Host cell mTORC1 is required for HCV RNA replication.
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.



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.



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.



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.
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.|German Center for Infection Research (DZIF), Hannover, Germany.
Stefanie
S
Stöhr
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
Rui
R
Costa
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.|German Center for Infection Research (DZIF), Hannover, Germany.
Lisa
L
Sandmann
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.|German Center for Infection Research (DZIF), Hannover, Germany.|Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany.
Sandra
S
Westhaus
Division 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.
Stephanie
S
Pfaender
Division 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.
Anggakusuma
Cell Growth and Development Biozentrum, Universität Basel, Basel, Switzerland.
Eva
E
Dazert
Center for Vaccinology, Ghent University, Ghent University Hospital, Ghent, Belgium.
Philip
P
Meuleman
German Center for Infection Research (DZIF), Hannover, Germany.|Department of General, Visceral and Transplantation Surgery, Medizinische Hochschule Hannover, Hannover, Germany.
Florian W R
FW
Vondran
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.|German Center for Infection Research (DZIF), Hannover, Germany.
Michael P
MP
Manns
Division 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.
Eike
E
Steinmann
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.|German Center for Infection Research (DZIF), Hannover, Germany.|Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany.
Thomas
T
von Hahn
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.|German Center for Infection Research (DZIF), Hannover, Germany.|Integrated Research and Treatment Centre-Transplantation (IFB-Tx), Hannover, Germany.
Sandra
S
Ciesek
D020868:Gene Silencing / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000628:therapy; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D016031:Liver Transplantation; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000494:pharmacology*; D012367:RNA, Viral / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000494:pharmacology*; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects*
D046912:Multiprotein Complexes; D012367:RNA, Viral; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
HEPATITIS C; LIVER TRANSPLANTATION