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

Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and 51 host genetic factors. We use human genome-wide genotyping arrays and new 52 whole-genome HCV viral sequencing technologies to perform a systematic genome- 53 to-genome study of 542 individuals chronically infected with HCV, predominately 54 genotype 3. We show that both HLA alleles and interferon lambda innate immune 55 system genes drive viral genome polymorphism, and that IFNL4 genotypes 56 determine HCV viral load through a mechanism that is dependent on a specific 57 polymorphism in the HCV polyprotein. We highlight the interplay between innate 58 immune responses and the viral genome in HCV control. generated data a cohort of 601 infected patients the BOSON 21 clinical to systematically look for associations between host and virus genomes, exploiting the fact that while host genetics remain fixed, the virus mutates, allowing it to evolve during infection. For this we developed targeted viral enrichment 22,23 to obtain whole HCV genomes, and used high-throughput genotyping arrays in combination with statistical imputation to obtain data on HLA alleles 24,25 and nucleotide polymorphisms across the human genome. We provide evidence that polymorphisms relevant to the innate ( IFNL4 ) and adaptive immune systems (HLA genes) are associated with HCV sequence polymorphisms. We show that an interaction between host IFNL4 genotypes and a viral site in the NS5A protein determines HCV viral load. By assessing viral evolution in individuals with different IFNL4 genotypes, we highlight systematic differences in the innate immune response and discuss how these might relate to previous associations with spontaneous clearance and clinical treatment. We demonstrate the potential for a joint analysis of and genomic data to provide information on underlying molecular and their importance in treating and preventing HCV, and other viral in the era of genomic analysis.

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