PMID- 29669837
OWN - NLM
STAT- MEDLINE
DCOM- 20180730
LR  - 20181213
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 92
IP  - 13
DP  - 2018 Jul 1
TI  - Amino Acid Substitutions within HLA-B*27-Restricted T Cell Epitopes Prevent 
      Recognition by Hepatitis Delta Virus-Specific CD8(+) T Cells.
LID - 10.1128/JVI.01891-17 [doi]
LID - e01891-17
AB  - 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-gamma) 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.IMPORTANCE Hepatitis 
      delta virus (HDV) causes severe chronic hepatitis, which affects 20 million 
      people worldwide. Only a small number of patients are able to clear the virus, 
      possibly mediated by a virus-specific T cell response. Here, we performed a 
      systematic screen to define CD8 epitopes and investigated the role of CD8 T cells 
      in the outcome of hepatitis delta and how they fail to eliminate HDV. Overall the 
      number of epitopes identified was very low compared to other hepatotropic 
      viruses. We identified, two HLA-B*27-restricted epitopes in patients with 
      resolved infections. In HLA-B*27-positive patients with chronic HDV infections, 
      however, we detected escape mutations within these identified epitopes that could 
      lead to viral evasion of immune responses. These findings support evidence 
      showing that HLA-B*27 is important for virus-specific CD8 T cell responses, 
      similar to other viral infections. These results have implications for the 
      clinical prognosis of HDV infection and for vaccine development.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - Karimzadeh, Hadi
AU  - Karimzadeh H
AD  - Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munchen, 
      Munich, Germany.
AD  - Institute of Virology, University Hospital of Essen, University of 
      Duisburg-Essen, Essen, Germany.
FAU - Kiraithe, Muthamia M
AU  - Kiraithe MM
AD  - University Hospital Freiburg, Department of Medicine II, University of Freiburg, 
      Faculty of Medicine, Freiburg, Germany.
FAU - Kosinska, Anna D
AU  - Kosinska AD
AD  - Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munchen, 
      Munich, Germany.
AD  - German Center for Infection Research (DZIF), Munich and Hannover Sites, 
      Braunschweig, Germany.
FAU - Glaser, Manuel
AU  - Glaser M
AD  - Center for Integrated Protein Science Munich at the Department of Biosciences, 
      Technische Universitat Munchen, Freising, Germany.
FAU - Fiedler, Melanie
AU  - Fiedler M
AD  - Institute of Virology, University Hospital of Essen, University of 
      Duisburg-Essen, Essen, Germany.
FAU - Oberhardt, Valerie
AU  - Oberhardt V
AD  - University Hospital Freiburg, Department of Medicine II, University of Freiburg, 
      Faculty of Medicine, Freiburg, Germany.
FAU - Salimi Alizei, Elahe
AU  - Salimi Alizei E
AD  - University Hospital Freiburg, Department of Medicine II, University of Freiburg, 
      Faculty of Medicine, Freiburg, Germany.
FAU - Hofmann, Maike
AU  - Hofmann M
AD  - University Hospital Freiburg, Department of Medicine II, University of Freiburg, 
      Faculty of Medicine, Freiburg, Germany.
FAU - Mok, Juk Yee
AU  - Mok JY
AD  - Sanquin, Amsterdam, The Netherlands.
FAU - Nguyen, Melanie
AU  - Nguyen M
AD  - Sanquin, Amsterdam, The Netherlands.
FAU - van Esch, Wim J E
AU  - van Esch WJE
AD  - Sanquin, Amsterdam, The Netherlands.
FAU - Budeus, Bettina
AU  - Budeus B
AD  - Department of Bioinformatics, University of Duisburg-Essen, Essen, Germany.
FAU - Grabowski, Jan
AU  - Grabowski J
AD  - German Center for Infection Research (DZIF), Munich and Hannover Sites, 
      Braunschweig, Germany.
AD  - Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical 
      School, Hannover, Germany.
FAU - Homs, Maria
AU  - Homs M
AD  - CIBERehd and Departments of Biochemistry/Microbiology and Hepatology, Vall 
      d'Hebron Hospital, University Autonoma de Barcelona (UAB), Barcelona, Spain.
FAU - Olivero, Antonella
AU  - Olivero A
AD  - Department of Medical Sciences, University of Turin, Turin, Italy.
FAU - Keyvani, Hossein
AU  - Keyvani H
AD  - Department of Virology, Iran University of Medical Sciences, Tehran, Iran.
FAU - Rodriguez-Frias, Francisco
AU  - Rodriguez-Frias F
AD  - CIBERehd and Departments of Biochemistry/Microbiology and Hepatology, Vall 
      d'Hebron Hospital, University Autonoma de Barcelona (UAB), Barcelona, Spain.
FAU - Tabernero, David
AU  - Tabernero D
AD  - CIBERehd and Departments of Biochemistry/Microbiology and Hepatology, Vall 
      d'Hebron Hospital, University Autonoma de Barcelona (UAB), Barcelona, Spain.
FAU - Buti, Maria
AU  - Buti M
AD  - CIBERehd and Departments of Biochemistry/Microbiology and Hepatology, Vall 
      d'Hebron Hospital, University Autonoma de Barcelona (UAB), Barcelona, Spain.
FAU - Heinold, Andreas
AU  - Heinold A
AD  - Institute of Transfusion Medicine, University of Duisburg-Essen, University 
      Hospital, Essen, Germany.
FAU - Alavian, Seyed Moayed
AU  - Alavian SM
AD  - Baqiyatallah Research Center for Gastroenterology and Liver Diseases, 
      Baqiyatallah University of Medical Sciences, Tehran, Iran.
FAU - Bauer, Tanja
AU  - Bauer T
AD  - Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munchen, 
      Munich, Germany.
AD  - German Center for Infection Research (DZIF), Munich and Hannover Sites, 
      Braunschweig, Germany.
FAU - Schulze Zur Wiesch, Julian
AU  - Schulze Zur Wiesch J
AD  - Department of Medicine, Section of Infectious Diseases, University Medical Center 
      Hamburg-Eppendorf, Hamburg, Germany.
FAU - Raziorrouh, Bijan
AU  - Raziorrouh B
AD  - University Hospital Munich-Grosshadern, Department of Medicine II, Munich, 
      Germany.
FAU - Hoffmann, Daniel
AU  - Hoffmann D
AD  - Department of Bioinformatics, University of Duisburg-Essen, Essen, Germany.
FAU - Smedile, Antonina
AU  - Smedile A
AD  - Department of Medical Sciences, University of Turin, Turin, Italy.
FAU - Rizzetto, Mario
AU  - Rizzetto M
AD  - Department of Medical Sciences, University of Turin, Turin, Italy.
FAU - Wedemeyer, Heiner
AU  - Wedemeyer H
AD  - German Center for Infection Research (DZIF), Munich and Hannover Sites, 
      Braunschweig, Germany.
AD  - Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical 
      School, Hannover, Germany.
FAU - Timm, Jorg
AU  - Timm J
AD  - Institute of Virology, Heinrich-Heine-University, University Hospital, 
      Duesseldorf, Germany.
FAU - Antes, Iris
AU  - Antes I
AD  - Center for Integrated Protein Science Munich at the Department of Biosciences, 
      Technische Universitat Munchen, Freising, Germany.
FAU - Neumann-Haefelin, Christoph
AU  - Neumann-Haefelin C
AD  - University Hospital Freiburg, Department of Medicine II, University of Freiburg, 
      Faculty of Medicine, Freiburg, Germany.
FAU - Protzer, Ulrike
AU  - Protzer U
AD  - Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munchen, 
      Munich, Germany.
AD  - German Center for Infection Research (DZIF), Munich and Hannover Sites, 
      Braunschweig, Germany.
FAU - Roggendorf, Michael
AU  - Roggendorf M
AD  - Institute of Virology, Technical University of Munich/Helmholtz Zentrum Munchen, 
      Munich, Germany michael.roggendorf@tum.de.
AD  - Institute of Virology, University Hospital of Essen, University of 
      Duisburg-Essen, Essen, Germany.
AD  - German Center for Infection Research (DZIF), Munich and Hannover Sites, 
      Braunschweig, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180613
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-B Antigens)
RN  - 0 (Hepatitis delta Antigens)
RN  - 0 (hepatitis delta virus large antigen)
SB  - IM
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - CD8-Positive T-Lymphocytes/*immunology/metabolism
MH  - Epitopes, T-Lymphocyte/*immunology/metabolism
MH  - HLA-B Antigens/genetics/*immunology/metabolism
MH  - Hepatitis D/genetics/*immunology/virology
MH  - Hepatitis Delta Virus/genetics/*immunology
MH  - Hepatitis delta Antigens/*immunology/metabolism
MH  - Humans
MH  - Mutation
MH  - Sequence Homology
PMC - PMC6002722
OTO - NOTNLM
OT  - cytotoxic T lymphocyte
OT  - epitope mapping
OT  - immune escape
OT  - immune selection
OT  - large hepatitis delta antigen
EDAT- 2018/04/20 06:00
MHDA- 2018/07/31 06:00
PMCR- 2018/12/13
CRDT- 2018/04/20 06:00
PHST- 2017/11/01 00:00 [received]
PHST- 2018/03/22 00:00 [accepted]
PHST- 2018/04/20 06:00 [pubmed]
PHST- 2018/07/31 06:00 [medline]
PHST- 2018/04/20 06:00 [entrez]
PHST- 2018/12/13 00:00 [pmc-release]
AID - JVI.01891-17 [pii]
AID - 01891-17 [pii]
AID - 10.1128/JVI.01891-17 [doi]
PST - epublish
SO  - J Virol. 2018 Jun 13;92(13):e01891-17. doi: 10.1128/JVI.01891-17. Print 2018 Jul 
      1.