IFN-λ4) on HCV diversity; IFN-λ4 plays a crucial role in spontaneous clearance or establishment of chronicity following acute infection. We performed viral genome-wide association studies using human and viral data from 485 patients of white ancestry infected with HCV genotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-λ4 protein production and activity, influence amino acid variation across the viral polyprotein - not restricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We also observed an association with viral di-nucleotide proportions. These results support a direct role for IFN-λ4 in exerting selective pressure across the viral genome, possibly by a novel mechanism.

KEYWORDS:

genetics; genome-to-genome analysis; genomics; hepatitis C virus; host-pathogen interactions; human; infectious disease; innate immunity; interferon lambda 4; microbiology; virus

Conflict of interest statement

MA, EA, CI, Ad, SL, CB, DB, AT, PP, VS, VC, EH, RB, AP, ET, PS, PK, CH, EB, CS, JM, VP No competing interests declared, GF Grants Consulting and Speaker/Advisory Board: AbbVie, Alcura, Bristol-Myers Squibb, Gilead, Janssen, GlaxoSmithKline, Merck, Roche, Springbank, Idenix, Tekmira, Novartis, WI Grants, Consulting and Advisory/ Speaker Board: Roche, Janssen Cilag, Gilead Sciences, Novartis, GlaxoSmithKline, Pfizer, Abbvie and Bristol-Myers Squibb, KA Grants, Consulting and Advisory/ Speaker Board: Achillion, Alnylam, Astellas, Abbvie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck, Roche, Novartis, Vir

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