Genome-to-genome analysis reveals the impact of the human innate and 1 adaptive immune systems on the hepatitis C virus 2

Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and 31 host genetic factors. We use human genome-wide genotyping arrays and new 32 whole-genome HCV viral sequencing technologies to perform a systematic genome- 33 to-genome study of 542 individuals chronically infected with HCV, predominately 34 genotype 3. We show that both HLA alleles and interferon lambda innate immune 35 system genes drive viral genome polymorphism, and that IFNL4 genotypes 36 determine HCV viral load through a mechanism that is dependent on a specific 37 polymorphism in the HCV polyprotein. We highlight the interplay between innate 38 immune responses and the viral genome in HCV control.

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