Hepatitis B virus infection of transplanted human hepatocytes causes a biochemical and histological hepatitis in immunocopetentent rats.
OBJECTIVE
To characterize the host response to hepatitis B virus (HBV) infection in human hepatocytes transplanted into immunocompetent rodent rats tolerized by, and transplanted with primary human hepatocytes.


METHODS
One week after the transplantation, rats were inoculated with HBV, and viral gene expression, replication, and host response was monitored.


RESULTS
HBV DNA was detectable in serum for at least 60 days. HBsAg levels rose steadily for 3 weeks post-inoculation and then plateaued at a level of about 0.6 pg/ml. HBV RNA was also found in liver at levels that remained constant through the time course. Immunofluorescence revealed clusters of hepatocytes that stained positive for HBcAg. The presence of HBV covalently closed circular DNA (cccDNA) in liver was demonstrated using nuclease digestion of single-stranded DNA followed by PCR. Serum ALT levels rose and reached a peak level of 180 IU/L on day 18, but remained elevated for 60 days. Histology revealed a progressive predominantly mononuclear lobular hepatitis.


CONCLUSIONS
These data indicate that human hepatocytes transplanted into rats rendered tolerant to these cells, when infected by HBV, results in biochemical as well as histological evidence of hepatitis that accompanies viral gene expression, and DNA replication.
Wu
Catherine H
CH
Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, , Farmington, CT 06030-1845, USA. wu@nso.uchc.edu
Ouyang
Edwin C
EC
Walton
Cherie
C
Promrat
Kittichai
K
Forouhar
Faripour
F
Wu
George Y
GY
D000818:Animals; D001483:Base Sequence; D017690:Cell Transplantation; D004279:DNA, Viral / Q000097:blood / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006509:Hepatitis B / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006512:Hepatitis B Core Antigens / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity; D022781:Hepatocytes / Q000637:transplantation; D006801:Humans; D007121:Immunocompetence; D008099:Liver / Q000473:pathology / Q000821:virology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D014183:Transplantation, Heterologous
D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D012333:RNA, Messenger; D012367:RNA, Viral