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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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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