Interferon lambda 4 impacts the genetic diversity of hepatitis C virus

M. Azim Ansari, Elihu Aranday-Cortes, Camilla L. C. Ip, Ana da Silva Filipe, Siu Hin Lau, Connor Bamford, David Bonsall, Amy Trebes, Paolo Piazza, Vattipally Sreenu, Vanessa M. Cowton, STOP-HCV Consortium, Emma Hudson, Rory Bowden, Arvind H. Patel, Graham R. Foster, William L. Irving, Kosh Agarwal, Emma C. Thomson, Peter SimmondsPaul Klenerman, Chris Holmes, Eleanor Barnes, Chris C. A. Spencer, John McLauchlan, Vincent Pedergnana

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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.

Original languageEnglish
Article numbere42463
Pages (from-to)1-23
Number of pages23
JournaleLife
Volume8
DOIs
Publication statusPublished - 3 Sep 2019

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    Ansari, M. A., Aranday-Cortes, E., Ip, C. L. C., da Silva Filipe, A., Lau, S. H., Bamford, C., Bonsall, D., Trebes, A., Piazza, P., Sreenu, V., Cowton, V. M., STOP-HCV Consortium, Hudson, E., Bowden, R., Patel, A. H., Foster, G. R., Irving, W. L., Agarwal, K., Thomson, E. C., ... Pedergnana, V. (2019). Interferon lambda 4 impacts the genetic diversity of hepatitis C virus. eLife, 8, 1-23. [e42463]. https://doi.org/10.7554/eLife.42463