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Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees.

Abstract：

:We have previously shown that hepatitis B virus (HBV) replication is controlled by noncytolytic mechanisms that depend primarily on the effector functions of the CD8(+) T cell response, especially the production of IFN-gamma in the liver. The mechanisms that control the nuclear pool of viral covalently closed circular DNA (cccDNA) transcriptional template of HBV, which must be eliminated to eradicate infection, have been difficult to resolve. To examine those mechanisms, we quantitated intrahepatic HBV cccDNA levels in acutely infected chimpanzees whose virological, immunological, and pathological features were previously described. Our results demonstrate that the elimination kinetics of the cccDNA are more rapid than the elimination of HBV antigen-positive hepatocytes during the early phase of viral clearance, and they coincide with the influx of small numbers of IFN-gamma producing CD8(+) T cells into the liver. In contrast, terminal clearance of the cccDNA is associated with the peak of liver disease and hepatocellular turnover and with a surge of IFN-gamma producing CD8(+) T cells in the liver. Collectively, these results suggest that cccDNA clearance is a two-step process mediated by the cellular immune response. The first step reduces the pool of cccDNA molecules noncytolytically, probably by eliminating their relaxed circular DNA precursors and perhaps by destabilizing them. The second step enhances this process by destroying infected hepatocytes and triggering their turnover. Surprisingly, despite this multipronged response, traces of cccDNA persist indefinitely in the liver, likely providing a continuous antigenic stimulus that confers lifelong immunity.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Wieland SF,Spangenberg HC,Thimme R,Purcell RH,Chisari FV

doi

10.1073/pnas.0308478100

keywords:

subject

Has Abstract

pub_date

2004-02-17 00:00:00

pages

2129-34

issue

eissn

0027-8424

issn

1091-6490

pii

0308478100

journal_volume

101

pub_type

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Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees.