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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-\u03bb4) on HCV diversity; IFN-\u03bb4 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-\u03bb4 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-\u03bb4 in exerting selective pressure across the viral genome, possibly by a novel mechanism.<\/jats:p>","DOI":"10.7554\/elife.42463","type":"journal-article","created":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T07:00:23Z","timestamp":1567494023000},"source":"Crossref","is-referenced-by-count":32,"title":["Interferon lambda 4 impacts the genetic diversity of hepatitis C virus"],"prefix":"10.7554","volume":"8","author":[{"given":"M Azim","family":"Ansari","sequence":"first","affiliation":[{"name":"Wellcome Centre Human Genetics, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2637-2307","authenticated-orcid":true,"given":"Elihu","family":"Aranday-Cortes","sequence":"additional","affiliation":[{"name":"MRC-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, Glasgow, United 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