Abstract
Hepatitis C virus (HCV) is a highly variable pathogen that frequently establishes chronic infection. This genetic variability is affected by the adaptive immune response but the contribution of other host factors is unclear. Here, we examined the role played by interferon lambda-4 (IFN-λ4) on HCV diversity; IFN-λ4 plays a crucial role in spontaneous clearance or establishment of chronicity following acute infection. We performed viral genome-wide association studies using human and viral data from 485 patients of white ancestry infected with HCV genotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-λ4 protein production and activity, influence amino acid variation across the viral polyprotein - not restricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We also observed an association with viral di-nucleotide proportions. These results support a direct role for IFN-λ4 in exerting selective pressure across the viral genome, possibly by a novel mechanism.
Highlights
Hepatitis C virus (HCV) infects an estimated 71 million people worldwide (World Health Organization, 2017) and can lead to severe liver disease in chronically infected patients
We did observe associations between the host interferon lambda 4 (IFNL4) single nucleotide polymorphism (SNP) rs12979860 and the fifth and seventh viral principal components (PCs) (p=1.3Â10À15 and 7.2 Â 10À9, respectively), which were not directed by host-virus population co-structuring, suggesting that the IFNL4 locus drives HCV nucleotide diversity (Figure 1—figure supplement 2b–d and Appendix 1)
We did not observe statistically significant enrichment of association signals in any specific HCV protein nor in HLA restricted epitope regions. This indicates that the host IFNL4 locus, and the innate immune response, can influence the amino acid residues that are encoded at specific sites on the HCV polyprotein
Summary
Hepatitis C virus (HCV) infects an estimated 71 million people worldwide (World Health Organization, 2017) and can lead to severe liver disease in chronically infected patients. The virus is highly variable and has been classified into seven distinct genotypes, and further divided into 67 subtypes, based on nucleotide sequence diversity (Simmonds, 2004). The factors that have driven the evolutionary path of HCV are multifactorial but undoubtedly are shaped by host genetics. Because of its major health burden, determining how both host and viral genetics contribute to the outcomes of infection is critical for a better understanding of HCV-mediated pathogenesis (Ploss and Dubuisson, 2012) and the immune response to viral infection
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