Abstract
Genetic polymorphism in the interferon lambda (IFN-λ) region is associated with spontaneous clearance of hepatitis C virus (HCV) infection and response to interferon-based treatment. Here, we evaluate associations between IFN-λ polymorphism and HCV variation in 8729 patients (Europeans 77%, Asians 13%, Africans 8%) infected with various viral genotypes, predominantly 1a (41%), 1b (22%) and 3a (21%). We searched for associations between rs12979860 genotype and variants in the NS3, NS4A, NS5A and NS5B HCV proteins. We report multiple associations in all tested proteins, including in the interferon-sensitivity determining region of NS5A. We also assessed the combined impact of human and HCV variation on pretreatment viral load and report amino acids associated with both IFN-λ polymorphism and HCV load across multiple viral genotypes. By demonstrating that IFN-λ variation leaves a large footprint on the viral proteome, we provide evidence of pervasive viral adaptation to innate immune pressure during chronic HCV infection.
Highlights
Infection with hepatitis C virus (HCV), a positive strand RNA virus of the Flaviviridae family, represents a major health problem, with an estimated 71 million chronically infected patients worldwide (WHO, 2017)
We show that the presence or absence of the IFN-l4 protein has a pervasive impact on HCV, by describing multiple associations between host and pathogen variants in subgroups defined by viral genotype or human ancestry
We used an integrated association analysis approach to explore the impact of human genetic variation in the interferon lambda (IFN-l) region on part of the HCV proteome during chronic infection
Summary
Infection with hepatitis C virus (HCV), a positive strand RNA virus of the Flaviviridae family, represents a major health problem, with an estimated 71 million chronically infected patients worldwide (WHO, 2017). Within each infected individual, multiple distinct HCV variants co-exist as quasipecies (Farci et al, 2000). Inter-host and intra-host HCV evolution is shaped by multiple forces, including human immune pressure (Merani et al, 2011). Using an unbiased association study framework, a genome-to-genome analysis aims at identifying the escape mutations that accumulate in the pathogen genome in response to host genetic variants. Ansari et al (2017) used this approach to analyze a cohort of individuals of white ancestry predominantly infected with genotype 3a HCV; they identified associations between viral variants and human polymorphisms in the interferon lambda (IFN-l) and HLA regions, Chaturvedi et al eLife 2019;8:e42542.
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