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Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8+ T Cells and Evolve at the Population Level

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Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8+ T Cells and Evolve at the Population Level. / Karimzadeh, Hadi; Kiraithe, Muthamia M; Oberhardt, Valerie; Salimi Alizei, Elahe; Bockmann, Jan; Schulze Zur Wiesch, Julian; Budeus, Bettina; Hoffmann, Daniel; Wedemeyer, Heiner; Cornberg, Markus; Krawczyk, Adalbert; Rashidi-Alavijeh, Jassin; Rodríguez-Frías, Francisco; Casillas, Rosario; Buti, Maria; Smedile, Antonina; Alavian, Seyed Moayed; Heinold, Andreas; Emmerich, Florian; Panning, Marcus; Gostick, Emma; Price, David A; Timm, Jörg; Hofmann, Maike; Raziorrouh, Bijan; Thimme, Robert; Protzer, Ulrike; Roggendorf, Michael; Neumann-Haefelin, Christoph.

in: GASTROENTEROLOGY, Jahrgang 156, Nr. 6, 05.2019, S. 1820-1833.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Karimzadeh, H, Kiraithe, MM, Oberhardt, V, Salimi Alizei, E, Bockmann, J, Schulze Zur Wiesch, J, Budeus, B, Hoffmann, D, Wedemeyer, H, Cornberg, M, Krawczyk, A, Rashidi-Alavijeh, J, Rodríguez-Frías, F, Casillas, R, Buti, M, Smedile, A, Alavian, SM, Heinold, A, Emmerich, F, Panning, M, Gostick, E, Price, DA, Timm, J, Hofmann, M, Raziorrouh, B, Thimme, R, Protzer, U, Roggendorf, M & Neumann-Haefelin, C 2019, 'Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8+ T Cells and Evolve at the Population Level', GASTROENTEROLOGY, Jg. 156, Nr. 6, S. 1820-1833. https://doi.org/10.1053/j.gastro.2019.02.003

APA

Karimzadeh, H., Kiraithe, M. M., Oberhardt, V., Salimi Alizei, E., Bockmann, J., Schulze Zur Wiesch, J., Budeus, B., Hoffmann, D., Wedemeyer, H., Cornberg, M., Krawczyk, A., Rashidi-Alavijeh, J., Rodríguez-Frías, F., Casillas, R., Buti, M., Smedile, A., Alavian, S. M., Heinold, A., Emmerich, F., ... Neumann-Haefelin, C. (2019). Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8+ T Cells and Evolve at the Population Level. GASTROENTEROLOGY, 156(6), 1820-1833. https://doi.org/10.1053/j.gastro.2019.02.003

Vancouver

Karimzadeh H, Kiraithe MM, Oberhardt V, Salimi Alizei E, Bockmann J, Schulze Zur Wiesch J et al. Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8+ T Cells and Evolve at the Population Level. GASTROENTEROLOGY. 2019 Mai;156(6):1820-1833. https://doi.org/10.1053/j.gastro.2019.02.003

Bibtex

@article{3a14ff1f990d479bbe26ba27599dee04,
title = "Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8+ T Cells and Evolve at the Population Level",
abstract = "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.",
keywords = "Alleles, CD8-Positive T-Lymphocytes/immunology, Cell Line, Epitopes, T-Lymphocyte/immunology, Evolution, Molecular, HLA-A Antigens/genetics, HLA-B Antigens/genetics, Hepatitis B, Chronic/genetics, Hepatitis D, Chronic/genetics, Hepatitis Delta Virus/genetics, Humans, Immune Tolerance, Immunologic Surveillance/immunology, Interferon-gamma/metabolism, Mutation, Polymorphism, Genetic, Superinfection/genetics",
author = "Hadi Karimzadeh and Kiraithe, {Muthamia M} and Valerie Oberhardt and {Salimi Alizei}, Elahe and Jan Bockmann and {Schulze Zur Wiesch}, Julian and Bettina Budeus and Daniel Hoffmann and Heiner Wedemeyer and Markus Cornberg and Adalbert Krawczyk and Jassin Rashidi-Alavijeh and Francisco Rodr{\'i}guez-Fr{\'i}as and Rosario Casillas and Maria Buti and Antonina Smedile and Alavian, {Seyed Moayed} and Andreas Heinold and Florian Emmerich and Marcus Panning and Emma Gostick and Price, {David A} and J{\"o}rg Timm and Maike Hofmann and Bijan Raziorrouh and Robert Thimme and Ulrike Protzer and Michael Roggendorf and Christoph Neumann-Haefelin",
note = "Copyright {\textcopyright} 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = may,
doi = "10.1053/j.gastro.2019.02.003",
language = "English",
volume = "156",
pages = "1820--1833",
journal = "GASTROENTEROLOGY",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "6",

}

RIS

TY - JOUR

T1 - Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8+ T Cells and Evolve at the Population Level

AU - Karimzadeh, Hadi

AU - Kiraithe, Muthamia M

AU - Oberhardt, Valerie

AU - Salimi Alizei, Elahe

AU - Bockmann, Jan

AU - Schulze Zur Wiesch, Julian

AU - Budeus, Bettina

AU - Hoffmann, Daniel

AU - Wedemeyer, Heiner

AU - Cornberg, Markus

AU - Krawczyk, Adalbert

AU - Rashidi-Alavijeh, Jassin

AU - Rodríguez-Frías, Francisco

AU - Casillas, Rosario

AU - Buti, Maria

AU - Smedile, Antonina

AU - Alavian, Seyed Moayed

AU - Heinold, Andreas

AU - Emmerich, Florian

AU - Panning, Marcus

AU - Gostick, Emma

AU - Price, David A

AU - Timm, Jörg

AU - Hofmann, Maike

AU - Raziorrouh, Bijan

AU - Thimme, Robert

AU - Protzer, Ulrike

AU - Roggendorf, Michael

AU - Neumann-Haefelin, Christoph

N1 - Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

PY - 2019/5

Y1 - 2019/5

N2 - 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.

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.

KW - Alleles

KW - CD8-Positive T-Lymphocytes/immunology

KW - Cell Line

KW - Epitopes, T-Lymphocyte/immunology

KW - Evolution, Molecular

KW - HLA-A Antigens/genetics

KW - HLA-B Antigens/genetics

KW - Hepatitis B, Chronic/genetics

KW - Hepatitis D, Chronic/genetics

KW - Hepatitis Delta Virus/genetics

KW - Humans

KW - Immune Tolerance

KW - Immunologic Surveillance/immunology

KW - Interferon-gamma/metabolism

KW - Mutation

KW - Polymorphism, Genetic

KW - Superinfection/genetics

U2 - 10.1053/j.gastro.2019.02.003

DO - 10.1053/j.gastro.2019.02.003

M3 - SCORING: Journal article

C2 - 30768983

VL - 156

SP - 1820

EP - 1833

JO - GASTROENTEROLOGY

JF - GASTROENTEROLOGY

SN - 0016-5085

IS - 6

ER -