In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus
Bruno B. Bordier, … , Andrew D. Hamilton, Jeffrey S. Glenn
Bruno B. Bordier, … , Andrew D. Hamilton, Jeffrey S. Glenn
Published August 1, 2003
Citation Information: J Clin Invest. 2003;112(3):407-414. https://doi.org/10.1172/JCI17704.
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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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Figure 1

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Intrahepatic replication of HDV following hydrodynamic transfection. Mic...
Intrahepatic replication of HDV following hydrodynamic transfection. Mice transgenic for HBV were hydrodynamically transfected with vector DNA (pcDNA3) or a vector bearing HDV replication-inducing sequences [pCMV·HDVI(+)]. Seven days later, mice were sacrificed and liver samples were analyzed for HDV RNA and protein. (a) Samples of total liver RNA from a mouse transfected with pcDNA3 (lane 1) or with pCMV·HDVI(+) (lane 2) were analyzed for HDV genomic RNA using Northern blots. Positions of molecular-weight markers are on the left; arrow indicates position of the replicated 1.7-kb RNA genome. (b) Samples of total liver RNA from a mouse transfected with pcDNA3 (lane 1) or with pCMV·HDVI(+) (lane 2) were analyzed for delta antigen using Western blots. Positions of molecular-weight markers are on the left; arrow indicates position of delta antigen (δAg). (c) Representative time course for HDV replication in hydrodynamically transfected mice. Mice transgenic for HBV were hydrodynamically transfected with pcDNA3 (lane 1) or pCMV·HDVI(+) (lanes 2–4) and were sacrificed at day 2 (lane 2), day 4 (lane 3), or day 7 (lanes 1 and 4) after transfection. Liver samples were analyzed for HDV RNA using Northern blots. To account for potential differences in transfection efficiency, a plasmid encoding hAAT was included in the transfection, and HDV replication was detected in mice who had similar serum levels of hAAT on day 2 after transfection. (d and e) Liver sections from the same mice as in a were fixed in formalin and stained by immunohistochemistry for detection of HDV delta antigen. (d) Mouse transfected with pcDNA3. (e) Mouse transfected with pCMV·HDVI(+). Brown-red spots indicate characteristic nuclear staining pattern of delta antigen.