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
PY - 2019/5/1
Y1 - 2019/5/1
N2 - © 2019 AGA Institute 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 - © 2019 AGA Institute 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 - Antigen Presentation
KW - Cytotoxic T Cell
KW - MHC Class I
KW - TCR
KW - Cell Line
KW - HLA-B Antigens/genetics
KW - Humans
KW - Immune Tolerance
KW - Interferon-gamma/metabolism
KW - Polymorphism, Genetic
KW - CD8-Positive T-Lymphocytes/immunology
KW - Hepatitis Delta Virus/genetics
KW - Alleles
KW - Hepatitis D, Chronic/genetics
KW - Hepatitis B, Chronic/genetics
KW - Epitopes, T-Lymphocyte/immunology
KW - Immunologic Surveillance/immunology
KW - Mutation
KW - Superinfection/genetics
KW - HLA-A Antigens/genetics
KW - Evolution, Molecular
UR - http://www.mendeley.com/research/mutations-hepatitis-d-virus-allow-it-escape-detection-cd8-t-cells-evolve-population-level
U2 - 10.1053/j.gastro.2019.02.003
DO - 10.1053/j.gastro.2019.02.003
M3 - Article
C2 - 30768983
SN - 0016-5085
VL - 156
SP - 1820
EP - 1833
JO - GASTROENTEROLOGY
JF - GASTROENTEROLOGY
ER -
