Abstract
Hepatitis delta virus (HDV) depends on the helper function of hepatitis B virus (HBV), which provides the envelope proteins for progeny virus secretion. Current infection-competent cell culture models do not support assembly and secretion of HDV. By stably transducing HepG2 cells with genes encoding the NTCP-receptor and the HBV envelope proteins we produce a cell line (HepNB2.7) that allows continuous secretion of infectious progeny HDV following primary infection. Evaluation of antiviral drugs shows that the entry inhibitor Myrcludex B (IC50: 1.4 nM) and interferon-α (IC50: 28 IU/ml, but max. 60–80% inhibition) interfere with primary infection. Lonafarnib inhibits virus secretion (IC50: 36 nM) but leads to a substantial intracellular accumulation of large hepatitis delta antigen and replicative intermediates, accompanied by the induction of innate immune responses. This work provides a cell line that supports the complete HDV replication cycle and presents a convenient tool for antiviral drug evaluation.
Highlights
Hepatitis delta virus (HDV) depends on the helper function of hepatitis B virus (HBV), which provides the envelope proteins for progeny virus secretion
By comparison of HepNB2.7 cells with a corresponding cell line deficient in HBx expression, we could exclude a contribution of HBx to HDV assembly and hepatitis B surface antigen (HBsAg) expression
We co-expressed NTCP and the HBV envelope proteins in HuH7NTCP cells, since these have a higher susceptibility for HDV than HepG2-NTCP cells[21]
Summary
Hepatitis delta virus (HDV) depends on the helper function of hepatitis B virus (HBV), which provides the envelope proteins for progeny virus secretion. Two novel potent HDV-specific antiviral drugs emerged and are approaching registration trials: (1) Lonafarnib is an orally active inhibitor of the farnesyl transferase, a cellular enzyme involved in post-translational modification of proteins. It inhibits prenylation of the large hepatitis delta antigen (L-HDAg) and thereby blocks assembly and secretion of virions in the cell[16,17]; (2) Myrcludex B (MyrB) is a peptidic inhibitor of the cellular receptor NTCP.
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