Effect of Flavivirus Infection by Cyclosporin A: Antiviral Effect of Cyclosporin A on RNA Virus Replication

• Main Authors: yen jin-bin, 顏金彬
• Other Authors: Liao Ching-Len Lin Yi-Ling
• Format: Others
• Language: zh-TW
• Published: 1998
• Online Access: http://ndltd.ncl.edu.tw/handle/80303448533554087114

碩士 === 國防醫學院 === 微生物暨免疫學研究所 === 86 === In cultured cell system, the antiviral effect of Cyclosporin A (CSA), an immune modulator, on Japanese encephalitis virus (JEV) and Dengue virus (DEN) was investigated in this study. Within 60 g/ml range, CSA appeared to inhibit, in a dose-dependent manner, the virus replication of JEV or DEN in baby hamster kidney (BHK-21), murine neuroblastoma N18, and human neuronal NT2 cells; in contrast, CSA had no inhibitory effect on virus replication in persistently JEV-infected B2-5 cell. Pretreatment of target cells with CSA did not enhance the antiviral effect of CSA on flaviviruses, and yet, CSA remained to be capable of inhibiting virus replication even when the late phase of virus replication was particularly sensitive to CSA inhibition. In primarily infected cells, CSA was found to profoundly reduce the intracellular accumulation of virus envelop protein, nonstructural protein-1 (NS-1) and NS-3, and restrain the extracellular release of NS-1. Moreover, CSA could block JEV- or DEN-induced apoptosis from infected cells in a dose-dependent manner. In similar experiments, the effect of FK506, which is structurally different from but functionally analogous to CSA, on JEV replication was also studied. Our results indicate the FK506, like CSA, could also abrogate JEV or DEN's replication in primarily infected cells, but not in persistently infected cells. These data suggest that the antiflaviviral effect of CSA and FK506 was likely due to their specific inhibition of calcineurin (phosphatase-2B) activity, a mechanism quite different from how CSA arrests HIV replication. However, calycurin A, which is a potent inhibitor of phosphatase-1 (one of the calcineurin substrates), failed to block flavivirus replication, indicating that CSA and FK506 might utilize yet other calcineurin substrate(s) to exert the inhibitory capability. Interestingly, neither CSA nor FK5067 could restrict the replication of Sindbis virus, an alphavirus, in cultured cells, reflecting that the antiviral effect of these two drugs was unable to apply universally to all positive-sense RNA viruses. The data herein thus provide the first molecular evidence demonstrating how immuno-suppressants CSA and FK506 could restr5ict the replication RNA viruses.