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An Age-based Multiscale Mathematical Model of the Hepatitis C Virus Life-cycle During Infection and Therapy: Including Translation and Replication

  • B. M. Quintela
  • J. M. Conway
  • J. M. Hyman
  • R. F. Reis
  • R. W. dos Santos
  • M. Lobosco
  • A. S. Perelson
Conference paper
Part of the IFMBE Proceedings book series (IFMBE, volume 60)

Abstract

The dynamics of hepatitis C virus (HCV) RNA during translation and replication were added to an age-based multiscale mathematical model of HCV infection and treatment. The model allows the study of the production of HCV inside infected cells, which are later released as virus in the plasma, available to infect other cells. This is the first model to our knowledge to consider both positive and negative strands of HCV RNA with an age-based multiscale approach. Simulation of the effectiveness of direct acting antiviral (DAA) drugs in blocking HCV RNA intracellular production and release of new virions, and enhancing their depletion were performed. Changes on the set of parameters allowed the validation of the model comparing it to distinct experiments: in vitro and in vivo under therapy.

Keywords

Mathematical Model Differential Equations Computational Biology HCV RNA 

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References

  1. 1.
    WHO . Guidelines for the screening, care and treatment of persons with chronic hepatitis C infection 2016. Date accessed: July, 2016.Google Scholar
  2. 2.
    Gastaminza P., Cheng G., Wieland S., Zhong J., Liao W., Chisari F. V.. Cellular Determinants of Hepatitis C Virus Assembly, Maturation, Degradation, and Secretion Journal of Virology. 2008;82:2120–2129.Google Scholar
  3. 3.
    Appel N., Schaller T., Penin F., Bartenschlager R.. From Structure to Function: New Insights into Hepatitis C Virus RNA Replication Journal of Biological Chemistry. 2006;281:9833–9836.Google Scholar
  4. 4.
    Afzal M. S., Alsaleh K., Farhat R., et al. Regulation of Core Expression During the Hepatitis C Virus Life Cycle Journal of General Virology. 2015;96:311–21.Google Scholar
  5. 5.
    Craggs J K, Ball J K, Thomson B J, Irving W L, Grabowska AM. Development of a strand-specific RT-PCR based assay to detect the replicative form of hepatitis C virus RNA J Virol Methods. 2001;94:111–20.Google Scholar
  6. 6.
    Goutagny N., Inchauspe G.. Emerging Therapies for Hepatitis C Infectionch. 12. Human Virus GuidesInternational Medical Press 2009.Google Scholar
  7. 7.
    Liang T. Jake, Ghany Marc G.. Current and Future Therapies for Hepatitis C Virus Infection The New England Journal of Medicine. 2013;368:1907–1917.Google Scholar
  8. 8.
    Myers R. P., Shah H., Burak K. W., Cooper C., Feld J. J.. An update on the management of the chronic Hepatitis C: 2015 consensus guidelines from the Canadian Association for the Study of the Liver Can J Gastroenterol Hepatol. 2015;(In press).Google Scholar
  9. 9.
    Rong L., Guedj J., Dahari H., et al. Analysis of Hepatitis C Virus Decline during Treatment with the Protease Inhibitor Danoprevir Using a Multiscale Model PLOS Computational Biology. 2013;9:e1002959.Google Scholar
  10. 10.
    Guedj J., Neumann A.U.. Understanding hepatitis C viral dynamics with direct-acting antiviral agents due to the interplay between intracellular replication and cellular infection dynamics Journal of Theoretical Biology. 2010;267:330–340.Google Scholar
  11. 11.
    Dixit N. M.. Advances in the mathematical modelling of Hepatitis C virus dynamics Journal of the Indian Institute of Science. 2008;88:37–43.Google Scholar
  12. 12.
    Dahari H., Layden–Almer J. E., Kallwitz E., et al. A Mathematical Model of Hepatitis C Virus Dynamics in Patients With High Baseline Viral Loads or Advanced Liver Disease Gastroenterology. 2009;136:1402–1409.Google Scholar
  13. 13.
    Ribeiro R. M., Li H., Wang S., et al. Quantifying the Diversification of Hepatitis C Virus (HCV) during Primary Infection: Estimates of the In Vivo Mutation Rate PLOS Pathogens. 2012;8:e1002881.Google Scholar
  14. 14.
    Canini L., Perelson A. S.. Viral kinetic modeling: state of the art J Pharmacokinet Pharmacodyn. 2014;41:431–443.Google Scholar
  15. 15.
    Chaterjee A., Guedj J., Perelson A. S.. Mathematical Modelling of HCV infection: what can it teach us in the era of direct-acting antiviral agents? Antiviral Therapy. 2012;17:1171–1182.Google Scholar
  16. 16.
    Dahari H., Sainz B., Perelson A. S., Uprichard S. L.. Modeling Subgenomic Hepatitis C Virus RNA Kinetics during Treatment with Alpha Interferon Journal of Virology. 2009;83:6383–6390.Google Scholar
  17. 17.
    Banerjee S., Keval R., Gakkhar S.. Modeling the dynamics of Hepatitis C virus with combined antiviral drug therapy: Interferon and Ribavirin Mathematical Biosciences. 2013;245:235 – 248.Google Scholar
  18. 18.
    Guedj J., Perelson A. S.. Second-phase Hepatitis C Virus RNA Decline During Telaprevir-Based Therapy Increases With Drug Effectiveness: Implications for Treatment Duration Viral Hepatitis. 2011;53:1801–8.Google Scholar
  19. 19.
    Guedj J., Dahari H., Rong L., et al. Modeling Shows that the NS5A inhibitor dacatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life PNAS. 2013;110:3991-3996.Google Scholar
  20. 20.
    Thieme H., Castillo-Chavez C.. How may infection-age-dependent infectivity affect the dynamics of HIV/AIDS? SIAM J. Appl. Math.. 1993;53:1337–79.Google Scholar
  21. 21.
    Martcheva M., Castillo-Chavez C.. Diseases with chronic stage in population with varying size? Math. Biosci.. 2003;182:1–25.Google Scholar
  22. 22.
    Thieme H., Castillo-Chavez C.. A two-strain tuberculosis model with age infection SIAM J. Appl. Math.. 2002;62:1634–56.Google Scholar
  23. 23.
    Nelson P. W., Gilchrist M. A., Coombs D., Hyman J. M., Perelson A. S.. An age-structured model of HIV Infection that Allows for Variations in the Death Rate of Productively Infected Cells Mathematical Biosciences. 2004;1.Google Scholar
  24. 24.
    Li Jia, Brauer Fred. Continuous-Time Age-Structured Models in Population Dynamics and Epidemiology in Mathematical Epidemiology (Brauer Fred, Driessche Pauline, Wu Jianhong. , eds.);1945 of Lecture Notes in Mathematics:205–227Springer Berlin Heidelberg 2008.Google Scholar
  25. 25.
    Moradpour D., Penin F., Rice C. M.. Replication of hepatitis C virus Nature Reviews Microbiology. 2007;5:453–463.Google Scholar
  26. 26.
    Shi S. T., Lai M. M. C.. HCV 5’ and 3’UTR: When Translation Meets Replicationch. 2. Norfolk (UK): Horizon Bioscience: in: Hepatitis C Viruses: Genomes and Molecular Biology. Tan SL, editor 2006. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1624/.
  27. 27.
    Keum S.J., Park S.M., Park J.H., Jung J.H., Shin E.J., Jang S.K.. The specific infectivity of hepatitis C virus changes through its life cycle Virology. 2012;433:462–470.Google Scholar
  28. 28.
    Neumann A. U., Lam N.P., Dahari H., Gretch D.R., Wiley T. E., al. . Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy Science. 1998;282:103–107.Google Scholar
  29. 29.
    Lee C.. Daclatasvir: potential role in hepatitis C Drug Des Devel Ther.. 2013;7:1223–1233.Google Scholar
  30. 30.
    Scheel T. K. H., Rice C. M.. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies Nat. Med.. 2013;19:837–849.Google Scholar
  31. 31.
    Webster B., Ott M., Greene W. C.. Evasion of Superinfection Exclusion and Elimination of Primary Viral RNA by an Adapted Strain of Hepatitis C Virus Journal of Virology. 2013;87:13354–13369.Google Scholar
  32. 32.
    Sanjuán R., Nebot M. R., Chirico N., Mansky L. M., Belshaw R.. Viral Mutation Rates Journal of Virology. 2010;84:9733–9748.Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • B. M. Quintela
    • 1
  • J. M. Conway
    • 2
  • J. M. Hyman
    • 3
  • R. F. Reis
    • 1
  • R. W. dos Santos
    • 1
  • M. Lobosco
    • 1
  • A. S. Perelson
    • 4
  1. 1.Pós-Graduação em Modelagem ComputacionalUniversidade Federal de Juiz de ForaJuiz de ForaBrazil
  2. 2.Department of MathematicsThe Pennsylvania State UniversityState CollegeUSA
  3. 3.Mathematics DepartmentTulane UniversityNew OrleansUSA
  4. 4.Los Alamos National Laboratory, Theoretical Biology and BiophysicsLos AlamosUSA

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