Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus

M. Azim Ansari; Vincent Pedergnana; Camilla L.C. Ip; Andrea Magri; Annette Von Delft; David Bonsall; Nimisha Chaturvedi; Istvan Bartha; David Smith; George Nicholson; Gilean McVean; Amy Trebes; Paolo Piazza; Jacques Fellay; Graham Cooke; Graham R. Foster; Emma Hudson; John McLauchlan; Peter Simmonds; Rory Bowden; Paul Klenerman; Eleanor Barnes; Chris C.A. Spencer; Jonathan Ball; Diana Brainard; Gary Burgess; John Dillon; Charles Gore; Neil Guha; Rachel Halford; Cham Herath; Chris Holmes; Anita Howe; William Irving; Salim Khakoo; Diana Koletzki; Natasha Martin; Benedetta Massetto; Tamyo Mbisa; John McHutchison; Jane McKeating; Alec Miners; Andrea Murray; Peter Shaw; Paul Targett-Adams; Emma Thomson; Peter Vickerman; Nicole Zitzmann

doi:10.1038/ng.3835

Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus

M. Azim Ansari, Vincent Pedergnana, Camilla L.C. Ip, Andrea Magri, Annette Von Delft, David Bonsall, Nimisha Chaturvedi, Istvan Bartha, David Smith, George Nicholson, Gilean McVean, Amy Trebes, Paolo Piazza, Jacques Fellay, Graham Cooke, Graham R. Foster, Emma Hudson, John McLauchlan, Peter Simmonds, Rory BowdenPaul Klenerman, Eleanor Barnes, Chris C.A. Spencer, Jonathan Ball, Diana Brainard, Gary Burgess, John Dillon, Charles Gore, Neil Guha, Rachel Halford, Cham Herath, Chris Holmes, Anita Howe, William Irving, Salim Khakoo, Diana Koletzki, Natasha Martin, Benedetta Massetto, Tamyo Mbisa, John McHutchison, Jane McKeating, Alec Miners, Andrea Murray, Peter Shaw, Paul Targett-Adams, Emma Thomson, Peter Vickerman, Nicole Zitzmann

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Abstract

Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. Here we use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals who were chronically infected with HCV, predominantly genotype 3. We show that both alleles of genes encoding human leukocyte antigen molecules and genes encoding components of the interferon lambda innate immune system drive viral polymorphism. Additionally, we show that IFNL4 genotypes determine HCV viral load through a mechanism dependent on a specific amino acid residue in the HCV NS5A protein. These findings highlight the interplay between the innate immune system and the viral genome in HCV control.

Original language	English
Pages (from-to)	666-673
Number of pages	8
Journal	Nature Genetics
Volume	49
Issue number	5
DOIs	https://doi.org/10.1038/ng.3835
Publication status	Published - 1 May 2017
Externally published	Yes

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Ansari, M. A., Pedergnana, V., Ip, C. L. C., Magri, A., Von Delft, A., Bonsall, D., Chaturvedi, N., Bartha, I., Smith, D., Nicholson, G., McVean, G., Trebes, A., Piazza, P., Fellay, J., Cooke, G., Foster, G. R., Hudson, E., McLauchlan, J., Simmonds, P., ... Zitzmann, N. (2017). Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus. Nature Genetics, 49(5), 666-673. https://doi.org/10.1038/ng.3835

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title = "Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus",

abstract = "Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. Here we use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals who were chronically infected with HCV, predominantly genotype 3. We show that both alleles of genes encoding human leukocyte antigen molecules and genes encoding components of the interferon lambda innate immune system drive viral polymorphism. Additionally, we show that IFNL4 genotypes determine HCV viral load through a mechanism dependent on a specific amino acid residue in the HCV NS5A protein. These findings highlight the interplay between the innate immune system and the viral genome in HCV control.",

author = "Ansari, \{M. Azim\} and Vincent Pedergnana and Ip, \{Camilla L.C.\} and Andrea Magri and \{Von Delft\}, Annette and David Bonsall and Nimisha Chaturvedi and Istvan Bartha and David Smith and George Nicholson and Gilean McVean and Amy Trebes and Paolo Piazza and Jacques Fellay and Graham Cooke and Foster, \{Graham R.\} and Emma Hudson and John McLauchlan and Peter Simmonds and Rory Bowden and Paul Klenerman and Eleanor Barnes and Spencer, \{Chris C.A.\} and Jonathan Ball and Diana Brainard and Gary Burgess and John Dillon and Charles Gore and Neil Guha and Rachel Halford and Cham Herath and Chris Holmes and Anita Howe and William Irving and Salim Khakoo and Diana Koletzki and Natasha Martin and Benedetta Massetto and Tamyo Mbisa and John McHutchison and Jane McKeating and Alec Miners and Andrea Murray and Peter Shaw and Paul Targett-Adams and Emma Thomson and Peter Vickerman and Nicole Zitzmann",

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doi = "10.1038/ng.3835",

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Ansari, MA, Pedergnana, V, Ip, CLC, Magri, A, Von Delft, A, Bonsall, D, Chaturvedi, N, Bartha, I, Smith, D, Nicholson, G, McVean, G, Trebes, A, Piazza, P, Fellay, J, Cooke, G, Foster, GR, Hudson, E, McLauchlan, J, Simmonds, P, Bowden, R, Klenerman, P, Barnes, E, Spencer, CCA, Ball, J, Brainard, D, Burgess, G, Dillon, J, Gore, C, Guha, N, Halford, R, Herath, C, Holmes, C, Howe, A, Irving, W, Khakoo, S, Koletzki, D, Martin, N, Massetto, B, Mbisa, T, McHutchison, J, McKeating, J, Miners, A, Murray, A, Shaw, P, Targett-Adams, P, Thomson, E, Vickerman, P & Zitzmann, N 2017, 'Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus', Nature Genetics, vol. 49, no. 5, pp. 666-673. https://doi.org/10.1038/ng.3835

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T1 - Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus

AU - Ansari, M. Azim

AU - Pedergnana, Vincent

AU - Ip, Camilla L.C.

AU - Magri, Andrea

AU - Von Delft, Annette

AU - Bonsall, David

AU - Chaturvedi, Nimisha

AU - Bartha, Istvan

AU - Smith, David

AU - Nicholson, George

AU - McVean, Gilean

AU - Trebes, Amy

AU - Piazza, Paolo

AU - Fellay, Jacques

AU - Cooke, Graham

AU - Foster, Graham R.

AU - Hudson, Emma

AU - McLauchlan, John

AU - Simmonds, Peter

AU - Bowden, Rory

AU - Klenerman, Paul

AU - Barnes, Eleanor

AU - Spencer, Chris C.A.

AU - Ball, Jonathan

AU - Brainard, Diana

AU - Burgess, Gary

AU - Dillon, John

AU - Gore, Charles

AU - Guha, Neil

AU - Halford, Rachel

AU - Herath, Cham

AU - Holmes, Chris

AU - Howe, Anita

AU - Irving, William

AU - Khakoo, Salim

AU - Koletzki, Diana

AU - Martin, Natasha

AU - Massetto, Benedetta

AU - Mbisa, Tamyo

AU - McHutchison, John

AU - McKeating, Jane

AU - Miners, Alec

AU - Murray, Andrea

AU - Shaw, Peter

AU - Targett-Adams, Paul

AU - Thomson, Emma

AU - Vickerman, Peter

AU - Zitzmann, Nicole

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. Here we use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals who were chronically infected with HCV, predominantly genotype 3. We show that both alleles of genes encoding human leukocyte antigen molecules and genes encoding components of the interferon lambda innate immune system drive viral polymorphism. Additionally, we show that IFNL4 genotypes determine HCV viral load through a mechanism dependent on a specific amino acid residue in the HCV NS5A protein. These findings highlight the interplay between the innate immune system and the viral genome in HCV control.

AB - Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. Here we use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals who were chronically infected with HCV, predominantly genotype 3. We show that both alleles of genes encoding human leukocyte antigen molecules and genes encoding components of the interferon lambda innate immune system drive viral polymorphism. Additionally, we show that IFNL4 genotypes determine HCV viral load through a mechanism dependent on a specific amino acid residue in the HCV NS5A protein. These findings highlight the interplay between the innate immune system and the viral genome in HCV control.

U2 - 10.1038/ng.3835

DO - 10.1038/ng.3835

M3 - Article

SN - 1061-4036

VL - 49

SP - 666

EP - 673

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus

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