Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8 + T Cells and Evolve at the Population Level
Karimzadeh, Hadi (Department of Internal Medicine II, University Hospital Munich-Grosshadern, Munich, Germany)
Kiraithe, Muthamia M. (Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany)
Oberhardt, Valerie (Faculty of Biology, University of Freiburg, Freiburg, Germany)
Salimi Alizei, Elahe (Faculty of Chemistry and Pharmacy, University of Freiburg, Freiburg, Germany)
Bockmann, Jan (German Center for Diabetes Research (DZD))
Schulze zur Wiesch, Julian (German Center for Diabetes Research (DZD))
Budeus, Bettina (Department of Bioinformatics, University of Duisburg-Essen, Essen, Germany)
Hoffmann, Daniel (Department of Bioinformatics, University of Duisburg-Essen, Essen, Germany)
Wedemeyer, Heiner (University Hospital Essen (Alemanya))
Cornberg, Markus (Hannover Medical School. Department of Gastroenterology, Hepatology and Endocrinology)
Krawczyk, Adalbert (Department of Infectious Diseases, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany)
Rashidi-Alavijeh, Jassin (University Hospital Essen (Alemanya))
Rodríguez Frías, Francisco (Hospital Universitari Vall d'Hebron)
Casillas, Rosario (Hospital Universitari Vall d'Hebron)
Buti, Maria (Hospital Universitari Vall d'Hebron)
Smedile, Antonina (Department of Medical Sciences, University of Turin, Turin, Italy)
Alavian, Seyed Moayed (Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran)
Heinold, Andreas (University Hospital Essen (Alemanya))
Emmerich, Florian (Institute for Transfusion Medicine and Gene Therapy, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany)
Panning, Marcus (Institute of Virology, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany)
Gostick, Emma (Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom)
Price, David A. (Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom)
Timm, Jörg (Institute of Virology, Heinrich-Heine-University, University Hospital, Duesseldorf, Germany)
Hofmann, Maike (University of Freiburg)
Raziorrouh, Bijan (Department of Internal Medicine II, University Hospital Munich-Grosshadern, Munich, Germany)
Thimme, Robert (Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany)
Protzer, Ulrike (German Center for Diabetes Research (DZD))
Roggendorf, Michael (German Center for Diabetes Research (DZD))
Neumann-Haefelin, Christoph (Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany)
Universitat Autònoma de Barcelona

Fecha:	2019
Resumen:	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. 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. 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. 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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Cytotoxic T Cell ; MHC Class I ; TCR ; Antigen Presentation ; HDAg ; HBV ; HCV ; HDV ; HIV ; HLA ; IC ; IFN ; IL-2 ; L-HDAg ; PBMC ; PBS ; PCR ; PD-1 ; S-HDAg ; TCF1
Publicado en:	Gastroenterology, Vol. 156 (may 2019) , p. 1820-1833, ISSN 1528-0012

DOI: 10.1053/j.gastro.2019.02.003
PMID: 30768983

14 p, 3.2 MB

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