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Host cell mTORC1 is required for HCV RNA replication.

Stefanie Stöhr1,2, Rui Costa1, Lisa Sandmann1,2

  • 1Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.

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Mammalian target of rapamycin (mTOR) inhibitors reduce Hepatitis C Virus (HCV) RNA replication by targeting mTORC1. This explains why these drugs improve outcomes in HCV-infected transplant recipients.

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Area of Science:

  • Hepatology
  • Virology
  • Immunology

Background:

  • Hepatitis C Virus (HCV) infection is a significant concern in organ transplant recipients.
  • Mammalian target of rapamycin (mTOR) inhibitors are used for immunosuppression in transplant patients.
  • Improved outcomes in HCV-infected liver transplant recipients on mTOR inhibitors suggest a direct antiviral effect, but the mechanism is unclear.

Purpose of the Study:

  • To investigate the role of mTOR signaling in the HCV replication cycle.
  • To determine if mTOR inhibitors directly impact HCV RNA replication.
  • To analyze HCV RNA levels in transplant patients treated with mTOR inhibitors.

Main Methods:

  • Virological assays were used to study mTOR signaling and HCV replication in cell cultures (Huh-7.5 cells, primary human hepatocytes).
  • Genetic manipulation (knockdown and overexpression) of mTORC1 and mTORC2 components (raptor, rictor) was performed.
  • HCV RNA levels were measured in 42 HCV-positive liver and kidney transplant patients switched to mTOR inhibitor therapy.

Main Results:

  • Rapamycin, an mTOR inhibitor, potently inhibited HCV RNA replication in vitro at clinically relevant concentrations.
  • mTORC1, but not mTORC2, was identified as essential for HCV RNA replication.
  • Switching to mTOR inhibitors in HCV-infected transplant patients significantly decreased HCV RNA levels in vivo.

Conclusions:

  • mTORC1 is a novel host factor required for HCV replication.
  • mTOR inhibition provides a mechanistic explanation for improved outcomes in HCV-positive transplant recipients.
  • mTOR-containing regimens warrant further investigation for HCV-positive solid organ transplant recipients.