Abstract:
BACKGROUND & AIMS: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.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
Nakagawa M,Sakamoto N,Tanabe Y,Koyama T,Itsui Y,Takeda Y,Chen CH,Kakinuma S,Oooka S,Maekawa S,Enomoto N,Watanabe Mdoi
10.1053/j.gastro.2005.06.031keywords:
subject
Has Abstractpub_date
2005-09-01 00:00:00pages
1031-41issue
3eissn
0016-5085issn
1528-0012pii
S0016-5085(05)01192-3journal_volume
129pub_type
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