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Preclinical assessment of antiviral combination therapy in a genetically humanized mouse model for hepatitis delta virus infection.

Author(s): Winer, Benjamin Y; Shirvani-Dastgerdi, Elham; Bram, Yaron; Sellau, Julie; Low, Benjamin E; et al

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Abstract: Chronic delta hepatitis, caused by hepatitis delta virus (HDV), is the most severe form of viral hepatitis, affecting at least 20 million hepatitis B virus (HBV)-infected patients worldwide. HDV/HBV co- or super- infections are major drivers for hepatocarcinogenesis. Antiviral treatments exist only for HBV and can only suppress but not cure infection. Development of more effective therapies has been impeded by the scarcity of suitable small animal models. Here, we created a transgenic (tg) mouse model for HDV expressing the functional receptor for HBV and HDV, the human sodium taurocholate co-transporting peptide NTCP. Both HBV and HDV entered hepatocytes in these mice in a glycoprotein-dependent manner, but one or more post-entry blocks prevented HBV replication. In contrast, HDV caused persistent infection in hNTCP tg mice coexpressing the HBV envelope, consistent with HDV dependency on the HBV surface antigen (HBsAg) for packaging and spread. In immunocompromised mice lacking functional B, T, and NK cells, viremia lasted at least 80 days but resolved within 14 days in immunocompetent animals, demonstrating that lymphocytes are critical for controlling HDV infection. Although acute HDV infection did not cause overt liver damage in this model, cell-intrinsic and cellular innate immune responses were induced. We further demonstrated that single and dual treatment with myrcludex B and lonafarnib efficiently suppressed viremia but failed to cure HDV infection at the doses tested. This small animal model with inheritable susceptibility to HDV opens opportunities for studying viral pathogenesis, immune responses, and for testing novel HDV therapeutics.
Publication Date: Jun-2018
Electronic Publication Date: 27-Jun-2018
Citation: Winer, Benjamin Y, Shirvani-Dastgerdi, Elham, Bram, Yaron, Sellau, Julie, Low, Benjamin E, Johnson, Heath, Huang, Tiffany, Hrebikova, Gabriela, Heller, Brigitte, Sharon, Yael, Giersch, Katja, Gerges, Sherif, Seneca, Kathleen, Pais, Mihai-Alexandru, Frankel, Angela S, Chiriboga, Luis, Cullen, John, Nahass, Ronald G, Lutgehetmann, Marc, Toettcher, Jared E, Wiles, Michael V, Schwartz, Robert E, Ploss, Alexander. (2018). Preclinical assessment of antiviral combination therapy in a genetically humanized mouse model for hepatitis delta virus infection.. Science translational medicine, 10 (447), 10.1126/scitranslmed.aap9328
DOI: doi:10.1126/scitranslmed.aap9328
ISSN: 1946-6234
EISSN: 1946-6242
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Science translational medicine
Version: Author's manuscript

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