Acute hepatitis in rats expressing human hepatitis B virus transgenes.
The molecular mechanisms responsible for hepatocyte death and the events leading to viral clearance in hepatitis B virus (HBV) infections are not well understood. Elucidation of the mechanisms involved have been complicated by the difficulty of infecting human hepatocytes with HBV in vitro and the lack of an appropriate animal model. We report an animal model of human HBV infection by in vivo transfection. We have directly introduced a replication-competent, cloned HBV construct into rat liver by using a membrane fusion-promoting cationic lipid. HBV mRNA and 3.2-kb HBV DNA were expressed in the liver by this in vivo transfection method. In the majority of rats, HBV virions and hepatitis B e antigen were found in the blood 3-7 days after transfection, after which antibody to the e antigen appeared. Two to three weeks after the transfection, glutamic-pyruvic transaminase levels were elevated in serum, hepatocyte death and lymphocyte infiltration were observed in the vicinity of the portal vein of liver, and HBV virions were no longer detected in the serum. Thus, transfection of HBV into rats resulted in histological and serological changes comparable to HBV-induced acute hepatitis in humans. In contrast, no hepatocellular injury was observed in T-lymphocyte-deficient nude rats transfected with the same HBV construct, and viremia was substantially prolonged, providing direct evidence that T lymphocytes play an essential role in liver cell injury and in the clearance of HBV. This rat hepatitis model will be useful for studying pathogenesis of HBV infection.
Takahashi
H
H
Gastrointestinal Unit, Harvard Medical School, Boston, MA.
Fujimoto
J
J
Hanada
S
S
Isselbacher
K J
KJ
D000208:Acute Disease; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D006510:Hepatitis B Antibodies / Q000276:immunology; D006513:Hepatitis B e Antigens / Q000097:blood / Q000276:immunology; D006515:Hepatitis B virus / Q000472:pathogenicity*; D006524:Hepatitis, Viral, Animal / Q000382:microbiology*; D008099:Liver / Q000473:pathology; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000235:genetics; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D014162:Transfection
D017931:DNA Primers; D006510:Hepatitis B Antibodies; D006513:Hepatitis B e Antigens; D012367:RNA, Viral; D000410:Alanine Transaminase