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. Antiretroviral therapies (ART) for HIV/AIDS are successful in slowing disease progression by inhibiting viral proteins. However, the ability of HIV to adapt to ARTs has given rise to drug-resistant virus strains that now represent ≥16% of newly infected people. This development calls for the generation of new treatment strategies. 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. We identified digoxin as a potent inhibitor of HIV-1 replication. The drug inhibited expression of HIV-1 structural proteins and a key factor involved in viral RNA export. This response was accomplished by altering the efficiency and splicing choices in HIV-1 RNA processing. Since this stage of the virus lifecycle is not targeted by current ARTs, the digoxin family of drugs represent a novel class of HIV-1 inhibitors. Since digoxin targets host factors and is already in clinical use, it and potentially the cardiac glycoside family of drugs has the possibility for swift development into a new ART for HIV-1 infection.