Z Gastroenterol 2019; 57(01): e85
DOI: 10.1055/s-0038-1677274
5. Viral Hepatitis, Immunology
Georg Thieme Verlag KG Stuttgart · New York

Viral escape contributes to the failure of hepatitis D virus (HDV)-specific CD8+ T cells and drives population-level evolution of HDV

Authors

  • V Oberhardt

    1   Department of Medicine II, University Hospital Freiburg, Freiburg, Germany

  • H Karimzadeh

    2   Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
    3   Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany

  • M Kiraithe

    1   Department of Medicine II, University Hospital Freiburg, Freiburg, Germany

  • E Salimi Alizei

    1   Department of Medicine II, University Hospital Freiburg, Freiburg, Germany

  • JH Bockmann

    4   Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

  • J Schulze zur Wiesch

    4   Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

  • B Budeus

    5   Department of Bioinformatics, University of Duisburg-Essen, Essen, Germany

  • D Hoffmann

    5   Department of Bioinformatics, University of Duisburg-Essen, Essen, Germany

  • H Wedemeyer

    6   German Center for Infection Research (DZIF), Munich and Hannover Sites, Germany
    7   Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    8   Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Germany

  • F Rodríguez-Frías

    9   CIBERehd and Departments of Biochemistry/Microbiology and Hepatology, Vall d'Hebron Hospital, University Autònoma de Barcelona (UAB), Barcelona, Spain

  • R Casillas

    9   CIBERehd and Departments of Biochemistry/Microbiology and Hepatology, Vall d'Hebron Hospital, University Autònoma de Barcelona (UAB), Barcelona, Spain

  • M Buti

    9   CIBERehd and Departments of Biochemistry/Microbiology and Hepatology, Vall d'Hebron Hospital, University Autònoma de Barcelona (UAB), Barcelona, Spain

  • A Smedile

    10   Department of Medical Sciences, University of Turin, Turin, Italy

  • SM Alavian

    11   Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran

  • A Heinold

    12   Institute of Transfusion Medicine, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany

  • F Emmerich

    13   Institute for Transfusion Medicine and Gene Therapy, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

  • M Panning

    14   Institute of Virology, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

  • E Gostick

    15   Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom

  • DA Price

    15   Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom

  • J Timm

    16   Institute of Virology, Heinrich-Heine-University, University Hospital, Duesseldorf, Germany

  • M Hofmann

    1   Department of Medicine II, University Hospital Freiburg, Freiburg, Germany

  • B Raziorrouh

    17   Department of Internal Medicine II, University Hospital Munich-Grosshadern, Munich, Germany

  • R Thimme

    1   Department of Medicine II, University Hospital Freiburg, Freiburg, Germany

  • U Protzer

    2   Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
    6   German Center for Infection Research (DZIF), Munich and Hannover Sites, Germany

  • M Roggendorf

    2   Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
    3   Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
    6   German Center for Infection Research (DZIF), Munich and Hannover Sites, Germany

  • C Neumann-Haefelin

    1   Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
04. Januar 2019 (online)

Auch verfügbar auf
 

Background and Aims:

Hepatitis D virus (HDV) super-infection of hepatitis B virus (HBV)-infected patients 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 mediate viral control, little is known about the repertoire of targeted epitopes, and it remains unclear why HDV-specific CD8+ T cells ultimately fail during persistent infection. We aimed to define how viral escape impacts the efficacy of HDV-specific CD8+ T-cells.

Methods:

104 patients with chronic HDV/HBV infection were analyzed for HLA class I associated viral sequence polymorphisms. Candidate HDV-specific CD8+ T-cell epitopes overlapping these sequence polymorphisms were predicted, tested, and characterized in patients with resolved (n = 17) or chronic (n = 13) HDV infection.

Results:

21 HLA class I-associated viral sequence polymorphisms were identified as highly significant (P < 0.005). Five of these polymorphisms were found to co-localize with experimentally confirmed HDV-specific CD8+ T-cell epitopes. Importantly, variant peptides were only partially cross-recognized, indicating viral escape. These newly identified epitopes were restricted by relatively infrequent HLA class I allotypes, with a preference for HLA-B. In contrast, frequent HLA class I alleles were not associated with viral sequence polymorphisms.

Conclusions:

Using a viral sequence-based approach, we identified new HDV-specific CD8+ T-cell epitopes, indicating a role for viral escape as a determinant of immune failure. In turn, viral escape was associated with uncommon HLA class I alleles, suggesting population-level evolution of HDV.