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.

Original publication

DOI

10.1038/ng.3835

Type

Journal article

Journal

Nature genetics

Publication Date

05/2017

Volume

49

Pages

666 - 673

Addresses

Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK.

Keywords

STOP-HCV Consortium, Humans, Hepacivirus, Hepatitis C, Chronic, Viral Nonstructural Proteins, Interleukins, HLA Antigens, Viral Load, Logistic Models, Genotype, Alleles, Genome, Viral, Genome, Human, Principal Component Analysis, Host-Pathogen Interactions, Immunity, Innate, Genetic Variation, Adaptive Immunity