TY - JOUR
T1 - Amino acid substitutions within HLA-B*27- restricted T cell epitopes prevent recognition by hepatitis delta virus-specific CD8+ T cells
AU - Karimzadeh, Hadi
AU - Kiraithe, Muthamia M.
AU - Kosinska, Anna D.
AU - Glaser, Manuel
AU - Fiedler, Melanie
AU - Oberhardt, Valerie
AU - Alizei, Elahe Salimi
AU - Hofmann, Maike
AU - Mok, Juk Yee
AU - Nguyen, Melanie
AU - van Esch, Wim J.E.
AU - Budeus, Bettina
AU - Grabowski, Jan
AU - Homs, Maria
AU - Olivero, Antonella
AU - Keyvani, Hossein
AU - Rodríguez-Frías, Francisco
AU - Tabernero, David
AU - Buti, Maria
AU - Heinold, Andreas
AU - Alavian, Seyed Moayed
AU - Bauer, Tanja
AU - Wiesch, Julian Schulze zur
AU - Raziorrouh, Bijan
AU - Hoffmann, Daniel
AU - Smedile, Antonina
AU - Rizzetto, Mario
AU - Wedemeyer, Heiner
AU - Timm, Jörg
AU - Antes, Iris
AU - Neumann-Haefelin, Christoph
AU - Protzer, Ulrike
AU - Roggendorf, Michael
PY - 2018/7/1
Y1 - 2018/7/1
N2 - © 2018 American Society for Microbiology. 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.
AB - © 2018 American Society for Microbiology. 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.
KW - Cytotoxic T lymphocyte
KW - Epitope mapping
KW - Immune escape
KW - Immune selection
KW - Large hepatitis delta antigen
U2 - 10.1128/JVI.01891-17
DO - 10.1128/JVI.01891-17
M3 - Article
SN - 0022-538X
VL - 92
JO - Journal of Virology
JF - Journal of Virology
IS - 13
M1 - e01891-17
ER -
