title: Suppression of hepatitis C virus replication by cyclosporin a is mediated by blockade of cyclophilins.
abstract: OBJECTIVE
  Cyclosporin A specifically suppresses hepatitis C virus (HCV) replication in vitro at clinically achievable concentrations. In this study, we investigated the mechanisms of action of cyclosporin A against HCV replication.
  
  
  METHODS
  The in vitro effects of cyclosporin A on HCV replication were analyzed using an HCV replicon system that expresses chimeric luciferase reporter protein.
  
  
  RESULTS
  The significant effects of cyclosporin A on expression of an HCV replicon and the absence of such effects of FK506, which shares mechanisms of action with cyclosporin A, suggested the involvement of intracellular ligands of cyclosporin A, the cyclophilins. Transient and stable knockdown of the expression of cytoplasmic cyclophilins A, B, and C by short hairpin RNA-expressing vectors suppressed HCV replication significantly. A cyclosporin analogue, cyclosporin D, which lacks immunosuppressive activity but exhibits cyclophilin binding, induced a similar suppression of HCV replication. Furthermore, cyclosporin A treatment of Huh7 cells induced an unfolded protein response exemplified by expression of cellular BiP/GRP78. Treatment of cells with thapsigargin and mercaptoethanol, which induce the unfolded protein responses, suppressed HCV replication, suggesting that the cyclosporin-induced unfolded protein responses might contribute to the suppression of HCV protein processing and replication.
  
  
  CONCLUSIONS
  The anti-HCV activity of cyclosporin A is mediated through a specific blockade of cyclophilins, and these molecules may constitute novel targets for anti-HCV therapeutics.
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanabe
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Koyama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Itsui
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Takeda
authors.forename: Cheng-Hsin
authors.initials: CH
authors.lastname: Chen
authors.forename: Sei
authors.initials: S
authors.lastname: Kakinuma
authors.forename: Shinya
authors.initials: S
authors.lastname: Oooka
authors.forename: Shinya
authors.initials: S
authors.lastname: Maekawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D021984:Cyclophilin A / Q000235:genetics; D000072622:Cyclophilin C; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016572:Cyclosporine / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D017353:Gene Deletion; D005822:Genetic Vectors; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase / Q000235:genetics; D010957:Plasmids; D012367:RNA, Viral / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D007166:Immunosuppressive Agents; D012367:RNA, Viral; C081786:cyclophilin B; D016572:Cyclosporine; D021984:Cyclophilin A; D021983:Cyclophilins; D000072622:Cyclophilin C; D019696:Peptidylprolyl Isomerase