Suppression of hepatitis C virus replication by cyclosporin a is mediated by blockade of cyclophilins.
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.
Nakagawa
Mina
M
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Sakamoto
Naoya
N
Tanabe
Yoko
Y
Koyama
Tomoyuki
T
Itsui
Yasuhiro
Y
Takeda
Yoshie
Y
Chen
Cheng-Hsin
CH
Kakinuma
Sei
S
Oooka
Shinya
S
Maekawa
Shinya
S
Enomoto
Nobuyuki
N
Watanabe
Mamoru
M
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*
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