In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus
Bruno B. Bordier, Junko Ohkanda, Ping Liu, So-Young Lee, F.H. Salazar, Patricia L. Marion, Kazuo Ohashi, Leonard Meuse, Mark A. Kay, John L. Casey, Saïd M. Sebti, Andrew D. Hamilton, Jeffrey S. Glenn
Bruno B. Bordier, Junko Ohkanda, Ping Liu, So-Young Lee, F.H. Salazar, Patricia L. Marion, Kazuo Ohashi, Leonard Meuse, Mark A. Kay, John L. Casey, Saïd M. Sebti, Andrew D. Hamilton, Jeffrey S. Glenn
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Article Virology

In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus

Abstract

Hepatitis delta virus (HDV) can dramatically worsen liver disease in patients coinfected with hepatitis B virus (HBV). No effective medical therapy exists for HDV. The HDV envelope requires HBV surface antigen proteins provided by HBV. Once inside a cell, however, HDV can replicate its genome in the absence of any HBV gene products. In vitro, HDV virion assembly is critically dependent on prenyl lipid modification, or prenylation, of its nucleocapsid-like protein large delta antigen. To overcome limitations of current animal models and to test the hypothesis that pharmacologic prenylation inhibition can prevent the production of HDV virions in vivo, we established a convenient mouse-based model of HDV infection capable of yielding viremia. Such mice were then treated with the prenylation inhibitors FTI-277 and FTI-2153. Both agents were highly effective at clearing HDV viremia. As expected, HDV inhibition exhibited duration-of-treatment dependence. These results provide the first preclinical data supporting the in vivo efficacy of prenylation inhibition as a novel antiviral therapy with potential application to HDV and a wide variety of other viruses.

Authors

Bruno B. Bordier, Junko Ohkanda, Ping Liu, So-Young Lee, F.H. Salazar, Patricia L. Marion, Kazuo Ohashi, Leonard Meuse, Mark A. Kay, John L. Casey, Saïd M. Sebti, Andrew D. Hamilton, Jeffrey S. Glenn

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In vivo treatment of HDV with prenylation inhibitors. (a) Mice hydrodyna...
In vivo treatment of HDV with prenylation inhibitors. (a) Mice hydrodynamically transfected to produce HDV viremia were treated with carrier alone (lanes 1 and 6), carrier plus FTI-277 (lanes 2–5), or carrier plus FTI-2153 (lanes 7–10) for 7 days. Serum aliquots were then assayed for HDV RNA by RT-PCR. (b) Corresponding liver samples were analyzed for HDV RNA using Northern blots. (c) Serum aliquots were also analyzed for ALT. (d) Mice hydrodynamically transfected to produce HDV viremia were treated with carrier alone (controls, filled circles) or carrier plus FTI-2153 (open circles) for the indicated number of days prior to sacrifice. Serum HDV RNA was quantitated by RT-PCR. HDV RNA per microgram of total liver RNA was quantitated by Northern blots and used to normalize for any differences in transfection efficiency. The mean serum HDV RNA genome equivalent (geq) for each group of mice is plotted (see Methods for additional details).