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

Hadi Karimzadeh, Muthamia M. Kiraithe, Anna D. Kosinska, Manuel Glaser, Melanie Fiedler, Valerie Oberhardt, Elahe Salimi Alizei, Maike Hofmann, Juk Yee Mok, Melanie Nguyen, Wim J.E. van Esch, Bettina Budeus, Jan Grabowski, Maria Homs, Antonella Olivero, Hossein Keyvani, Francisco Rodríguez-Frías, David Tabernero, Maria Buti, Andreas HeinoldSeyed Moayed Alavian, Tanja Bauer, Julian Schulze zur Wiesch, Bijan Raziorrouh, Daniel Hoffmann, Antonina Smedile, Mario Rizzetto, Heiner Wedemeyer, Jörg Timm, Iris Antes, Christoph Neumann-Haefelin, Ulrike Protzer, Michael Roggendorf

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22 Scopus citations


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.

Original languageEnglish
Article numbere01891-17
JournalJournal of Virology
Issue number13
StatePublished - 1 Jul 2018


  • Cytotoxic T lymphocyte
  • Epitope mapping
  • Immune escape
  • Immune selection
  • Large hepatitis delta antigen


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