title: Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis B virus.
abstract: Studies of hepatitis B virus (HBV) mutants have been hampered by the lack of a small animal model with long-term infection of cloned HBV. Using a mouse model in which liver cells were highly replaced with human hepatocytes that survived over a long time with mature human hepatocyte function, we performed transmission experiments of HBV. Human serum containing HBV and the virus produced in HepG2 cell lines that transiently or stably transfected with 1.4 genome length HBV DNA were inoculated. Genetically modified e-antigen-negative mutant strain also was produced and inoculated into the mouse model. A high-level (approximately 10(10) copies/mL) viremia was observed in mice inoculated with HBV-positive human serum samples. The level of viremia tended to be high in mice with a continuously high human hepatocyte replacement index. High levels and long-lasting viremia also were observed in mice injected with the in vitro generated HBV. The viremia continued up to 22 weeks until death or killing. Passage experiments showed that the serum of these mice contained infectious HBV. Genetically engineered hepatitis B e antigen-negative mutant clone also was shown to be infectious. Lamivudine effectively reduced the level of viremia in these infected mice. In conclusion, this mouse model of HBV infection is a useful tool for the study of HBV virology and evaluation of anti-HBV drugs. Our results indicate that HBeAg is dispensable for active viral production and transmission.
authors.affiliation: Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima-shi, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Tsuge
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiraga
authors.forename: Hideki
authors.initials: H
authors.lastname: Takaishi
authors.forename: Chiemi
authors.initials: C
authors.lastname: Noguchi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Oga
authors.forename: Michio
authors.initials: M
authors.lastname: Imamura
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Eiji
authors.initials: E
authors.lastname: Iwao
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ochi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yoshizato
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002678:Chimera; D004279:DNA, Viral / Q000097:blood; D005818:Genetic Engineering; D006509:Hepatitis B / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000635:transmission; D006515:Hepatitis B virus / Q000235:genetics*; D022781:Hepatocytes; D006651:Histocytochemistry; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D009154:Mutation; D013997:Time Factors; D014766:Viremia / Q000503:physiopathology
chemical_list: D004279:DNA, Viral; D019259:Lamivudine