title: Digoxin suppresses HIV-1 replication by altering viral RNA processing.
abstract: To develop new approaches to control HIV-1 replication, we examined the capacity of recently described small molecular modulators of RNA splicing for their effects on viral RNA metabolism. Of the drugs tested, digoxin was found to induce a dramatic inhibition of HIV-1 structural protein synthesis, a response due, in part, to reduced accumulation of the corresponding viral mRNAs. In addition, digoxin altered viral RNA splice site use, resulting in loss of the essential viral factor Rev. Digoxin induced changes in activity of the CLK family of SR protein kinases and modification of several SR proteins, including SRp20 and Tra2β, which could account for the effects observed. Consistent with this hypothesis, overexpression of SRp20 elicited changes in HIV-1 RNA processing similar to those observed with digoxin. Importantly, digoxin was also highly active against clinical strains of HIV-1 in vitro, validating this novel approach to treatment of this infection.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Wong
authors.forename: Ahalya
authors.initials: A
authors.lastname: Balachandran
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
authors.forename: Alan
authors.initials: A
authors.lastname: Cochrane
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004077:Digoxin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015757:Genes, rev / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012326:RNA Splicing / Q000187:drug effects; D012367:RNA, Viral / Q000187:drug effects / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D014764:Viral Proteins; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D015704:CD4 Antigens; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D012367:RNA, Viral; D016601:RNA-Binding Proteins; C491388:SRSF3 protein, human; C097083:TRA2B protein, human; D014764:Viral Proteins; D000068103:Serine-Arginine Splicing Factors; D004077:Digoxin
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