Modeling hepatitis C virus kinetics during liver transplantation reveals the role of the liver in virus clearance

  1. Louis Shekhtman
  2. Miquel Navasa
  3. Natasha Sansone
  4. Gonzalo Crespo
  5. Gitanjali Subramanya
  6. Tje Lin Chung
  7. E Fabian Cardozo-Ojeda
  8. Sofia Pérez-del-Pulgar
  9. Alan S Perelson
  10. Scott J Cotler
  11. Xavier Forns
  12. Susan L Uprichard  Is a corresponding author
  13. Harel Dahari  Is a corresponding author
  1. Loyola University Medical Center, Stritch School of Medicine, United States
  2. University of Barcelona, Spain
  3. University of Illinois, Chicago, United States
  4. Fred Hutchinson Cancer Research Center, United States
  5. Los Alamos National Laboratory, United States

Abstract

While the liver, specifically hepatocytes, are widely accepted as the main source of hepatitis C virus (HCV) production, the role of the liver/hepatocytes in clearance of circulating HCV remains unknown. Frequent HCV kinetic data were recorded and mathematically modeled from 5 liver-transplant patients throughout the anhepatic (absence of liver) phase and for 4 hours post-reperfusion. During the anhepatic phase, HCV remained at pre-anhepatic levels (n=3) or declined (n=2) with t1/2~1h. Immediately post-reperfusion, virus declined in a biphasic manner in 4 patients consisting of a rapid decline (t1/2=5min) followed by a slower decline (t1/2=67min). Consistent with the majority of patients in the anhepatic phase, when we monitored HCV clearance at 37°C from culture medium in the absence/presence of chronically infected hepatoma cells that were inhibited from secreting HCV, the HCV t1/2 in cell culture was longer in the absence of chronically HCV-infected cells. The results suggest that the liver plays a major role in the clearance of circulating HCV and that hepatocytes may be involved.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Louis Shekhtman

    Division of Hepatology, Department of Medicine, Loyola University Medical Center, Stritch School of Medicine, Maywood, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5273-8363
  2. Miquel Navasa

    Liver Unit, Hospital Clínic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
  3. Natasha Sansone

    Department of Microbiology and Immunology, University of Illinois, Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  4. Gonzalo Crespo

    Liver Unit, Hospital Clínic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
  5. Gitanjali Subramanya

    Division of Hepatology, Department of Medicine, Loyola University Medical Center, Stritch School of Medicine, Maywood, United States
    Competing interests
    No competing interests declared.
  6. Tje Lin Chung

    Division of Hepatology, Department of Medicine, Loyola University Medical Center, Stritch School of Medicine, Maywood, United States
    Competing interests
    No competing interests declared.
  7. E Fabian Cardozo-Ojeda

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8690-9896
  8. Sofia Pérez-del-Pulgar

    Liver Unit, Hospital Clínic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
  9. Alan S Perelson

    Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, United States
    Competing interests
    No competing interests declared.
  10. Scott J Cotler

    Division of Hepatology, Department of Medicine, Loyola University Medical Center, Stritch School of Medicine, Maywood, United States
    Competing interests
    No competing interests declared.
  11. Xavier Forns

    3Liver Unit, Hospital Clínic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
    Competing interests
    Xavier Forns, XF acted as advisor for Gilead and AbbVie.
  12. Susan L Uprichard

    Division of Hepatology, Department of Medicine, Loyola University Medical Center, Stritch School of Medicine, Maywood, United States
    For correspondence
    suprichard@luc.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5691-1557
  13. Harel Dahari

    Division of Hepatology, Department of Medicine, Loyola University Medical Center, Stritch School of Medicine, Maywood, United States
    For correspondence
    hdahari@luc.edu
    Competing interests
    No competing interests declared.

Funding

National Institute of Allergy and Infectious Diseases (R01-AI078881)

  • Susan L Uprichard

National Institute of Allergy and Infectious Diseases (R01-AI116868)

  • Alan S Perelson

Instituto de Salud Carlos III (PI15/00151 and PI13/00155)

  • Xavier Forns

Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (grant 2017_SGR_1753)

  • Xavier Forns

CERCA Programme/Generalitat de Catalunya

  • Xavier Forns

Germany Academic Exchange Service

  • Tje Lin Chung

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The study was approved by the Ethics Committee at Hospital Clinic Barcelona (Record 2010/5810) and all patients provided a written informed consent.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Louis Shekhtman
  2. Miquel Navasa
  3. Natasha Sansone
  4. Gonzalo Crespo
  5. Gitanjali Subramanya
  6. Tje Lin Chung
  7. E Fabian Cardozo-Ojeda
  8. Sofia Pérez-del-Pulgar
  9. Alan S Perelson
  10. Scott J Cotler
  11. Xavier Forns
  12. Susan L Uprichard
  13. Harel Dahari
(2021)
Modeling hepatitis C virus kinetics during liver transplantation reveals the role of the liver in virus clearance
eLife 10:e65297.
https://doi.org/10.7554/eLife.65297

Share this article

https://doi.org/10.7554/eLife.65297

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