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.
Highlights
Current highly active anti-retroviral therapies (HAARTs) have successfully delayed the progression of HIV-1-infected individuals to AIDS by targeting viral entry and all HIV-1 enzymes [1,2]
Antiretroviral therapies (ART) for HIV/AIDS are successful in slowing disease progression by inhibiting viral proteins
Since HIV is dependent upon RNA processing under control of the host, we searched for compounds/drugs that inhibit HIV-1 replication at this step
Summary
Current highly active anti-retroviral therapies (HAARTs) have successfully delayed the progression of HIV-1-infected individuals to AIDS by targeting viral entry and all HIV-1 enzymes [1,2]. The clinical application of ARTs is being affected by the spread of drug resistant viral strains [3,4,5]; detection of drug resistant forms of HIV-1 in newly infected patients has increased ,3-fold from 2000 to 2007 to 16% [6,7]. To overcome these hurdles, more drugs with better profiles, and especially, novel mechanisms of action, are necessary for continued success in combating HIV-1 [1,2,8]. Imbalances in RNA processing can dramatically affect viral replication [27,28,29]; undersplicing results in the loss of key regulatory proteins such as Tat and Rev (from MS RNA), while oversplicing would reduce incompletely-spliced RNAs (US, SS) encoding viral structural proteins (Gag, Env) and accessory factors (Vif, Vpr, Vpu)
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