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ERAP1 allotypes impact the epitope repertoire of virus-specific CD8+ T cell responses in acute hepatitis C virus infection

ERAP1 allotypes impact the epitope repertoire of virus-specific CD8+ T cell responses in acute hepatitis C virus infection
ERAP1 allotypes impact the epitope repertoire of virus-specific CD8+ T cell responses in acute hepatitis C virus infection
Background & AimsEndoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms are linked with human leukocyte antigen (HLA) class I-associated autoinflammatory disorders, including ankylosing spondylitis and Behçet’s disease. Disease-associated ERAP1 allotypes exhibit distinct functional properties, but it remains unclear how differential peptide trimming in vivo affects the repertoire of epitopes presented to CD8+ T cells. The aim of this study was to determine the impact of ERAP1 allotypes on the virus-specific CD8+ T cell epitope repertoire in an HLA-B*27:05+ individual with acute hepatitis C virus (HCV) infection. MethodsWe performed genetic and functional analyses of ERAP1 allotypes and characterized the HCV-specific CD8+ T cell repertoire at the level of fine epitope specificity and HLA class I restriction. ResultsTwo hypoactive allotypic variants of ERAP1 were identified in an individual with acute HCV infection. The associated repertoire of virus-derived epitopes recognized by CD8+ T cells was uncommon in two respects. First, reactivity was directed away from classically immunodominant epitopes, preferentially targeting either novel or subdominant epitopes. Second, reactivity was biased towards longer epitopes (10–11mers). Despite the presence of favorable prognostic indicators, these atypical immune responses failed to clear HCV. ConclusionsERAP1 allotypes modify the virus-specific CD8+ T cell epitope repertoire in vivo, leading to altered immunodominance patterns that may contribute to the failure of antiviral immunity after infection with HCV. Lay summaryEndoplasmic reticulum aminopeptidase 1 (ERAP1) plays a key role in antigen presentation. Genetic variants of ERAP1 are linked with human leukocyte antigen (HLA) class I-associated autoinflammatory disorders, such as ankylosing spondylitis and Behçet’s disease, but it remains unclear how these functionally distinct allotypes influence the repertoire of epitopes presented to CD8+ T cells. We found that ERAP1 allotypes can modify the virus-specific CD8+ T cell epitope repertoire in vivo, leading to altered immunodominance patterns that may contribute to the failure of antiviral immunity after infection with hepatitis C virus (HCV).
0168-8278
Kemming, Janine
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Reeves, Emma
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Nitschke, Katja
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Widmeier, Vanessa
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Emmerich, Florian
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Hermle, Tobias
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Gostick, Emma
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Walker, Andreas
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Timm, Jorg
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Price, David
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Hofmann, Maike
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Thimme, Robert
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James, Edward
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Neumann-Haefelin, Christophe
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Kemming, Janine
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Reeves, Emma
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Nitschke, Katja
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Widmeier, Vanessa
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Emmerich, Florian
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Hermle, Tobias
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Gostick, Emma
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Walker, Andreas
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Timm, Jorg
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Price, David
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Hofmann, Maike
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Thimme, Robert
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James, Edward
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Neumann-Haefelin, Christophe
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Kemming, Janine, Reeves, Emma, Nitschke, Katja, Widmeier, Vanessa, Emmerich, Florian, Hermle, Tobias, Gostick, Emma, Walker, Andreas, Timm, Jorg, Price, David, Hofmann, Maike, Thimme, Robert, James, Edward and Neumann-Haefelin, Christophe (2019) ERAP1 allotypes impact the epitope repertoire of virus-specific CD8+ T cell responses in acute hepatitis C virus infection. Journal of Hepatology. (doi:10.1016/j.jhep.2019.01.034).

Record type: Article

Abstract

Background & AimsEndoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms are linked with human leukocyte antigen (HLA) class I-associated autoinflammatory disorders, including ankylosing spondylitis and Behçet’s disease. Disease-associated ERAP1 allotypes exhibit distinct functional properties, but it remains unclear how differential peptide trimming in vivo affects the repertoire of epitopes presented to CD8+ T cells. The aim of this study was to determine the impact of ERAP1 allotypes on the virus-specific CD8+ T cell epitope repertoire in an HLA-B*27:05+ individual with acute hepatitis C virus (HCV) infection. MethodsWe performed genetic and functional analyses of ERAP1 allotypes and characterized the HCV-specific CD8+ T cell repertoire at the level of fine epitope specificity and HLA class I restriction. ResultsTwo hypoactive allotypic variants of ERAP1 were identified in an individual with acute HCV infection. The associated repertoire of virus-derived epitopes recognized by CD8+ T cells was uncommon in two respects. First, reactivity was directed away from classically immunodominant epitopes, preferentially targeting either novel or subdominant epitopes. Second, reactivity was biased towards longer epitopes (10–11mers). Despite the presence of favorable prognostic indicators, these atypical immune responses failed to clear HCV. ConclusionsERAP1 allotypes modify the virus-specific CD8+ T cell epitope repertoire in vivo, leading to altered immunodominance patterns that may contribute to the failure of antiviral immunity after infection with HCV. Lay summaryEndoplasmic reticulum aminopeptidase 1 (ERAP1) plays a key role in antigen presentation. Genetic variants of ERAP1 are linked with human leukocyte antigen (HLA) class I-associated autoinflammatory disorders, such as ankylosing spondylitis and Behçet’s disease, but it remains unclear how these functionally distinct allotypes influence the repertoire of epitopes presented to CD8+ T cells. We found that ERAP1 allotypes can modify the virus-specific CD8+ T cell epitope repertoire in vivo, leading to altered immunodominance patterns that may contribute to the failure of antiviral immunity after infection with hepatitis C virus (HCV).

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Accepted/In Press date: 31 January 2019
e-pub ahead of print date: 13 February 2019

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Local EPrints ID: 428396
URI: https://eprints.soton.ac.uk/id/eprint/428396
ISSN: 0168-8278
PURE UUID: 0fac9dfc-58ba-4d26-8563-dd47eec8737e

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Date deposited: 22 Feb 2019 17:30
Last modified: 19 Jul 2019 16:41

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Contributors

Author: Janine Kemming
Author: Emma Reeves
Author: Katja Nitschke
Author: Vanessa Widmeier
Author: Florian Emmerich
Author: Tobias Hermle
Author: Emma Gostick
Author: Andreas Walker
Author: Jorg Timm
Author: David Price
Author: Maike Hofmann
Author: Robert Thimme
Author: Edward James
Author: Christophe Neumann-Haefelin

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