Virion half-life in chronic hepatitis B infection is strongly correlated with levels of viremia

[Guest guest]

http://www3.interscience.wiley.com/journal/121376563/abstract?CRETRY=1 & SRETRY=0

Hepatology

Published Online: 11 Aug 2008

Viral Hepatitis

Virion half-life in chronic hepatitis B infection is strongly correlated with

levels of viremia

Maura Dandri 1 *§, M. Murray 2, Marc Lutgehetmann 1, Tassilo Volz 1, Ansgar

W. Lohse 1, Joerg sen 1

1Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg,

Germany

2School of Mathematics and Statistics, University of New South Wales, Sydney,

NSW, Australia

email: Maura Dandri (m.dandri@...)

*Correspondence to Maura Dandri, Medizinische Klinik und Poliklinik, Zentrum für

Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, istrasse 52,

D-20246 Hamburg, Germany

Potential conflict of interest: Nothing to report.

These authors contributed equally to this study.

§fax: 49-40-42803-7232.

Funded by:

Deutsche Forschungsgemeinschaft; Grant Number: Pe/608 2-5

European Union Vigilance Network (6th framework program) for the Management of

Antiviral Drug Resistance (Virgil)

Abstract

Analysis of hepatitis B virus (HBV) kinetics with mathematical models may

disclose new aspects of HBV infection and host response mechanisms. To determine

the kinetics of virion decay from the blood of patients in different phases of

chronic infection, we applied mathematical modeling to real-time polymerase

chain reaction assays, which enable quantification of viremia and intrahepatic

HBV productivity by measuring both copy number and activity of covalently closed

circular DNA (relaxed circular DNA/covalently closed circular DNA) in the liver

of 80 untreated chronically active HBV carriers (38 hepatitis B e antigen

[HBeAg]-positive and 42 HBeAg-negative individuals). We found that the half-life

of circulating virions is very fast (median 46 and 2.5 minutes in HBeAg-positive

and HBeAg-negative individuals, respectively) and strongly related to viremia,

with clearance rates significantly accelerating as viral loads decrease. To

investigate whether immune components can influence the kinetics of virion

decay, we analyzed viral dynamics in immunodeficient urokinase-type plasminogen

activator chimera mice. Virion half-life in mice (range, 44 minutes to>4 hours)

was comparable to estimates determined in high viremic carriers, implying that

clearance rates in these patients are mostly determined by common nonspecific

mechanisms. Notably, the lack of correlation between virion half-life and

viremia in mice indicated that immune components significantly accelerate virion

clearance rates in individuals with low titers. Conclusion: Our analyses suggest

that both host defense mechanisms and levels of circulating virions affect the

kinetics of HBV decay assessed in the serum of chronic carriers. Identification

of the factors affecting clearance rates will be important for future antiviral

drug developments and it may give insights into the mechanisms involved in

clearance of other chronic infections, such as human immunodeficiency virus and

hepatitis C virus. (HEPATOLOGY 2008.)

--------------------------------------------------------------------------------

Received: 20 December 2007; Accepted: 5 June 2008

Digital Object Identifier (DOI)

[Guest guest]

http://www3.interscience.wiley.com/journal/121376563/abstract?CRETRY=1 & SRETRY=0

Hepatology

Published Online: 11 Aug 2008

Viral Hepatitis

Virion half-life in chronic hepatitis B infection is strongly correlated with

levels of viremia

Maura Dandri 1 *§, M. Murray 2, Marc Lutgehetmann 1, Tassilo Volz 1, Ansgar

W. Lohse 1, Joerg sen 1

1Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg,

Germany

2School of Mathematics and Statistics, University of New South Wales, Sydney,

NSW, Australia

email: Maura Dandri (m.dandri@...)

*Correspondence to Maura Dandri, Medizinische Klinik und Poliklinik, Zentrum für

Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, istrasse 52,

D-20246 Hamburg, Germany

Potential conflict of interest: Nothing to report.

These authors contributed equally to this study.

§fax: 49-40-42803-7232.

Funded by:

Deutsche Forschungsgemeinschaft; Grant Number: Pe/608 2-5

European Union Vigilance Network (6th framework program) for the Management of

Antiviral Drug Resistance (Virgil)

Abstract

Analysis of hepatitis B virus (HBV) kinetics with mathematical models may

disclose new aspects of HBV infection and host response mechanisms. To determine

the kinetics of virion decay from the blood of patients in different phases of

chronic infection, we applied mathematical modeling to real-time polymerase

chain reaction assays, which enable quantification of viremia and intrahepatic

HBV productivity by measuring both copy number and activity of covalently closed

circular DNA (relaxed circular DNA/covalently closed circular DNA) in the liver

of 80 untreated chronically active HBV carriers (38 hepatitis B e antigen

[HBeAg]-positive and 42 HBeAg-negative individuals). We found that the half-life

of circulating virions is very fast (median 46 and 2.5 minutes in HBeAg-positive

and HBeAg-negative individuals, respectively) and strongly related to viremia,

with clearance rates significantly accelerating as viral loads decrease. To

investigate whether immune components can influence the kinetics of virion

decay, we analyzed viral dynamics in immunodeficient urokinase-type plasminogen

activator chimera mice. Virion half-life in mice (range, 44 minutes to>4 hours)

was comparable to estimates determined in high viremic carriers, implying that

clearance rates in these patients are mostly determined by common nonspecific

mechanisms. Notably, the lack of correlation between virion half-life and

viremia in mice indicated that immune components significantly accelerate virion

clearance rates in individuals with low titers. Conclusion: Our analyses suggest

that both host defense mechanisms and levels of circulating virions affect the

kinetics of HBV decay assessed in the serum of chronic carriers. Identification

of the factors affecting clearance rates will be important for future antiviral

drug developments and it may give insights into the mechanisms involved in

clearance of other chronic infections, such as human immunodeficiency virus and

hepatitis C virus. (HEPATOLOGY 2008.)

--------------------------------------------------------------------------------

Received: 20 December 2007; Accepted: 5 June 2008

Digital Object Identifier (DOI)