title: Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus.
abstract: Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. Here we use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals who were chronically infected with HCV, predominantly genotype 3. We show that both alleles of genes encoding human leukocyte antigen molecules and genes encoding components of the interferon lambda innate immune system drive viral polymorphism. Additionally, we show that IFNL4 genotypes determine HCV viral load through a mechanism dependent on a specific amino acid residue in the HCV NS5A protein. These findings highlight the interplay between the innate immune system and the viral genome in HCV control.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Oxford Martin School, University of Oxford, Oxford, UK.|Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK.
authors.forename: M Azim
authors.initials: MA
authors.lastname: Ansari
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Pedergnana
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK.
authors.forename: Camilla
authors.initials: C
authors.lastname: L C Ip
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Magri
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK.
authors.forename: Annette
authors.initials: A
authors.lastname: Von Delft
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bonsall
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Nimisha
authors.initials: N
authors.lastname: Chaturvedi
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Istvan
authors.initials: I
authors.lastname: Bartha
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Smith
authors.affiliation: Department of Statistics, University of Oxford, Oxford, UK.
authors.forename: George
authors.initials: G
authors.lastname: Nicholson
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
authors.forename: Gilean
authors.identifier: http://orcid.org/0000-0002-5012-4162
authors.initials: G
authors.lastname: McVean
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Trebes
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Piazza
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Jacques
authors.identifier: http://orcid.org/0000-0002-8240-939X
authors.initials: J
authors.lastname: Fellay
authors.affiliation: Wright-Fleming Institute, Imperial College London, London, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Cooke
authors.affiliation: Queen Mary University of London, London, UK.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Foster
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Hudson
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: John
authors.initials: J
authors.lastname: McLauchlan
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Simmonds
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Rory
authors.identifier: http://orcid.org/0000-0001-8596-0366
authors.initials: R
authors.lastname: Bowden
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Barnes
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Chris C A
authors.initials: CCA
authors.lastname: Spencer
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D000483:Alleles; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D016679:Genome, Viral / Q000235:genetics*; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D016174:Hepacivirus / Q000235:genetics* / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000821:virology; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007378:Interleukins / Q000235:genetics; D016015:Logistic Models; D025341:Principal Component Analysis; D019562:Viral Load / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000235:genetics; D000095022:Interferon Lambda; D012324:RNA-Dependent RNA Polymerase
chemical_list: D006680:HLA Antigens; D007378:Interleukins; D017361:Viral Nonstructural Proteins; C579163:IFNL4 protein, human; D000095022:Interferon Lambda; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase