Mechanisms of CD8+ T cell failure in chronic hepatitis E virus infection

Kemming, Janine, Gundlach, Swantje, Panning, Marcus, Huzly, Daniela, Huang, Jiabin, Lütgehetmann, Marc, Pischke, Sven, Schulze zur Wiesch, Julian, Emmerich, Florian, Llewellyn-Lacey, Sian, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Tanriver, Yakup, Warnatz, Klaus, Boettler, Tobias, Thimme, Robert, Hofmann, Maike, Fischer, Nicole and Neumann-Haefelin, Christoph 2022. Mechanisms of CD8+ T cell failure in chronic hepatitis E virus infection. Journal of Hepatology 77 (4) , pp. 978-990. 10.1016/j.jhep.2022.05.019

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Abstract

Background and aims In immunosuppressed patients, persistent hepatitis E virus (HEV) infection is common and may lead to cirrhosis and liver failure. HEV clearance depends on an effective virus-specific CD8+ T cell response, however, the knowledge gap of HEV-specific CD8+ T cell epitopes hindered analysis of the mechanisms of T cell failure in persistent infection thus far. Methods We comprehensively studied HEV-specific CD8+ T cell responses in 46 patients with self-limiting (n=34) or chronic HEV infection (n=12), by epitope-specific expansion, functional testing, ex vivo peptide HLA class I tetramer multi-parametric staining, and viral sequence analysis. Results We identified 25 HEV-specific CD8+ T cell epitopes restricted by 9 different HLA class I alleles. In self-limiting HEV infection, HEV-specific CD8+ T cells were vigorous, contracted after resolution of infection, and formed functional memory responses. In contrast, in chronic infection, the HEV-specific CD8+ T cell response was diminished, declined over time, and displayed phenotypic features of exhaustion. However, improved proliferation and interferon-γ production of HEV-specific CD8+ T cells and evolution of a memory-like phenotype was observed upon reduction of immunosuppression and/or ribavirin treatment and was associated with viral clearance. In one patient, mutational viral escape in a targeted CD8+ T cell epitope contributed to CD8+ T cell failure. Conclusion Chronic HEV infection is associated with HEV-specific CD8+ T cell exhaustion, indicating that T cell exhaustion driven by persisting antigen recognition also occurs in severely immunosuppressed hosts. Functional reinvigoration of virus-specific T cells is at least partially possible when antigen is cleared. In a minority of patients, viral escape also contributes to HEV-specific CD8+ T cell failure and thus needs to be taken into account in personalized immunotherapeutic approaches. Lay Summary In immunosuppressed patients, chronic HEV infection is common. For resolution of infection a functional HEV-specific CD8+ T cell response is essential, however, in immunosuppressed individuals CD8+ T cell exhaustion and viral escape contribute to CD8+ T cell failure.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Start Date: 2022-05-25
Publisher:	Elsevier
ISSN:	0168-8278
Date of First Compliant Deposit:	7 June 2022
Date of Acceptance:	16 May 2022
Last Modified:	03 May 2023 00:22
URI:	https://orca.cardiff.ac.uk/id/eprint/150264

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