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

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
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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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.