Impaired Intrahepatic Hepatitis B Virus Productivity Contributes to Low Viremia in Most HBeAg-Negati

[Guest guest]

Impaired Intrahepatic Hepatitis B Virus Productivity Contributes to Low Viremia

in Most HBeAg-Negative Patients

Tassilo Volz, 2, Marc Lutgehetmann, 2, Wachtler, ,

Quaas‡, M. Murray§, Maura Dandri, 2 and Joerg sen, 1, 2, ,

‡Institute of Pathology, University Hospital Hamburg-Eppendorf, Hamburg,

Germany

Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

§School of Mathematics and Statistics, University of New South Wales, Sydney,

Australia

Received 21 March 2007; accepted 11 June 2007. Available online 3 July 2007.

Refers to: The Natural History and the Staging of Chronic Hepatitis B: Time for

Reevaluation of the Virus–Host Relationship Based on Molecular Virology and

Immunopathogenesis Considerations?

Gastroenterology, Volume 133, Issue 3, September 2007, Pages 1031-1035

, Locarnini and Kumar Visvanathan

Background & Aims: Knowledge of factors regulating transcriptional activity of

hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) may help in

understanding mechanisms of viral decay and how these processes are thwarted in

chronically HBV-infected patients. Methods: Liver biopsies from 119

treatment-naive chronically infected patients (42 HBeAg-positive and 77

HBeAg-negative) were determined for HBV transcriptional and replicative

activity. Results: Significantly lower median serum HBV DNA (−4 log),

intrahepatic HBV DNA (−2 log), and cccDNA (−1 log) amounts were measured in

HBeAg-negative versus HBeAg-positive patients. Despite a good correlation found

between intrahepatic amounts of progeny virions and serum HBV DNA in all

patients, cccDNA levels did not correlate with serum titers in HBeAg-negative

individuals. Analysis of HBV RNA transcripts showed that impaired virion

productivity in HBeAg-negative individuals was due to lower steady-state levels

of pregenomic RNA produced per cccDNA. Interestingly, preS/S RNA levels and

serum HBsAg concentrations did not differ between HBeAg-positive and

HBeAg-negative patients when normalized for cccDNA contents, showing that

subviral particle production was not impaired in HBeAg-negative patients and

correlated with cccDNA levels. Although the majority of HBeAg-negative

individuals harbored cccDNA with common precore and/or basal core promoter

mutations, occurrence of these variants was not responsible for reduced viral

replication. Instead, replacement of wild-type cccDNA with core promoter mutants

reestablished high virion productivity. Conclusions: Lower viremia in

HBeAg-negative individuals is not only due to lower cccDNA content but also to

impaired virion productivity, which can arise without emergence of HBeAg

variants and without affecting HBsAg production.

Address requests for reprints to: Joerg sen, MD, 1. Medizinische Klinik und

Poliklinik, Zentrum für Innere Medizin, Universitätsklinikum

Hamburg-Eppendorf, istr. 52, D - 20246 Hamburg, Germany. fax: (49)

40-42803-8065.

1 J.P. was supported by the Deutsche Forschungsgemeinschaft (Pe/608 2-5) and the

European Union 6th framework program (Virgil network of excellence).

2 T.V. and M.L. contributed equally to this work, as did M.D. and J.P.

Gastroenterology

Volume 133, Issue 3, September 2007, Pages 843-852

http://www.sciencedirect.com/science?_ob=ArticleURL & _udi=B6WFX-4P40KHH-6 & _user=1\

0 & _coverDate=09%2F30%2F2007 & _rdoc=1 & _fmt= & _orig=search & _sort=d & view=c & _acct=C000\

050221 & _version=1 & _urlVersion=0 & _userid=10 & md5=30c50568e96046cb7e4e8ebe7e341721

_________________________________________________________________

Capture your memories in an online journal!

http://www.reallivemoms.com?ocid=TXT_TAGHM & loc=us

[Guest guest]

Impaired Intrahepatic Hepatitis B Virus Productivity Contributes to Low Viremia

in Most HBeAg-Negative Patients

Tassilo Volz, 2, Marc Lutgehetmann, 2, Wachtler, ,

Quaas‡, M. Murray§, Maura Dandri, 2 and Joerg sen, 1, 2, ,

‡Institute of Pathology, University Hospital Hamburg-Eppendorf, Hamburg,

Germany

Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

§School of Mathematics and Statistics, University of New South Wales, Sydney,

Australia

Received 21 March 2007; accepted 11 June 2007. Available online 3 July 2007.

Refers to: The Natural History and the Staging of Chronic Hepatitis B: Time for

Reevaluation of the Virus–Host Relationship Based on Molecular Virology and

Immunopathogenesis Considerations?

Gastroenterology, Volume 133, Issue 3, September 2007, Pages 1031-1035

, Locarnini and Kumar Visvanathan

Background & Aims: Knowledge of factors regulating transcriptional activity of

hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) may help in

understanding mechanisms of viral decay and how these processes are thwarted in

chronically HBV-infected patients. Methods: Liver biopsies from 119

treatment-naive chronically infected patients (42 HBeAg-positive and 77

HBeAg-negative) were determined for HBV transcriptional and replicative

activity. Results: Significantly lower median serum HBV DNA (−4 log),

intrahepatic HBV DNA (−2 log), and cccDNA (−1 log) amounts were measured in

HBeAg-negative versus HBeAg-positive patients. Despite a good correlation found

between intrahepatic amounts of progeny virions and serum HBV DNA in all

patients, cccDNA levels did not correlate with serum titers in HBeAg-negative

individuals. Analysis of HBV RNA transcripts showed that impaired virion

productivity in HBeAg-negative individuals was due to lower steady-state levels

of pregenomic RNA produced per cccDNA. Interestingly, preS/S RNA levels and

serum HBsAg concentrations did not differ between HBeAg-positive and

HBeAg-negative patients when normalized for cccDNA contents, showing that

subviral particle production was not impaired in HBeAg-negative patients and

correlated with cccDNA levels. Although the majority of HBeAg-negative

individuals harbored cccDNA with common precore and/or basal core promoter

mutations, occurrence of these variants was not responsible for reduced viral

replication. Instead, replacement of wild-type cccDNA with core promoter mutants

reestablished high virion productivity. Conclusions: Lower viremia in

HBeAg-negative individuals is not only due to lower cccDNA content but also to

impaired virion productivity, which can arise without emergence of HBeAg

variants and without affecting HBsAg production.

Address requests for reprints to: Joerg sen, MD, 1. Medizinische Klinik und

Poliklinik, Zentrum für Innere Medizin, Universitätsklinikum

Hamburg-Eppendorf, istr. 52, D - 20246 Hamburg, Germany. fax: (49)

40-42803-8065.

1 J.P. was supported by the Deutsche Forschungsgemeinschaft (Pe/608 2-5) and the

European Union 6th framework program (Virgil network of excellence).

2 T.V. and M.L. contributed equally to this work, as did M.D. and J.P.

Gastroenterology

Volume 133, Issue 3, September 2007, Pages 843-852

http://www.sciencedirect.com/science?_ob=ArticleURL & _udi=B6WFX-4P40KHH-6 & _user=1\

0 & _coverDate=09%2F30%2F2007 & _rdoc=1 & _fmt= & _orig=search & _sort=d & view=c & _acct=C000\

050221 & _version=1 & _urlVersion=0 & _userid=10 & md5=30c50568e96046cb7e4e8ebe7e341721

_________________________________________________________________

Capture your memories in an online journal!

http://www.reallivemoms.com?ocid=TXT_TAGHM & loc=us