Digoxin Suppresses HIV-1 Replication by Altering Viral RNA Processing

PLoS Pathogens

Mario A. Ostrowski¹  Raymond W. Wong²  Alan Cochrane³  Ahalya Balachandran³ 

[1] Department of Immunology, University of Toronto, Toronto, Canada;Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada;Department of Molecular Genetics, University of Toronto, Toronto, Canada

关键词: HIV-1;    RNA processing;    Gene expression;    Viral replication;    RNA splicing;    RNA synthesis;    Drug therapy;    Protein expression;   

DOI  :  10.1371/journal.ppat.1003241

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY