DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Antibody Responses during Hepatitis B Viral Infection

Abstract

Hepatitis B is a DNA virus that infects liver cells and can cause both acute and chronic disease. It is believed that both viral and host factors are responsible for determining whether the infection is cleared or becomes chronic. Here we investigate the mechanism of protection by developing a mathematical model of the antibody response following hepatitis B virus (HBV) infection. We fitted the model to data from seven infected adults identified during acute infection and determined the ability of the virus to escape neutralization through overproduction of non-infectious subviral particles, which have HBs proteins on their surface, but do not contain nucleocapsid protein and viral nucleic acids. We showed that viral clearance can be achieved for high anti-HBV antibody levels, as in vaccinated individuals, when: (1) the rate of synthesis of hepatitis B subviral particles is slow; (2) the rate of synthesis of hepatitis B subviral particles is high but either anti-HBV antibody production is fast, the antibody affinity is high, or the levels of pre-existent HBV-specific antibody at the time of infection are high, as could be attained by vaccination. We further showed that viral clearance can be achieved for low equilibrium antiHBV antibody levels, as in unvaccinatedmore » individuals, when a strong cellular immune response controls early infection.« less

Authors:
 [1];  [2];  [2]
  1. Virginia Polytechnic Inst. and State Univ. (Virginia Tech), Blacksburg, VA (United States). Dept. of Mathematics
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Division
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
OSTI Identifier:
1627236
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 10; Journal Issue: 7; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 97 MATHEMATICS AND COMPUTING; Biochemistry & Molecular Biology; Mathematical & Computational Biology

Citation Formats

Ciupe, Stanca M., Ribeiro, Ruy M., and Perelson, Alan S. Antibody Responses during Hepatitis B Viral Infection. United States: N. p., 2014. Web. doi:10.1371/journal.pcbi.1003730.
Ciupe, Stanca M., Ribeiro, Ruy M., & Perelson, Alan S. Antibody Responses during Hepatitis B Viral Infection. United States. https://doi.org/10.1371/journal.pcbi.1003730
Ciupe, Stanca M., Ribeiro, Ruy M., and Perelson, Alan S. Thu . "Antibody Responses during Hepatitis B Viral Infection". United States. https://doi.org/10.1371/journal.pcbi.1003730. https://www.osti.gov/servlets/purl/1627236.
@article{osti_1627236,
title = {Antibody Responses during Hepatitis B Viral Infection},
author = {Ciupe, Stanca M. and Ribeiro, Ruy M. and Perelson, Alan S.},
abstractNote = {Hepatitis B is a DNA virus that infects liver cells and can cause both acute and chronic disease. It is believed that both viral and host factors are responsible for determining whether the infection is cleared or becomes chronic. Here we investigate the mechanism of protection by developing a mathematical model of the antibody response following hepatitis B virus (HBV) infection. We fitted the model to data from seven infected adults identified during acute infection and determined the ability of the virus to escape neutralization through overproduction of non-infectious subviral particles, which have HBs proteins on their surface, but do not contain nucleocapsid protein and viral nucleic acids. We showed that viral clearance can be achieved for high anti-HBV antibody levels, as in vaccinated individuals, when: (1) the rate of synthesis of hepatitis B subviral particles is slow; (2) the rate of synthesis of hepatitis B subviral particles is high but either anti-HBV antibody production is fast, the antibody affinity is high, or the levels of pre-existent HBV-specific antibody at the time of infection are high, as could be attained by vaccination. We further showed that viral clearance can be achieved for low equilibrium antiHBV antibody levels, as in unvaccinated individuals, when a strong cellular immune response controls early infection.},
doi = {10.1371/journal.pcbi.1003730},
journal = {PLoS Computational Biology (Online)},
number = 7,
volume = 10,
place = {United States},
year = {Thu Jul 31 00:00:00 EDT 2014},
month = {Thu Jul 31 00:00:00 EDT 2014}
}

Works referenced in this record:

Immunology of hepatitis B virus and hepatitis C virus infection
journal, March 2005

  • Rehermann, Barbara; Nascimbeni, Michelina
  • Nature Reviews Immunology, Vol. 5, Issue 3
  • DOI: 10.1038/nri1573

Virus-neutralizing Antibodies to Hepatitis B Virus: The Nature of an Immunogenic Epitope on the S Gene Peptide
journal, November 1986


Intracellular Inactivation of the Hepatitis B Virus by Cytotoxic T Lymphocytes
journal, January 1996


Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids
journal, July 2005

  • Wieland, S. F.; Eustaquio, A.; Whitten-Bauer, C.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 28
  • DOI: 10.1073/pnas.0504273102

The role of cells refractory to productive infection in acute hepatitis B viral dynamics
journal, March 2007

  • Ciupe, S. M.; Ribeiro, R. M.; Nelson, P. W.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 12
  • DOI: 10.1073/pnas.0603626104

Viruses, Immunity, and Cancer: Lessons from Hepatitis B
journal, April 2000


Kinetics of the immune response during HBV and HCV infection
journal, July 2003


Correlation of Virus and Host Response Markers with Circulating Immune Complexes during Acute and Chronic Woodchuck Hepatitis Virus Infection
journal, December 2008

  • Glebe, Dieter; Lorenz, Heike; Gerlich, Wolfram H.
  • Journal of Virology, Vol. 83, Issue 4
  • DOI: 10.1128/JVI.01934-08

Host factors involved in hepatitis B virus maturation, assembly, and egress
journal, September 2012


Viral and cellular determinants involved in hepadnaviral entry
journal, January 2007


Hepatitis B small surface antigen particles are octahedral
journal, October 2005

  • Gilbert, R. J. C.; Beales, L.; Blond, D.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 41
  • DOI: 10.1073/pnas.0505062102

Morphogenesis of hepatitis B virus and its subviral envelope particles
journal, November 2009


Viral dynamics in hepatitis B virus infection.
journal, April 1996

  • Nowak, M. A.; Bonhoeffer, S.; Hill, A. M.
  • Proceedings of the National Academy of Sciences, Vol. 93, Issue 9
  • DOI: 10.1073/pnas.93.9.4398

Modelling viral and immune system dynamics
journal, January 2002

  • Perelson, Alan S.
  • Nature Reviews Immunology, Vol. 2, Issue 1
  • DOI: 10.1038/nri700

HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time
journal, March 1996


Modeling Plasma Virus Concentration during Primary HIV Infection
journal, April 2000

  • Stafford, Max A.; Corey, Lawrence; Cao, Yunzhen
  • Journal of Theoretical Biology, Vol. 203, Issue 3
  • DOI: 10.1006/jtbi.2000.1076

Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy
journal, June 1999

  • Tsiang, Manuel; Rooney, James F.; Toole, John J.
  • Hepatology, Vol. 29, Issue 6
  • DOI: 10.1002/hep.510290626

Liver Regeneration
journal, April 1997


Modeling the mechanisms of acute hepatitis B virus infection
journal, July 2007

  • Ciupe, Stanca M.; Ribeiro, Ruy M.; Nelson, Patrick W.
  • Journal of Theoretical Biology, Vol. 247, Issue 1
  • DOI: 10.1016/j.jtbi.2007.02.017

Virus dynamics and drug therapy
journal, June 1997

  • Bonhoeffer, S.; May, R. M.; Shaw, G. M.
  • Proceedings of the National Academy of Sciences, Vol. 94, Issue 13
  • DOI: 10.1073/pnas.94.13.6971

13 Modelling the in vivo growth rate of HIV: implications for vaccination
book, January 2005


Dynamics of hepatitis B virus clearance in chimpanzees
journal, November 2005

  • Murray, J. M.; Wieland, S. F.; Purcell, R. H.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 49
  • DOI: 10.1073/pnas.0508913102

Analysis of intrahepatic HBV-specific cytotoxic T-cells during and after acute HBV infection in humans
journal, August 2006

  • Sprengers, Dave; Molen, Renate G. van der; Kusters, Johannes G.
  • Journal of Hepatology, Vol. 45, Issue 2
  • DOI: 10.1016/j.jhep.2005.12.022

Modeling the adaptive immune response in HBV infection
journal, January 2011

  • Yousfi, Noura; Hattaf, Khalid; Tridane, Abdessamad
  • Journal of Mathematical Biology, Vol. 63, Issue 5
  • DOI: 10.1007/s00285-010-0397-x

Use of Laser Capture Microdissection to Map Hepatitis C Virus–Positive Hepatocytes in Human Liver
journal, December 2013


Mathematical model of immune processes
journal, April 1977


Exploring the Mechanisms of Primary Antibody Responses to T Cell-Dependent Antigens
journal, August 1996

  • Oprea, Mihaela; Perelson, Alan S.
  • Journal of Theoretical Biology, Vol. 181, Issue 3
  • DOI: 10.1006/jtbi.1996.0127

Diseases of the Liver and Biliary System
book, December 2001


Hepatitis B virus clearance rate estimates
journal, February 2009

  • Dahari, Harel; Cotler, Scott J.; Layden, Thomas J.
  • Hepatology, Vol. 49, Issue 5
  • DOI: 10.1002/hep.22874

Unbinding forces of single antibody-antigen complexes correlate with their thermal dissociation rates
journal, August 2000

  • Schwesinger, F.; Ros, R.; Strunz, T.
  • Proceedings of the National Academy of Sciences, Vol. 97, Issue 18
  • DOI: 10.1073/pnas.97.18.9972

Early high-affinity neutralizing anti-viral IgG responses without further overall improvements of affinity.
journal, February 1995

  • Roost, H. P.; Bachmann, M. F.; Haag, A.
  • Proceedings of the National Academy of Sciences, Vol. 92, Issue 5
  • DOI: 10.1073/pnas.92.5.1257

Human immunodeficiency virus type 1 neutralizing antibodies accelerate clearance of cell–free virions from blood plasma
journal, February 1999

  • Igarashi, Tatsuhiko; Brown, Charles; Azadegan, Ali
  • Nature Medicine, Vol. 5, Issue 2
  • DOI: 10.1038/5576

Molecular epidemiology of a large outbreak of hepatitis B linked to autohaemotherapy
journal, July 2000


Kinetics of Acute Hepatitis B Virus Infection in Humans
journal, April 2001

  • Whalley, Simon A.; Murray, John M.; Brown, Dave
  • The Journal of Experimental Medicine, Vol. 193, Issue 7
  • DOI: 10.1084/jem.193.7.847

Occupancy and mechanism in antibody-mediated neutralization of animal viruses
journal, September 2002


Stoichiometry of Antibody Neutralization of Human Immunodeficiency Virus Type 1
journal, March 2005


Restricted occupancy models for neutralization of HIV virions and populations
journal, August 2011


Virus Neutralisation: New Insights from Kinetic Neutralisation Curves
journal, February 2013


Sensitivity analysis of a nonlinear lumped parameter model of HIV infection dynamics
journal, September 2004


Model for competition from self during passive immunization, with application to broadly neutralizing antibodies for HIV
journal, January 2012


Antibody Levels and Protection after Hepatitis B Vaccination: Results of a 15-Year Follow-up
journal, March 2005


Antibody Levels and Protection after Hepatitis B Vaccine: Results of a 22‐Year Follow‐Up Study and Response to a Booster Dose
journal, November 2009

  • McMahon, Brian J.; Dentinger, Catherine M.; Bruden, Dana
  • The Journal of Infectious Diseases, Vol. 200, Issue 9
  • DOI: 10.1086/606119

Immunoglobulin Concentrations in Sera of Normal Children: Quantitation against an International Reference Preparation
journal, June 1974


The global health burden of infection-associated cancers in the year 2002
journal, January 2006

  • Parkin, Donald Maxwell
  • International Journal of Cancer, Vol. 118, Issue 12
  • DOI: 10.1002/ijc.21731

Recovery efficiencies of nucleic acid extraction kits as measured by quantitative LightCyclerTM PCR
journal, April 2001


Liver Regeneration
book, October 2009


Mathematical model of immune processes
journal, November 1977


Liver Regeneration
book, January 2006


Stoichiometry of Antibody Neutralization of Human Immunodeficiency Virus Type 1
journal, June 2005


Diseases of the Liver and Biliary System
journal, April 1959


Diseases of the Liver and Biliary System
journal, December 1997


Liver Regeneration
book, January 2015


Liver regeneration
book, January 2017


Diseases of the Liver and Biliary System
journal, February 2003


Liver Regeneration
book, November 2010


Liver Regeneration
book, January 2020


Virion half-life in chronic hepatitis B infection is strongly correlated with levels of viremia
journal, August 2008

  • Dandri, Maura; Murray, John M.; Lutgehetmann, Marc
  • Hepatology, Vol. 48, Issue 4
  • DOI: 10.1002/hep.22469

Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy
journal, June 1999

  • Tsiang, Manuel; Rooney, James F.; Toole, John J.
  • Hepatology, Vol. 29, Issue 6
  • DOI: 10.1002/hep.510290626

The global health burden of infection-associated cancers in the year 2002
journal, January 2006

  • Parkin, Donald Maxwell
  • International Journal of Cancer, Vol. 118, Issue 12
  • DOI: 10.1002/ijc.21731

Modeling Plasma Virus Concentration during Primary HIV Infection
journal, April 2000

  • Stafford, Max A.; Corey, Lawrence; Cao, Yunzhen
  • Journal of Theoretical Biology, Vol. 203, Issue 3
  • DOI: 10.1006/jtbi.2000.1076

Modeling the adaptive immune response in HBV infection
journal, January 2011

  • Yousfi, Noura; Hattaf, Khalid; Tridane, Abdessamad
  • Journal of Mathematical Biology, Vol. 63, Issue 5
  • DOI: 10.1007/s00285-010-0397-x

Host factors involved in hepatitis B virus maturation, assembly, and egress
journal, September 2012


Mathematical model of immune processes
journal, April 1977


Sensitivity analysis of a nonlinear lumped parameter model of HIV infection dynamics
journal, September 2004


Early intrahepatic CD8 responses in HBV pathogenesis: A new piece of the puzzle
journal, August 2006


Immunology of hepatitis B virus and hepatitis C virus infection
journal, March 2005

  • Rehermann, Barbara; Nascimbeni, Michelina
  • Nature Reviews Immunology, Vol. 5, Issue 3
  • DOI: 10.1038/nri1573

Modelling viral and immune system dynamics
journal, January 2002

  • Perelson, Alan S.
  • Nature Reviews Immunology, Vol. 2, Issue 1
  • DOI: 10.1038/nri700

Use of Laser Capture Microdissection to Map Hepatitis C Virus–Positive Hepatocytes in Human Liver
journal, December 2013


Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids
journal, July 2005

  • Wieland, S. F.; Eustaquio, A.; Whitten-Bauer, C.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 28
  • DOI: 10.1073/pnas.0504273102

Hepatitis B small surface antigen particles are octahedral
journal, October 2005

  • Gilbert, R. J. C.; Beales, L.; Blond, D.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 41
  • DOI: 10.1073/pnas.0505062102

Dynamics of hepatitis B virus clearance in chimpanzees
journal, November 2005

  • Murray, J. M.; Wieland, S. F.; Purcell, R. H.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 49
  • DOI: 10.1073/pnas.0508913102

The role of cells refractory to productive infection in acute hepatitis B viral dynamics
journal, March 2007

  • Ciupe, S. M.; Ribeiro, R. M.; Nelson, P. W.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 12
  • DOI: 10.1073/pnas.0603626104

Kinetic and affinity limits on antibodies produced during immune responses.
journal, February 1995

  • Foote, J.; Eisen, H. N.
  • Proceedings of the National Academy of Sciences, Vol. 92, Issue 5
  • DOI: 10.1073/pnas.92.5.1254

Unbinding forces of single antibody-antigen complexes correlate with their thermal dissociation rates
journal, August 2000

  • Schwesinger, F.; Ros, R.; Strunz, T.
  • Proceedings of the National Academy of Sciences, Vol. 97, Issue 18
  • DOI: 10.1073/pnas.97.18.9972

Kinetics of Acute Hepatitis B Virus Infection in Humans
journal, April 2001

  • Whalley, Simon A.; Murray, John M.; Brown, Dave
  • The Journal of Experimental Medicine, Vol. 193, Issue 7
  • DOI: 10.1084/jem.193.7.847

Occupancy and mechanism in antibody-mediated neutralization of animal viruses
journal, September 2002


Morphogenesis of hepatitis B virus and its subviral envelope particles
journal, November 2009


HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time
journal, March 1996


Drastic Reduction in the Production of Subviral Particles Does Not Impair Hepatitis B Virus Virion Secretion
journal, August 2009

  • Garcia, Tamako; Li, Jisu; Sureau, Camille
  • Journal of Virology, Vol. 83, Issue 21
  • DOI: 10.1128/jvi.00905-09

Apoptosis and Regeneration of Hepatocytes during Recovery from Transient Hepadnavirus Infections
journal, February 2000


Relative Sensitivity of Hepatitis B Virus and Other Hepatotropic Viruses to the Antiviral Effects of Cytokines
journal, March 2000


Intrahepatic Induction of Alpha/Beta Interferon Eliminates Viral RNA-Containing Capsids in Hepatitis B Virus Transgenic Mice
journal, May 2000


Stoichiometry of Antibody Neutralization of Human Immunodeficiency Virus Type 1
journal, June 2005


Recovery efficiencies of nucleic acid extraction kits as measured by quantitative LightCyclerTM PCR
journal, April 2001


Control of rate and extent of the proliferative response after partial hepatectomy
journal, October 1997

  • Lambotte, Luc; Saliez, Alain; Triest, Sandrine
  • American Journal of Physiology-Gastrointestinal and Liver Physiology, Vol. 273, Issue 4
  • DOI: 10.1152/ajpgi.1997.273.4.g905

Metabolic properties of IgG subclasses in man
journal, April 1970

  • Morell, Andreas; Terry, William D.; Waldmann, Thomas A.
  • Journal of Clinical Investigation, Vol. 49, Issue 4
  • DOI: 10.1172/jci106279

Virus Neutralisation: New Insights from Kinetic Neutralisation Curves
journal, February 2013


Works referencing / citing this record:

Global stability and optimal control for a hepatitis B virus infection model with immune response and drug therapy
journal, November 2018

  • Yosyingyong, Pensiri; Viriyapong, Ratchada
  • Journal of Applied Mathematics and Computing, Vol. 60, Issue 1-2
  • DOI: 10.1007/s12190-018-01226-x

Modeling the Effects of Morphine-Altered Virus Specific Antibody Responses on HIV/SIV Dynamics
journal, April 2019


Trade-offs in antibody repertoires to complex antigens
journal, September 2015

  • Childs, Lauren M.; Baskerville, Edward B.; Cobey, Sarah
  • Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 370, Issue 1676
  • DOI: 10.1098/rstb.2014.0245

The immunoglobulin γ marker 17 allotype and KIR/HLA genes prevent the development of chronic hepatitis B in humans
journal, November 2019

  • Di Bona, Danilo; Pandey, Janardan P.; Aiello, Anna
  • Immunology, Vol. 159, Issue 2
  • DOI: 10.1111/imm.13133

Modeling the dynamics of hepatitis B infection, immunity, and drug therapy
journal, August 2018


Mathematical modeling of within-host Zika virus dynamics
journal, August 2018

  • Best, Katharine; Perelson, Alan S.
  • Immunological Reviews, Vol. 285, Issue 1
  • DOI: 10.1111/imr.12687

Mathematical Modeling of the Adaptive Immune Responses in the Early Stage of the HBV Infection
journal, January 2018

  • Allali, Karam; Meskaf, Adil; Tridane, Abdessamad
  • International Journal of Differential Equations, Vol. 2018
  • DOI: 10.1155/2018/6710575

A multi-scale spatial model of hepatitis-B viral dynamics
journal, December 2017


Chronic hepatitis B virus and liver fibrosis: A mathematical model
journal, April 2018


Immune Evasion Strategies during Chronic Hepatitis B and C Virus Infection
journal, September 2017


In-host modeling
journal, May 2017


The Role of Aggregates of Therapeutic Protein Products in Immunogenicity: An Evaluation by Mathematical Modeling
journal, January 2015

  • Yin, Liusong; Chen, Xiaoying; Tiwari, Abhinav
  • Journal of Immunology Research, Vol. 2015
  • DOI: 10.1155/2015/401956

Epidemiology of viral hepatitis in the Republic of Congo: review
journal, December 2017


Modelling the Impact of Cell-To-Cell Transmission in Hepatitis B Virus
journal, August 2016