Amino acid substitutions within HLA-B*27- restricted T cell epitopes prevent recognition by hepatitis delta virus-specific CD8+ T cells

Karimzadeh, H. and Kiraithe, M.M. and Kosinska, A.D. and Glaser, M. and Fiedler, M. and Oberhardt, V. and Alizei, E.S. and Hofmann, M. and Mok, J.Y. and Nguyen, M. and van Esch, W.J.E. and Budeus, B. and Grabowski, J. and Homs, M. and Olivero, A. and Keyvani, H. and Rodríguez-Frías, F. and Tabernero, D. and Buti, M. and Heinold, A. and Alavian, S.M. and Bauer, T. and Wiesch, J.S. and Raziorrouh, B. and Hoffmann, D. and Smedile, A. and Rizzetto, M. and Wedemeyer, H. and Timm, J. and Antes, I. and Neumann-Haefelin, C. and Protzer, U. and Roggendorf, M. (2018) Amino acid substitutions within HLA-B*27- restricted T cell epitopes prevent recognition by hepatitis delta virus-specific CD8+ T cells. Journal of Virology, 92 (13).


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Virus-specific CD8 T cell response seems to play a significant role in the outcome of hepatitis delta virus (HDV) infection. However, the HDV-specific T cell epitope repertoire and mechanisms of CD8 T cell failure in HDV infection have been poorly characterized. We therefore aimed to characterize HDV-specific CD8 T cell epitopes and the impacts of viral mutations on immune escape. In this study, we predicted peptide epitopes binding the most frequent human leukocyte antigen (HLA) types and assessed their HLA binding capacities. These epitopes were characterized in HDV-infected patients by intracellular gamma interferon (IFN-γ) staining. Sequence analysis of large hepatitis delta antigen (L-HDAg) and HLA typing were performed in 104 patients. The impacts of substitutions within epitopes on the CD8 T cell response were evaluated experimentally and by in silico studies. We identified two HLA-B*27-restricted CD8 T cell epitopes within L-HDAg. These novel epitopes are located in a relatively conserved region of L-HDAg. However, we detected molecular footprints within the epitopes in HLA-B*27-positive patients with chronic HDV infections. The variant peptides were not cross-recognized in HLA-B*27-positive patients with resolved HDV infections, indicating that the substitutions represent viral escape mutations. Molecular modeling of HLA-B*27 complexes with the L-HDAg epitope and its potential viral escape mutations indicated that the structural and electrostatic properties of the bound peptides differ considerably at the T cell receptor interface, which provides a possible molecular explanation for the escape mechanism. This viral escape from the HLA-B*27-restricted CD8 T cell response correlates with a chronic outcome of hepatitis D infection. T cell failure resulting from immune escape may contribute to the high chronicity rate in HDV infection. © 2018 American Society for Microbiology.

Item Type: Article
Additional Information: cited By 0
Uncontrolled Keywords: epitope; gamma interferon; hepatitis delta antigen; HLA B27 antigen; T lymphocyte receptor; epitope; hepatitis delta antigen; hepatitis delta virus large antigen; HLA B antigen, amino acid substitution; antigen binding cell; Article; CD8+ T lymphocyte; clinical outcome; cohort analysis; controlled study; Hepatitis delta virus; human; human cell; in vitro study; infectious hepatitis; major clinical study; nonhuman; phylogeny; priority journal; prognosis; virus detection; virus mutation; virus virulence; amino acid sequence; amino acid substitution; CD8+ T lymphocyte; delta agent hepatitis; genetics; Hepatitis delta virus; immunology; metabolism; mutation; sequence homology; virology, Amino Acid Sequence; Amino Acid Substitution; CD8-Positive T-Lymphocytes; Epitopes, T-Lymphocyte; Hepatitis D; Hepatitis delta Antigens; Hepatitis Delta Virus; HLA-B Antigens; Humans; Mutation; Sequence Homology
Subjects: WH Hemic and Lymphatic Systems
Depositing User: eprints admin
Date Deposited: 23 Dec 2018 10:49
Last Modified: 03 Jul 2019 06:22

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