Viral Interference of Hepatitis C and E Virus Replication in Novel Experimental Co-Infection Systems

  • Cells. 2022 Mar 8;11(6):927. doi: 10.3390/cells11060927.
Thomas Burkard  1 ,  Nora Proske  2  3 ,  Kathrin Resner  2 ,  Laura Collignon  4 ,  Leonard Knegendorf  2 ,  Martina Friesland  2 ,  Lieven Verhoye  4 ,  Ibrahim M Sayed  4  5 ,  Yannick Brüggemann  1 ,  Maximilian K Nocke  1 ,  Patrick Behrendt  2  3  6 ,  Heiner Wedemeyer  3 ,  Philip Meuleman  4 ,  Daniel Todt  1  7 ,  Eike Steinmann  1  8
Affiliations
  • 1. Department of Molecular and Medical Virology, Ruhr University Bochum, 44801 Bochum, Germany.
  • 2. TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Institute for Experimental Virology, 30625 Hannover, Germany.
  • 3. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
  • 4. Laboratory of Liver Infectious Diseases, Ghent University, 9000 Gent, Belgium.
  • 5. Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.
  • 6. German Centre for Infection Research (DZIF), Partner Site Hannover Braunschweig, 30625 Hannover, Germany.
  • 7. European Virus Bioinformatics Center (EVBC), 07743 Jena, Germany.
  • 8. German Centre for Infection Research (DZIF), External Partner Site, 44801 Bochum, Germany.
PMID: 35326378 DOI: 10.3390/cells11060927
Abstract

Background: Hepatitis C virus (HCV) constitutes a global health problem, while hepatitis E virus (HEV) is the major cause of acute viral hepatitis globally. HCV/HEV co-infections have been poorly characterized, as they are hampered by the lack of robust HEV Cell Culture systems. This study developed experimental models to study HCV/HEV co-infections and investigate viral interference in cells and humanized mice.

Methods: We used state-of-the art human hepatocytes tissue culture models to assess HEV and HCV replication in co- or super-transfection settings. Findings were confirmed by co- and super-infection experiments in human hepatocytes and in vivo in human liver chimeric mice.

Results: HEV was inhibited by concurrent HCV replication in human hepatocytes. This exclusion phenotype was linked to the protease activity of HCV. These findings were corroborated by the fact that in HEV on HCV super-infected mice, HEV viral loads were reduced in individual mice. Similarly, HCV on HEV super-infected mice showed reduced HCV viral loads.

Conclusion: Direct interference of both viruses with HCV NS3/4A as the determinant was observed. In vivo, we detected reduced replication of both viruses after super-infection in individual mice. These findings provide new insights into the pathogenesis of HCV-HEV co-infections and should contribute to its clinical management in the future.

Keywords
HCV protease; Hepatitis C virus (HCV); Hepatitis E virus (HEV); co-infection; human hepatocytes; human liver chimeric mice; sofosbuvir.
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