Pervasive adaptation of hepatitis C virus to interferon lambda polymorphism across multiple genotypes

Genetic polymorphism in the interferon lambda (IFN-{lambda}) region is associated with spontaneous clearance of hepatitis C virus (HCV) infection and with response to interferon-based antiviral treatment. Here, we evaluate the associations between IFN- {lambda} polymorphism and HCV variation through a genome-to-genome analysis in 8,729 patients from diverse ancestral backgrounds infected with various HCV genotypes. We searched for associations between rs12979860 genotype, a tag for IFN-{lambda} haplotypes, and amino acid variants in the NS3, NS4A, NS5A and NS5B HCV proteins. We report multiple associations between host and pathogen variants in the full cohort as well as in subgroups defined by viral genotype and human ancestry. We also assess the combined impact of human and HCV variation on pre-treatment viral load. By demonstrating that IFN-{lambda} genetic variation leaves a large footprint in the viral genome, this study provides strong evidence of pervasive viral adaptation to host innate immune pressure during chronic HCV infection.