Dept. of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Retrovirology. 2011 Jun 17;8:47. doi: 10.1186/1742-4690-8-47.
RNA processing plays a critical role in the replication of HIV-1, regulated in part through the action of host SR proteins. To explore the impact of modulating SR protein activity on virus replication, the effect of increasing or inhibiting the activity of the Cdc2-like kinase (CLK) family of SR protein kinases on HIV-1 expression and RNA processing was examined.
Despite their high homology, increasing individual CLK expression had distinct effects on HIV-1, CLK1 enhancing Gag production while CLK2 inhibited the virus. Parallel studies on the anti-HIV-1 activity of CLK inhibitors revealed a similar discrepant effect on HIV-1 expression. TG003, an inhibitor of CLK1, 2 and 4, had no effect on viral Gag synthesis while chlorhexidine, a CLK2, 3 and 4 inhibitor, blocked virus production. Chlorhexidine treatment altered viral RNA processing, decreasing levels of unspliced and single spliced viral RNAs, and reduced Rev accumulation. Subsequent experiments in the context of HIV-1 replication in PBMCs confirmed the capacity of chlorhexidine to suppress virus replication.
Together, these findings establish that HIV-1 RNA processing can be targeted to suppress virus replication as demonstrated by manipulating individual CLK function and identified chlorhexidine as a lead compound in the development of novel anti-viral therapies.
RNA 处理在 HIV-1 的复制中起着关键作用，部分通过宿主 SR 蛋白的作用进行调节。为了探讨调节 SR 蛋白活性对病毒复制的影响，研究了增加或抑制 Cdc2 样激酶（CLK）家族 SR 蛋白激酶活性对 HIV-1 表达和 RNA 处理的影响。
尽管它们具有高度同源性，但增加单个 CLK 的表达对 HIV-1 有明显不同的影响，CLK1 增强 Gag 的产生，而 CLK2 抑制病毒。对 CLK 抑制剂抗 HIV-1 活性的平行研究揭示了对 HIV-1 表达的类似不一致影响。TG003 是 CLK1、2 和 4 的抑制剂，对病毒 Gag 合成没有影响，而氯己定是 CLK2、3 和 4 的抑制剂，可阻断病毒产生。氯己定处理改变了病毒 RNA 处理，降低了未剪接和单剪接病毒 RNA 的水平，并减少了 Rev 的积累。随后在 PBMC 中 HIV-1 复制的背景下进行的实验证实了氯己定抑制病毒复制的能力。
总之，这些发现表明，可以通过操纵单个 CLK 功能来靶向 HIV-1 RNA 处理以抑制病毒复制，并确定氯己定为开发新型抗病毒疗法的先导化合物。
