Strain-specific responsiveness of hepatitis D virus to interferon-alpha treatment
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | JHEP Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555923000046 |
| _version_ | 1827980663021633536 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Katja Giersch |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T21:55:55Z |
| format | Article |
| id | doaj.art-01d54f34c762458ab95d9601864425ef |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-04-09T21:55:55Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-01d54f34c762458ab95d9601864425ef2023-03-24T04:23:15ZengElsevierJHEP Reports2589-55592023-04-0154100673Strain-specific responsiveness of hepatitis D virus to interferon-alpha treatmentKatja Giersch0Paulina Perez-Gonzalez1Lennart Hendricks2Nora Goldmann3Jonathan Kolbe4Lennart Hermanussen5Jan-Hendrick Bockmann6Tassilo Volz7Annika Volmari8Lena Allweiss9Joerg Petersen10Dieter Glebe11Marc Lütgehetmann12Maura Dandri13Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Medical Virology, National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University Giessen, Giessen, GermanyDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment 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, GermanyDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment 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, GermanyIFI Institute for Interdisciplinary Medicine at Asklepios Clinic St. Georg, Hamburg, GermanyInstitute 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, GermanyGerman 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, GermanyDepartment 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.http://www.sciencedirect.com/science/article/pii/S2589555923000046HDVHuman liver chimeric miceResistanceAntiviralGenotype |
| spellingShingle | 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 Strain-specific responsiveness of hepatitis D virus to interferon-alpha treatment JHEP Reports HDV Human liver chimeric mice Resistance Antiviral Genotype |
| title | Strain-specific responsiveness of hepatitis D virus to interferon-alpha treatment |
| title_full | Strain-specific responsiveness of hepatitis D virus to interferon-alpha treatment |
| title_fullStr | Strain-specific responsiveness of hepatitis D virus to interferon-alpha treatment |
| title_full_unstemmed | Strain-specific responsiveness of hepatitis D virus to interferon-alpha treatment |
| title_short | Strain-specific responsiveness of hepatitis D virus to interferon-alpha treatment |
| title_sort | strain specific responsiveness of hepatitis d virus to interferon alpha treatment |
| topic | HDV Human liver chimeric mice Resistance Antiviral Genotype |
| url | http://www.sciencedirect.com/science/article/pii/S2589555923000046 |
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