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

Kemming, Janine, Reeves, Emma, Nitschke, Katja, Widmeier, Vanessa, Emmerich, Florian, Hermle, Tobias, Gostick, Emma, Walker, Andreas, Timm, Jörg, Price, David A., Hofmann, Maike, Thimme, Robert, James, Edward and Neumann-Haefelin, Christoph 2019. ERAP1 allotypes shape the epitope repertoire of virus-specific CD8+ T cell responses in acute hepatitis C virus infection. Journal of Hepatology 70 (6) , pp. 1072-1081. 10.1016/j.jhep.2019.01.034

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Abstract

Background & Aims Endoplasmic 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. Methods We 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, in a patient who had acquired an HCV genotype 1a infection through a needle-stick injury. Results Two 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 a couple of respects. Firstly, reactivity was directed away from classically immunodominant epitopes, preferentially targeting either novel or subdominant epitopes. Secondly, reactivity was biased towards longer epitopes (10–11-mers). Despite the patient exhibiting favorable prognostic indicators, these atypical immune responses failed to clear the virus and the patient developed persistent low-level infection with HCV. Conclusions ERAP1 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an open access article under the CC BY-NC-ND license
Publisher: Elsevier
ISSN: 0168-8278
Date of First Compliant Deposit: 10 June 2019
Date of Acceptance: 31 January 2019
Last Modified: 19 Nov 2019 15:47
URI: http://orca.cf.ac.uk/id/eprint/122308

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