RT Journal Article
SR Electronic
T1 Host cell mTORC1 is required for HCV RNA replication
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 2017
OP 2028
DO 10.1136/gutjnl-2014-308971
VO 65
IS 12
A1 Stefanie Stöhr
A1 Rui Costa
A1 Lisa Sandmann
A1 Sandra Westhaus
A1 Stephanie Pfaender
A1 Anggakusuma
A1 Eva Dazert
A1 Philip Meuleman
A1 Florian W R Vondran
A1 Michael P Manns
A1 Eike Steinmann
A1 Thomas von Hahn
A1 Sandra Ciesek
YR 2016
UL http://gut.bmj.com/content/65/12/2017.abstract
AB 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.