Strain-specific responsiveness of hepatitis D virus to interferon-alpha treatment
Katja Giersch,
Paulina Perez-Gonzalez,
Lennart Hendricks,
Nora Goldmann,
Jonathan Kolbe,
Lennart Hermanussen,
Jan-Hendrick Bockmann,
Tassilo Volz,
Annika Volmari,
Lena Allweiss,
Joerg Petersen,
Dieter Glebe,
Marc Lütgehetmann,
Maura Dandri
Affiliations
Katja Giersch
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Paulina Perez-Gonzalez
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Lennart Hendricks
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Nora Goldmann
Institute of Medical Virology, National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University Giessen, Giessen, Germany
Jonathan Kolbe
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Lennart Hermanussen
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Jan-Hendrick Bockmann
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center of Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems and Giessen-Marburg-Langen Partner Sites, Germany
Tassilo Volz
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Annika Volmari
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Lena Allweiss
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center of Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems and Giessen-Marburg-Langen Partner Sites, Germany
Joerg Petersen
IFI Institute for Interdisciplinary Medicine at Asklepios Clinic St. Georg, Hamburg, Germany
Dieter Glebe
Institute of Medical Virology, National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University Giessen, Giessen, Germany; German Center of Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems and Giessen-Marburg-Langen Partner Sites, Germany
Marc Lütgehetmann
German Center of Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems and Giessen-Marburg-Langen Partner Sites, Germany; Department of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Maura Dandri
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center of Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems and Giessen-Marburg-Langen Partner Sites, Germany; Corresponding author. Address: I. Dept. of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D 20246 Hamburg, Germany. Tel.: +49-40–7410-52949; fax: +49-40–7410-57232..
Background & Aims: Pegylated interferon alpha (pegIFNα) is commonly used for the treatment of people infected with HDV. However, its mode of action in HDV-infected cells remains elusive and only a minority of people respond to pegIFNα therapy. Herein, we aimed to assess the responsiveness of three different cloned HDV strains to pegIFNα. We used a previously cloned HDV genotype 1 strain (dubbed HDV-1a) that appeared insensitive to interferon-α in vitro, a new HDV strain (HDV-1p) we isolated from an individual achieving later sustained response to IFNα therapy, and one phylogenetically distant genotype 3 strain (HDV-3). Methods: PegIFNα was administered to human liver chimeric mice infected with HBV and the different HDV strains or to HBV/HDV infected human hepatocytes isolated from chimeric mice. Virological parameters and host responses were analysed by qPCR, sequencing, immunoblotting, RNA in situ hybridisation and immunofluorescence staining. Results: PegIFNα treatment efficiently reduced HDV RNA viraemia (∼2-log) and intrahepatic HDV markers both in mice infected with HBV/HDV-1p and HBV/HDV-3. In contrast, HDV parameters remained unaffected by pegIFNα treatment both in mice (up to 9 weeks) and in isolated cells infected with HBV/HDV-1a. Notably, HBV viraemia was efficiently lowered (∼2-log) and human interferon-stimulated genes similarly induced in all three HBV/HDV-infected mouse groups receiving pegIFNα. Genome sequencing revealed highly conserved ribozyme and L-hepatitis D antigen post-translational modification sites among all three isolates. Conclusions: Our comparative study indicates the ability of pegIFNα to lower HDV loads in stably infected human hepatocytes in vivo and the existence of complex virus-specific determinants of IFNα responsiveness. Impact and implications: Understanding factors counteracting HDV infections is paramount to develop curative therapies. We compared the responsiveness of three different cloned HDV strains to pegylated interferon alpha in chronically infected mice. The different responsiveness of these HDV isolates to treatment highlights a previously underestimated heterogeneity among HDV strains.
