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Host cell mTORC1 is required for HCV RNA replication
  1. Stefanie Stöhr1,2,
  2. Rui Costa1,
  3. Lisa Sandmann1,2,
  4. Sandra Westhaus1,2,3,
  5. Stephanie Pfaender4,
  6. Anggakusuma4,
  7. Eva Dazert5,
  8. Philip Meuleman6,
  9. Florian W R Vondran2,7,
  10. Michael P Manns1,2,
  11. Eike Steinmann4,
  12. Thomas von Hahn1,2,3,
  13. Sandra Ciesek1,2,8
  1. 1Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
  2. 2German Center for Infection Research (DZIF), Hannover, Germany
  3. 3Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
  4. 4Division of Experimental Virology, 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), Hannover, Germany
  5. 5Cell Growth and Development Biozentrum, Universität Basel, Basel, Switzerland
  6. 6Center for Vaccinology, Ghent University, Ghent University Hospital, Ghent, Belgium
  7. 7Department of General, Visceral and Transplantation Surgery, Medizinische Hochschule Hannover, Hannover, Germany
  8. 8Integrated Research and Treatment Centre—Transplantation (IFB-Tx), Hannover, Germany
  1. Correspondence to Dr Sandra Ciesek, Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Carl-Neuberg-Str. 1, Hannover 30625, Germany; Ciesek.sandra{at}mh-hannover.de

Abstract

Objective Chronically HCV-infected orthotopic liver transplantation (OLT) recipients appear to have improved outcomes when their immunosuppressive regimen includes a mammalian target of rapamycin (mTOR) inhibitor. The mechanism underlying this observation is unknown.

Design We used virological assays to investigate mTOR signalling on the HCV replication cycle. Furthermore, we analysed HCV RNA levels of 42 HCV-positive transplanted patients treated with an mTOR inhibitor as part of their immunosuppressive regimen.

Results The mTOR inhibitor rapamycin was found to be a potent inhibitor for HCV RNA replication in Huh-7.5 cells as well as primary human hepatocytes. Half-maximal inhibition was observed at 0.01 µg/mL, a concentration that is in the range of serum levels seen in transplant recipients and does not affect cell proliferation. Early replication cycle steps such as cell entry and RNA translation were not affected. Knockdown of raptor, an essential component of mTORC1, but not rictor, an essential component of mTORC2, inhibited viral RNA replication. In addition, overexpression of raptor led to higher viral RNA replication, demonstrating that mTORC1, but not mTORC2, is required for HCV RNA replication. In 42 HCV-infected liver-transplanted or kidney-transplanted patients who were switched to an mTOR inhibitor, we could verify that mTOR inhibition decreased HCV RNA levels in vivo.

Conclusions Our data identify mTORC1 as a novel HCV replication factor. These findings suggest an underlying mechanism for the observed benefits of mTOR inhibition in HCV-positive OLT recipients and potentiate further investigation of mTOR-containing regimens in HCV-positive recipients of solid organ transplants.

  • HEPATITIS C
  • LIVER TRANSPLANTATION

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Footnotes

  • SS and RC contributed equally.

  • Contributors SS and RC contributed equally. SS: acquisition of data, analysis and interpretation of data. RC and LS and SP and TvH: acquisition of data, analysis and interpretation of data. SW: analysis and interpretation of data. A and PM: acquisition of data. EDK and ES: material support, analysis and interpretation of data. FWRV and MPM: material support. SC: study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, obtained funding.

  • Funding This work was supported by Deutsche Forschungsgemeinschaft through collaborative research centre 738, by the Germany Center for Infection Research (DZIF) and the Integrated Research and Treatment Centre—Transplantation (IFB-Tx). RC is a scholar of the Hannover Biomedical Research School.

  • Competing interests None declared.

  • Ethics approval Ethics Committee of Hannover Medical School.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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