PMID- 30768983
OWN - NLM
STAT- MEDLINE
DCOM- 20190513
LR  - 20200225
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Print)
IS  - 0016-5085 (Linking)
VI  - 156
IP  - 6
DP  - 2019 May
TI  - Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8(+) T Cells and 
      Evolve at the Population Level.
PG  - 1820-1833
LID - S0016-5085(19)30366-X [pii]
LID - 10.1053/j.gastro.2019.02.003 [doi]
AB  - BACKGROUND & AIMS: Hepatitis D virus (HDV) superinfection in patients with 
      hepatitis B virus (HBV) is associated with rapid progression to liver cirrhosis 
      and hepatocellular carcinoma. Treatment options are limited, and no vaccine is 
      available. Although HDV-specific CD8(+) T cells are thought to control the virus, 
      little is known about which HDV epitopes are targeted by virus-specific CD8(+) T 
      cells or why these cells ultimately fail to control the infection. We aimed to 
      define how HDV escapes the CD8(+) T-cell-mediated response. METHODS: We collected 
      plasma and DNA samples from 104 patients with chronic HDV and HBV infection at 
      medical centers in Europe and the Middle East, sequenced HDV, typed human 
      leukocyte antigen (HLA) class I alleles from patients, and searched for 
      polymorphisms in HDV RNA associated with specific HLA class I alleles. We 
      predicted epitopes in HDV that would be recognized by CD8(+) T cells and 
      corresponded with the identified virus polymorphisms in patients with resolved 
      (n = 12) or chronic (n = 13) HDV infection. RESULTS: We identified 21 
      polymorphisms in HDV that were significantly associated with specific HLA class I 
      alleles (P < .005). Five of these polymorphisms were found to correspond to 
      epitopes in HDV that are recognized by CD8(+) T cells; we confirmed that CD8(+) T 
      cells in culture targeted these HDV epitopes. HDV variant peptides were only 
      partially cross-recognized by CD8(+) T cells isolated from patients, indicating 
      that the virus had escaped detection by these cells. These newly identified HDV 
      epitopes were restricted by relatively infrequent HLA class I alleles, and they 
      bound most frequently to HLA-B. In contrast, frequent HLA class I alleles were 
      not associated with HDV sequence polymorphisms. CONCLUSIONS: We analyzed 
      sequences of HDV RNA and HLA class I alleles that present epitope peptides to 
      CD8(+) T cells in patients with persistent HDV infection. We identified 
      polymorphisms in the HDV proteome that associate with HLA class I alleles. Some 
      variant peptides in epitopes from HDV were only partially recognized by CD8(+) T 
      cells isolated from patients; these could be mutations that allow HDV to escape 
      the immune response, resulting in persistent infection. HDV escape from the 
      immune response was associated with uncommon HLA class I alleles, indicating that 
      HDV evolves, at the population level, to evade recognition by common HLA class I 
      alleles.
CI  - Copyright (c) 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Karimzadeh, Hadi
AU  - Karimzadeh H
AD  - Institute of Virology, School of Medicine, Technical University of 
      Munich/Helmholtz Zentrum Munchen, Munich, Germany; Institute of Virology, 
      University Hospital of Essen, University of Duisburg-Essen, Essen, Germany; 
      Department of Internal Medicine II, University Hospital Munich-Grosshadern, 
      Munich, Germany.
FAU - Kiraithe, Muthamia M
AU  - Kiraithe MM
AD  - Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, 
      University of Freiburg, Freiburg, Germany.
FAU - Oberhardt, Valerie
AU  - Oberhardt V
AD  - Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, 
      University of Freiburg, Freiburg, Germany; Faculty of Biology, University of 
      Freiburg, Freiburg, Germany.
FAU - Salimi Alizei, Elahe
AU  - Salimi Alizei E
AD  - Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, 
      University of Freiburg, Freiburg, Germany; Faculty of Chemistry and Pharmacy, 
      University of Freiburg, Freiburg, Germany.
FAU - Bockmann, Jan
AU  - Bockmann J
AD  - Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, 
      Germany; German Center for Infection Research (DZIF), Sites 
      Hamburg-Lubeck-Borstel-Riems, Hannover-Braunschweig and Munich, Germany.
FAU - Schulze Zur Wiesch, Julian
AU  - Schulze Zur Wiesch J
AD  - Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, 
      Germany; German Center for Infection Research (DZIF), Sites 
      Hamburg-Lubeck-Borstel-Riems, Hannover-Braunschweig and Munich, Germany.
FAU - Budeus, Bettina
AU  - Budeus B
AD  - Department of Bioinformatics, University of Duisburg-Essen, Essen, Germany.
FAU - Hoffmann, Daniel
AU  - Hoffmann D
AD  - Department of Bioinformatics, University of Duisburg-Essen, Essen, Germany.
FAU - Wedemeyer, Heiner
AU  - Wedemeyer H
AD  - German Center for Infection Research (DZIF), Sites Hamburg-Lubeck-Borstel-Riems, 
      Hannover-Braunschweig and Munich, Germany; Department of Gastroenterology, 
      Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 
      Department of Gastroenterology and Hepatology, University Hospital of Essen, 
      University of Duisburg-Essen, Essen, Germany.
FAU - Cornberg, Markus
AU  - Cornberg M
AD  - German Center for Infection Research (DZIF), Sites Hamburg-Lubeck-Borstel-Riems, 
      Hannover-Braunschweig and Munich, Germany; Department of Gastroenterology, 
      Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
FAU - Krawczyk, Adalbert
AU  - Krawczyk A
AD  - Institute of Virology, University Hospital of Essen, University of 
      Duisburg-Essen, Essen, Germany; Department of Infectious Diseases, University 
      Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
FAU - Rashidi-Alavijeh, Jassin
AU  - Rashidi-Alavijeh J
AD  - Department of Gastroenterology and Hepatology, University Hospital of Essen, 
      University of Duisburg-Essen, Essen, Germany.
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 - Casillas, Rosario
AU  - Casillas R
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 - Smedile, Antonina
AU  - Smedile A
AD  - Department of Medical Sciences, University of Turin, Turin, Italy.
FAU - Alavian, Seyed Moayed
AU  - Alavian SM
AD  - Baqiyatallah Research Center for Gastroenterology and Liver Diseases, 
      Baqiyatallah University of Medical Sciences, Tehran, Iran.
FAU - Heinold, Andreas
AU  - Heinold A
AD  - Institute of Transfusion Medicine, University Hospital of Essen, University of 
      Duisburg-Essen, Essen, Germany.
FAU - Emmerich, Florian
AU  - Emmerich F
AD  - Institute for Transfusion Medicine and Gene Therapy, University Hospital 
      Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Panning, Marcus
AU  - Panning M
AD  - Institute of Virology, University Hospital Freiburg, Faculty of Medicine, 
      University of Freiburg, Freiburg, Germany.
FAU - Gostick, Emma
AU  - Gostick E
AD  - Division of Infection and Immunity, Cardiff University School of Medicine, 
      Cardiff, United Kingdom.
FAU - Price, David A
AU  - Price DA
AD  - Division of Infection and Immunity, Cardiff University School of Medicine, 
      Cardiff, United Kingdom.
FAU - Timm, Jorg
AU  - Timm J
AD  - Institute of Virology, Heinrich-Heine-University, University Hospital, 
      Duesseldorf, Germany.
FAU - Hofmann, Maike
AU  - Hofmann M
AD  - Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, 
      University of Freiburg, Freiburg, Germany.
FAU - Raziorrouh, Bijan
AU  - Raziorrouh B
AD  - Department of Internal Medicine II, University Hospital Munich-Grosshadern, 
      Munich, Germany.
FAU - Thimme, Robert
AU  - Thimme R
AD  - Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, 
      University of Freiburg, Freiburg, Germany.
FAU - Protzer, Ulrike
AU  - Protzer U
AD  - Institute of Virology, School of Medicine, Technical University of 
      Munich/Helmholtz Zentrum Munchen, Munich, Germany; German Center for Infection 
      Research (DZIF), Sites Hamburg-Lubeck-Borstel-Riems, Hannover-Braunschweig and 
      Munich, Germany.
FAU - Roggendorf, Michael
AU  - Roggendorf M
AD  - Institute of Virology, School of Medicine, Technical University of 
      Munich/Helmholtz Zentrum Munchen, Munich, Germany; Institute of Virology, 
      University Hospital of Essen, University of Duisburg-Essen, Essen, Germany; 
      German Center for Infection Research (DZIF), Sites Hamburg-Lubeck-Borstel-Riems, 
      Hannover-Braunschweig and Munich, Germany. Electronic address: 
      michael.roggendorf@tum.de.
FAU - Neumann-Haefelin, Christoph
AU  - Neumann-Haefelin C
AD  - Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, 
      University of Freiburg, Freiburg, Germany. Electronic address: 
      christoph.neumann-haefelin@uniklinik-freiburg.de.
LA  - eng
GR  - Wellcome Trust/United Kingdom
GR  - 100326Z/12/Z/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190212
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-A Antigens)
RN  - 0 (HLA-B Antigens)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Alleles
MH  - CD8-Positive T-Lymphocytes/*immunology/metabolism
MH  - Cell Line
MH  - Epitopes, T-Lymphocyte/immunology
MH  - Evolution, Molecular
MH  - HLA-A Antigens/*genetics/immunology
MH  - HLA-B Antigens/*genetics/immunology
MH  - Hepatitis B, Chronic/*genetics
MH  - Hepatitis D, Chronic/*genetics
MH  - Hepatitis Delta Virus/*genetics/*immunology
MH  - Humans
MH  - Immune Tolerance
MH  - Immunologic Surveillance/*immunology
MH  - Interferon-gamma/metabolism
MH  - Mutation
MH  - Polymorphism, Genetic
MH  - Superinfection/*genetics
PMC - PMC6486497
OTO - NOTNLM
OT  - Antigen Presentation
OT  - Cytotoxic T Cell
OT  - MHC Class I
OT  - TCR
EDAT- 2019/02/16 06:00
MHDA- 2019/05/14 06:00
PMCR- 2019/05/01
CRDT- 2019/02/16 06:00
PHST- 2018/09/19 00:00 [received]
PHST- 2019/01/16 00:00 [revised]
PHST- 2019/02/03 00:00 [accepted]
PHST- 2019/02/16 06:00 [pubmed]
PHST- 2019/05/14 06:00 [medline]
PHST- 2019/02/16 06:00 [entrez]
PHST- 2019/05/01 00:00 [pmc-release]
AID - S0016-5085(19)30366-X [pii]
AID - 10.1053/j.gastro.2019.02.003 [doi]
PST - ppublish
SO  - Gastroenterology. 2019 May;156(6):1820-1833. doi: 10.1053/j.gastro.2019.02.003. 
      Epub 2019 Feb 12.