title: Differential effect of CLK SR Kinases on HIV-1 gene expression: potential novel targets for therapy.
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.
authors.affiliation: Dept. of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Wong
authors.forename: Ahalya
authors.initials: A
authors.lastname: Balachandran
authors.forename: Annie Yq
authors.initials: AY
authors.lastname: Mao
authors.forename: Wendy
authors.initials: W
authors.lastname: Dobson
authors.forename: Scott
authors.initials: S
authors.lastname: Gray-Owen
authors.forename: Alan
authors.initials: A
authors.lastname: Cochrane
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D012367:RNA, Viral; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases