title: Rapamycin and everolimus facilitate hepatitis E virus replication: revealing a basal defense mechanism of PI3K-PKB-mTOR pathway.
abstract: OBJECTIVE
  Humans are frequently exposed to hepatitis E virus (HEV). Nevertheless, the disease mainly affects pregnant women and immunocompromised individuals. Organ recipients receiving immunosuppressants, such as rapalogs, to prevent rejection have a high risk for developing chronic hepatitis following HEV infection. Rapalogs constitute potent inhibitors of mTOR including rapamycin and everolimus. As a master kinase, the mechanism-of-action of mTOR is not only associated with the immunosuppressive capacity of rapalogs but is also tightly regulated during pregnancy because of increased nutritional demands.
  
  
  METHODS
  We thus investigated the role of mTOR in HEV infection by using two state-of-the-art cell culture models: a subgenomic HEV containing luciferase reporter and a full-length HEV infectious cell culture system.
  
  
  RESULTS
  In both subgenomic and full-length HEV models, HEV infection was aggressively escalated by treatment of rapamycin or everolimus. Inhibition of mTOR was confirmed by Western blot showing the inhibition of its downstream target, S6 phosphorylation. Consistently, stable silencing of mTOR by lentiviral RNAi resulted in a significant increase in intracellular HEV RNA, suggesting an antiviral function of mTOR in HEV infection. By targeting a series of other up- and downstream elements of mTOR signaling, we further revealed an effective basal defense mechanism of the PI3K-PKB-mTOR pathway against HEV, which is through the phosphorylated eIF4E-binding protein 1 (4E-BP1), however independent of autophagy formation.
  
  
  CONCLUSIONS
  The discovery that PI3K-PKB-mTOR pathway limits HEV infection through 4E-BP1 and acts as a gate-keeper in human HEV target cells bears significant implications in managing immunosuppression in HEV-infected organ transplantation recipients.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands; Division of Gastroenterology, University Health Network, Toronto, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands. Electronic address: q.pan@erasmusmc.nl.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D000068338:Everolimus; D016751:Hepatitis E / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D016752:Hepatitis E virus / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D010750:Phosphoproteins / Q000276:immunology; D010766:Phosphorylation / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D012097:Repressor Proteins / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000276:immunology*; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D000068338:Everolimus; D007166:Immunosuppressive Agents; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C087000:EIF4EBP1 protein, human; C546842:MTOR protein, human
keywords: Everolimus; Hepatitis E virus; PI3K-PKB-mTOR pathway; Rapamycin