TY  - JOUR
A1  - Stöhr, Stefanie
A1  - Costa, Rui
A1  - Sandmann, Lisa
A1  - Westhaus, Sandra
A1  - Pfänder, Stephanie
A1  - Kusuma, Angga
A1  - Dazert, Eva
A1  - Meuleman, Philip
A1  - Vondran, Florian
A1  - Manns, Michael P.
A1  - Steinmann, Eike
A1  - Hahn, Thomas von
A1  - Ciesek, Sandra
T1  - Host cell mTORC1 is required for HCV RNA replication
T2  - Gut
N2  - 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.
KW  - Hepatitis c
KW  - liver transplantation
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/54535
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-545352
SN  - 1468-3288
SN  - 0017-5749
N1  - This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
VL  - 65
IS  - 12
SP  - 2017
EP  - 2028
PB  - BMJ Publishing Group
CY  - London
ER  -