Development of a Novel Mouse Model to Evaluate Drug Candidates against Hepatitis B Virus

• Published in: Antiviral chemistry & chemotherapy Vol. 18; no. 4; pp. 213 - 223
• Main Authors: Feitelson, Mark A, Clayton, Marcia M, Sun, Bill, Schinazi, Raymond F
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 2007; International Medical Press; Sage Publications Ltd
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Deoxyribonucleic acid; Disease Models, Animal; DNA; Drinking water; Drug development; Drug Evaluation, Preclinical - methods; Hepatitis; Hepatitis B; Hepatitis B - blood; Hepatitis B - drug therapy; Hepatitis B - virology; Hepatitis B virus - drug effects; Hepatitis B virus - isolation & purification; Human viral diseases; Infectious diseases; Lamivudine; Lamivudine - pharmacology; Medical sciences; Mice; Mice, Nude; Organophosphonates - pharmacology; Pharmacology. Drug treatments; Replication; Reproducibility of Results; Tenofovir; Toxicity; Tumors; Viral diseases; Viral hepatitis; Viremia; nucleoside analogues; HepAD38 cells; mouse model; hepatitis B virus; Drug; Animal model; Drug combination; Rodentia; Orthohepadnavirus; Preclinical trial; Hepatic disease; Research and development; Infection; Virus; Viral hepatitis B; In vivo; Vertebrata; Mammalia; Mouse; Hepadnaviridae; Viral disease; Digestive diseases; Nucleoside analog; Antiviral; Hepatitis B virus
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632020701800405

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 ∼109copies/ml serum within 35 days of HepAD38 injection, whereas in tet-treated mice, virus titres remained at 104-105copies/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.