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. ORCID: https://orcid.org/0000-0001-9416-2737, 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:	23 Aug 2024 20:54
URI:	https://orca.cardiff.ac.uk/id/eprint/122308

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