In vivo proliferation of hepadnavirus-infected hepatocytes induces loss

liver411

Hepatology. 2010 Jul;52(1):16-24.

In vivo proliferation of hepadnavirus-infected hepatocytes induces loss of
covalently closed circular DNA in mice.

Lutgehetmann M, Volz T, Köpke A, Broja T, Tigges E, Lohse AW, Fuchs E, Murray
JM, Petersen J, Dandri M.

Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg,
Germany.

Abstract
Chronic hepatitis B virus (HBV) infection is maintained by the presence of
covalently closed circular DNA (cccDNA), the template of viral transcription
and replication. In quiescent hepatocytes, cccDNA is a stable molecule that
can persist throughout the hepatocyte lifespan. However, in chronic HBV
infection, immunomediated cell injury and compensatory hepatocyte
proliferation may favor cccDNA decline and selection of cccDNA-free cells. To
investigate the impact of liver regeneration on cccDNA stability and activity
in vivo, we used the urokinase-type plasminogen activator (uPA)/severe
combined immunodeficiency (SCID) mouse model. Primary tupaia hepatocytes
(PTHs) chronically infected with woolly monkey HBV (WM-HBV) were isolated from
one highly viremic uPA/SCID chimeric mouse and transplanted into 20 uPA
recipients. Expansion of transplanted PTHs and viral load changes were
determined by real-time polymerase chain reaction and immunohistochemistry.
Transplantation of WM-HBV infected hepatocytes led to an average of 3.8 PTH
doublings within 80 days, 75% reduction of virion productivity (relaxed
circular DNA/cccDNA), and lower expression levels of pregenomic RNA and
hepatitis B core antigen. Remarkably, a median 2-log decline of cccDNA per
cell determined during PTH proliferation was due to both dilution of the
cccDNA pool among daughter cells and a 0.5-log loss of intrahepatic cccDNA
loads (P = 0.02). Intrahepatic viral DNA sequences persisting at the end of
the study were mostly present as replicative intermediates and not as
integrated virus. CONCLUSION: Cell division in the setting of liver
regeneration and without administration of antiviral drugs induced strong
destabilization of the cccDNA reservoir, resulting in cccDNA clearance in the
great majority of chronically infected hepatocytes.

PMID: 20578126



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