Effect of nucleoside analogue therapy on duck hepatitis B viral replication in hepatocytes and bile duct epithelial cells in vivo.
BACKGROUND
Recent studies have implicated bile duct epithelial cells (BDEC) as a reservoir of hepatitis B virus (HBV) infection that may be particularly important in the development of post-liver transplant recurrence of hepatitis B. The aim of this study was to compare the effects of antiviral therapy on duck HBV (DHBV) expression in hepatocytes and BDEC and to determine if this was affected by biliary hyperplasia.


METHODS
Ducklings congenitally infected with DHBV received penciclovir (10 mg/kg per day) treatment from 9 days of age. In order to mimic the biliary hyperplasia that often accompanies severe post-liver transplant HBV recurrence, half the animals underwent bile duct ligation. Duck HBV-DNA in serum was measured at day 1, and serum and liver DHBV-DNA were determined when the animals were killed on day 17. Intrahepatic expression of viral preS1 antigen and DHBV-DNA was measured by immunohistochemistry and in situ hybridization, respectively.


RESULTS
Viraemia became undetectable in the penciclovir-treated animals at day 17, following 8 days of therapy. Examination of liver tissue revealed that all hepatocytes and the majority of BDEC contained DHBV preS1 antigen and DHBV-DNA. Penciclovir greatly reduced the intrahepatic viral burden, but there was no antiviral effect on viral markers within BDEC. Despite the increased number of BDEC after bile duct ligation, the same proportion of BDEC was seen to be infected, and this was unaffected by antiviral therapy.


CONCLUSIONS
In the duck model with and without biliary hyperplasia, penciclovir controls DHBV replication and reduces viral burden in hepatocytes, but not in BDEC. The BDEC appear to be an important reservoir of virus that is relatively unaffected by antiviral treatment, and may play an important role in disease persistence and relapse following cessation of therapy.
Nicoll
A
A
Victorian Infectious Diseases Reference Laboratory, North Melbourne, Australia.
Locarnini
S
S
Chou
S T
ST
Smallwood
R
R
Angus
P
P
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001652:Bile Ducts / Q000473:pathology / Q000821:virology*; D002455:Cell Division / Q000187:drug effects; D004279:DNA, Viral / Q000032:analysis; D004195:Disease Models, Animal; D004372:Ducks / Q000821:virology*; D004847:Epithelial Cells / Q000473:pathology / Q000821:virology; D006147:Guanine; D018347:Hepadnaviridae Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000276:immunology; D015611:Hepatitis B Virus, Duck / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006965:Hyperplasia; D017403:In Situ Hybridization; D008099:Liver / Q000473:pathology / Q000821:virology*; D011498:Protein Precursors / Q000276:immunology; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome; D014759:Viral Envelope Proteins / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D011498:Protein Precursors; D018894:Reverse Transcriptase Inhibitors; D014759:Viral Envelope Proteins; C050806:presurface protein 1, hepatitis B surface antigen; C053539:penciclovir; D006147:Guanine; D000212:Acyclovir