title: Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus.
abstract: OBJECTIVE
  Many recipients of organ transplants develop chronic hepatitis, due to infection with the hepatitis E virus (HEV). Although chronic HEV infection is generally associated with immunosuppressive therapies, little is known about how different immunosuppressants affect HEV infection.
  
  
  METHODS
  A subgenomic HEV replication model, in which expression of a luciferase reporter gene is measured, and a full-length infection model were used. We studied the effects of different immunosuppressants, including steroids, calcineurin inhibitors (tacrolimus [FK506] and cyclosporin A), and mycophenolic acid (MPA, an inhibitor of inosine monophosphate dehydrogenase) on HEV replication in human hepatoma cell line Huh7. Expression of cyclophilins A and B (the targets of cyclosporin A) were knocked down using small hairpin RNAs.
  
  
  RESULTS
  Steroids had no significant effect on HEV replication. Cyclosporin A promoted replication of HEV in the subgenomic and infectious models. Knockdown of cyclophilin A and B increased levels of HEV genomic RNA by 4.0- ± 0.6-fold and 7.2- ± 1.9-fold, respectively (n = 6; P < .05). A high dose of FK506 promoted infection of liver cells with HEV. In contrast, MPA inhibited HEV replication. Incubation of cells with guanosine blocked the antiviral activity of MPA, indicating that the antiviral effects of this drug involve nucleotide depletion. The combination of MPA and ribavirin had a greater ability to inhibit HEV replication than MPA or ribavirin alone.
  
  
  CONCLUSIONS
  Cyclophilins A and B inhibit replication of HEV; this might explain the ability of cyclosporin A to promote HEV infection. On the other hand, the immunosuppressant MPA inhibits HEV replication. These findings should be considered when physicians select immunosuppressive therapies for recipients of organ transplants who are infected with HEV.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, 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, Netherlands.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Debing
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands; Bio-X Center, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
authors.forename: Kan
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands.
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: Van Der Laan
authors.affiliation: Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, 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, 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, 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, Netherlands. Electronic address: q.pan@erasmusmc.nl.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D045744:Cell Line, Tumor; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D016751:Hepatitis E / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D016752:Hepatitis E virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006521:Hepatitis, Chronic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009173:Mycophenolic Acid / Q000494:pharmacology*; D034622:RNA Interference; D012367:RNA, Viral / Q000096:biosynthesis; D012254:Ribavirin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D012367:RNA, Viral; C081786:cyclophilin B; D012254:Ribavirin; D016572:Cyclosporine; D019703:Calcineurin; D021984:Cyclophilin A; D021983:Cyclophilins; D009173:Mycophenolic Acid
keywords: Cell Culture Model; Immunity; Liver Disease; Transplantation