Inhibition of cyclophilins alters lipid trafficking and blocks hepatitis C virus secretion.
Inhibition of cyclophilins alters lipid trafficking and blocks hepatitis C virus secretion.
复制标题
DOI：
10.1186/1743-422x-8-329
复制
发表时间：
2011-06-28
期刊：
影响因子：
4.8
通讯作者：
Wiedmann B
中科院分区：
文献类型：
--
作者：
Anderson LJ;Lin K;Compton T;Wiedmann B
宿主亲环蛋白（cyp）抑制剂，如NIM811，有效地抑制丙型肝炎病毒（HCV）的复制，并在最近的临床试验中显示出治疗慢性HCV的重大前景。因此，重要的是要充分了解这些治疗药物的作用机制。从全面的系统生物学方法获得的数据导致的假设，亲环蛋白抑制剂的抗病毒活性介导的，通过损害细胞的机器上的HCV依赖于交通辅因子形成的复制复合物。事实上，我们的研究结果表明，当亲环蛋白被NIM811抑制时，VLDL途径内的脂质和蛋白质运输受损。用NIM811处理复制子或HCV感染的细胞后，细胞内脂滴（LD）的大小增加一倍以上，数量减少。响应亲环素抑制的LD的变化取决于病毒蛋白的表达。此外，在用NIM811处理的细胞中，apoB在围绕扩大的LD的新月形或环形结构中积累，并且不再分泌。使用siRNA沉默cypA或cyp40对LD大小和apoB定位具有与化合物处理类似的效果，表明这些亲环蛋白可能在脂质和apoB运输中起重要作用。有趣的是，apoB分泌的减少与HCV感染细胞中病毒颗粒释放的减少相关。总之，这些结果增加了一个新的水平的复杂性亲环素抑制的作用机制，并表明亲环素在病毒生命周期中的作用超出复制病毒释放。
Host cyclophilin (cyp) inhibitors, such as NIM811, efficiently inhibit replication of hepatitis C virus (HCV) and have shown significant promise in recent clinical trials for the treatment of chronic HCV. It is therefore important to fully understand the mechanism of action of these therapeutic agents. Data obtained from comprehensive systems biology approaches have led to the hypothesis that the antiviral activity of cyclophilin inhibitors is mediated through impairing the cellular machinery on which HCV relies to traffic cofactors necessary for formation of the replication complex. Indeed, our results demonstrate when cyclophilins are inhibited by NIM811, lipid and protein trafficking within the VLDL pathway is impaired. Following treatment of replicon or HCV infected cells with NIM811, intracellular lipid droplets (LD) more than double in size and decrease in number. Changes in the LDs in response to cyclophilin inhibition are dependent upon expression of viral proteins. Additionally, in cells treated with NIM811, apoB accumulates in a crescent or ring shaped structure surrounding the enlarged LDs and is no longer secreted. Silencing of cypA or cyp40 using siRNA had a similar effect on LD size and apoB localization as compound treatment, suggesting these cyclophilins may play an important role in lipid and apoB trafficking. Interestingly, the decrease in apoB secretion correlates with a decrease in release of viral particles in HCV infected cells. Altogether, these results add a new level of complexity to the mechanism of action of cyclophilin inhibition, and suggest the role for cyclophilins in the virus life cycle extends beyond replication to virus release.