Interferon lambda 4 impacts the genetic diversity of hepatitis C virus

Ansari, M. A. et al. (2019) Interferon lambda 4 impacts the genetic diversity of hepatitis C virus. eLife, 8, e42463. (doi: 10.7554/eLife.42463) (PMID:31478835) (PMCID:PMC6721795)

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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.

Item Type:Articles
Additional Information:The authors would like to thank Gilead Sciences for the provision of samples and data from the BOSON clinical study for use in these analyses and HCV Research UK (funded by the Medical Research Foundation [C0365]) for their assistance in handling and coordinating the release of samples for these analyses. The authors would also like to thank Daniel J Wilson and Jacques Fellay for helpful comments. The work was supported by Core funding to the Wellcome Trust Centre for Human Genetics provided by the Wellcome Trust (090532/Z/09/Z). E.B is funded by the MRC as an MRC Senior Clinical Fellow with additional support from the Oxford NHIR BRC as a principal fellow. Professor Barnes is a National Institute for Health Research (NIHR) Senior Investigator. P.K is funded by the Oxford Martin School, NIHR Biomedical Research Centre, Oxford, by the Wellcome Trust (109965MA) and NIH (U19AI082630). C.C.A.S is funded by the Wellcome Trust (097364/Z/11/Z). The views expressed in this article are those of the author(s) and notnecessarily those of the NHS, the NIHR, or the Department of Health.
Glasgow Author(s) Enlighten ID:Aranday-Cortes, Dr Elihu and Cowton, Dr Vanessa and Da Silva Filipe, Dr Ana and Bamford, Dr Connor and Vattipally, Dr Sreenu and Thomson, Professor Emma and Patel, Professor Arvind and McLauchlan, Professor John
Creator Roles:
Aranday-Cortes, E.Conceptualization, Data curation, Formal analysis, Validation, Writing – original draft, Writing – review and editing
McLauchlan, J.Conceptualization, Funding acquisition, Supervision, Validation, Writing – original draft, Writing – review and editing
Da Silva Filipe, A.Data curation, Formal analysis, Resources, Writing – review and editing
Bamford, C.Data curation, Formal analysis, Resources, Writing – review and editing
Cowton, V.Formal analysis, Investigation, Resources, Writing – review and editing
Patel, A.Investigation, Resources, Writing – review and editing
Vattipally, S.Resources, Software, Writing – review and editing
Thomson, E.Resources, Writing – review and editing
Authors: Ansari, M. A., Aranday-Cortes, E., Ip, C. L.C., Da Silva Filipe, A., Hin, L. S., Bamford, C. G.G., Bonsall, D., Piazza, P., Sreenu, V., Cowton, V. M., STOP-HCV Consortium, ., Hudson, E., Bowden, R., Patel, A. H., Foster, G., Irving, W. L., Agarwal, K., Thomson, E. C., Simmonds, P., Klenerman, P., Holmes, C., Barnes, E., Spencer, C. C.A., McLauchlan, J., and Pedergnana, V.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN (Online):2050-084X
Copyright Holders:Copyright © 2019 Ansari et al.
First Published:First published in eLife 8:e42463
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
644641Establishment of a Resource for Long-Term Study of Hepatitis C Virus Infection in the UKJohn McLauchlanMedical Research Foundation (MEDRESFO)C0365MVLS III - CENTRE FOR VIRUS RESEARCH
645101T-cell mediated evolution of hepatitis C virus during acute infectionEmma ThomsonWellcome Trust (WELLCOTR)102789/Z/13/ZMVLS III - CENTRE FOR VIRUS RESEARCH
656491Basis of the host range and tissue tropism for hepatitis C virusArvind PatelMedical Research Council (MRC)MC_UU_12014/2MVLS III - CENTRE FOR VIRUS RESEARCH