Increased liver pathology in hepatitis C virus transgenic mice expressing the hepatitis B virus X protein.
Transgenic mice expressing the full-length HCV coding sequence were crossed with mice that express the HBV X gene-encoded regulatory protein HBx (ATX mice) to test the hypothesis that HBx expression accelerates HCV-induced liver pathogenesis. At 16 months (mo) of age, hepatocellular carcinoma was identified in 21% of HCV/ATX mice, but in none of the single transgenic animals. Analysis of 8-mo animals revealed that, relative to HCV/WT mice, HCV/ATX mice had more severe steatosis, greater liver-to-body weight ratios, and a significant increase in the percentage of hepatocytes staining for proliferating cell nuclear antigen. Furthermore, primary hepatocytes from HCV, ATX, and HCV/ATX transgenic mice were more resistant to fas-mediated apoptosis than hepatocytes from nontransgenic littermates. These results indicate that HBx expression contributes to increased liver pathogenesis in HCV transgenic mice by a mechanism that involves an imbalance in hepatocyte death and regeneration within the context of severe steatosis.
Keasler
Victor V
VV
Department of Molecular Virology and Microbiology, Baylor College of Medicine (BCM-385), One Baylor Plaza, Houston, TX 77030-3411, USA.
Lerat
Herve
H
Madden
Charles R
CR
Finegold
Milton J
MJ
McGarvey
Michael J
MJ
Mohammed
Essam M A
EM
Forbes
Stuart J
SJ
Lemon
Stanley M
SM
Hadsell
Darryl L
DL
Grona
Shala J
SJ
Hollinger
F Blaine
FB
Slagle
Betty L
BL
D000818:Animals; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein