Development of a novel mouse model to evaluate drug candidates against hepatitis B virus

• Type of Material: Article
• Authors: Mark A. Feitelson, Thomas Jefferson University; Marcia M. Clayton, Thomas Jefferson University; Bill Sun, Thomas Jefferson University; Raymond Schinazi, Emory University
• Language: English
• Date: 2007-01-01
• Publisher: Emory University Libraries
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2007 International Medical Press.
• Final Published Version (URL): http://dx.doi.org/10.1177/095632020701800405
• Title of Journal or Parent Work: Antiviral Chemistry and Chemotherapy
• Volume: 18
• Issue: 4
• Start Page: 213
• End Page: 223
• Grant/Funding Information: This work was supported by NIH grants CA48656, CA66971 and CA104025 to MAF; by NIH grants 5R37-AI-41980 and 5R37-AI-25899; support from the Emory Center for AIDS Research 5P30-AI-50409; and from the US Department of Veterans Affairs (to RFS). A portion of this work was presented at the HepDART 2005 meeting, held on the Kohala Coast of the Big Island of Hawaii on December 11–15, 2005.
• Keywords: Animals; Tenofovir; Mice, Nude; Antiviral Agents; Disease Models, Animal; Reproducibility of Results; Lamivudine; Hepatitis B; Organophosphonates; Cell Line; Mice; Drug Evaluation, Preclinical; Hepatitis B virus; Adenine
• Research Categories: Biology, Virology; Biology, Cell

Abstract

Woodchuck hepatitis virus (WHV)-infected woodchucks have been used for preclinical development of drugs against hepatitis B virus (HBV). However, there is no simple in vivo model to evaluate small amounts of compounds against HBV. To develop such a model, HepAD38 cells, in which HBV replication is regulated by tetracycline (tet), were grown as subcutaneous tumours in nude mice. Mice developing viraemia were then left untreated or given tet in the drinking water. In some of the mice given tet, it was removed and the mice were injected intraperitoneally with phosphate buffer saline (PBS), lamivudine (3TC), clevudine (CLV) or tenofovir dipivoxil fumarate (TDF). Virus DNA titres were measured by real-time PCR during and after drug treatment. In water-fed and PBS-injected mice, virus titres reached ∼109 copies/ml serum within 35 days of HepAD38 injection, whereas in tet-treated mice. virus titres remained at 104-105 copies/ml. HBV DNA levels were suppressed by 3TC, TDF and CLV, with the latter two drugs showing more sustained virus suppression compared with 3TC. Combination therapy with CLV plus TDF was much more effective than either drug alone in suppressing virus titre for at least 3 weeks after the end of treatment. There was no demonstrable toxicity to HepAD38 cells in drug-treated mice. Hence, a robust tet-controlled system for HBV replication in vivo was demonstrated, validated with monotherapies against HBV and shown to be useful in assessing combination therapy. This system will be useful for preclinical assessment of small amounts of single or multiple compounds against HBV in vivo.