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Báo cáo y học: "Differential effect of CLK SR Kinases on HIV-1 gene expression: potential novel targets for therapy"

Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học Respiratory Research cung cấp cho các bạn kiến thức về ngành y đề tài: Differential effect of CLK SR Kinases on HIV-1 gene expression: potential novel targets for therapy. | Wong et al. Retrovirology 2011 8 47 http www.retrovirology.eom content 8 1 47 RETROVIROLOGY RESEARCH Open Access Differential effect of CLK SR Kinases on HIV-1 gene expression potential novel targets for therapy Raymond Wong1 Ahalya Balachandran2 Annie YQ Mao2 Wendy Dobson2 Scott Gray-Owen2 and Alan Cochrane2 Abstract Background 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. Results 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. Conclusions 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. Background The dependence of HIV-1 replication on the appropriate balance of its RNA processing suggests that this step in the virus lifecycle might be an attractive target for therapeutic intervention 1-3 . From a single 9 kb transcript over 40 mRNAs are generated by a process of subopti-mal splicing that generates three