Preclinical assessment of antiviral combination therapy in a genetically humanized mouse model for hepatitis delta virus infection.
Sci Transl Med 2018 Jun 27; 10(447:eaap9328
M.V.W. was funded the The Jackson Laboratory
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 superinfections 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. We created a transgenic (tg) mouse model for HDV expressing the functional receptor for HBV and HDV, the human sodium taurocholate cotransporting peptide NTCP. Both HBV and HDV entered hepatocytes in these mice in a glycoprotein-dependent manner, but one or more postentry blocks prevented HBV replication. In contrast, HDV persistently infected 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 natural killer 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 and immune responses and for testing novel HDV therapeutics.
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; and Ploss, Alexander, "Preclinical assessment of antiviral combination therapy in a genetically humanized mouse model for hepatitis delta virus infection." (2018). Faculty Research 2018. 149.