TY - JOUR TI - Interferon lambda 4 impacts the genetic diversity of hepatitis C virus AU - Ansari, M Azim AU - Aranday-Cortes, Elihu AU - Ip, Camilla LC AU - da Silva Filipe, Ana AU - Lau, Siu Hin AU - Bamford, Connor AU - Bonsall, David AU - Trebes, Amy AU - Piazza, Paolo AU - Sreenu, Vattipally AU - Cowton, Vanessa M AU - STOP-HCV Consortium AU - Hudson, Emma AU - Bowden, Rory AU - Patel, Arvind H AU - Foster, Graham R AU - Irving, William L AU - Agarwal, Kosh AU - Thomson, Emma C AU - Simmonds, Peter AU - Klenerman, Paul AU - Holmes, Chris AU - Barnes, Eleanor AU - Spencer, Chris CA AU - McLauchlan, John AU - Pedergnana, Vincent A2 - O'Brien, Thomas A2 - Garrett, Wendy S VL - 8 PY - 2019 DA - 2019/09/03 SP - e42463 C1 - eLife 2019;8:e42463 DO - 10.7554/eLife.42463 UR - https://doi.org/10.7554/eLife.42463 AB - 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. KW - hepatitis C virus KW - genome-to-genome analysis KW - host-pathogen interactions KW - interferon lambda 4 KW - innate immunity JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -