A novel cell-based high-throughput screen for inhibitors of HIV-1 gene expression and budding identifies the cardiac glycosides.

Abstract

OBJECTIVES:

Highly active antiretroviral therapy (HAART) is the mainstay of treatment for HIV-1 infection. While current HAART regimens have been extremely effective, issues of associated toxicity, cost and resistance remain and there is a need for novel antiretroviral compounds to complement the existing therapy. We sought to develop a novel high-throughput method for identifying compounds that block later steps in the life cycle not targeted by current therapy.

METHODS:

We designed a high-throughput screen to identify inhibitors of post-integration steps in the HIV-1 life cycle. The screening method was applied to a library of compounds that included numerous FDA-approved small molecules.

RESULTS:

Among the small molecules that inhibited late stages in HIV-1 replication were members of the cardiac glycoside family. We demonstrate that cardiac glycosides potently inhibit HIV-1 gene expression, thereby reducing the production of infectious HIV-1. We demonstrate that this inhibition is dependent upon the human Na(+)/K(+)-ATPase, but independent of cardiac glycoside-induced increases in intracellular Ca(2+).

CONCLUSIONS:

We have validated a novel high-throughput screen to identify small molecule inhibitors of HIV-1 gene expression, virion assembly and budding. Using this screen, we have demonstrated that a number of FDA-approved compounds developed for other purposes potently inhibit HIV-1 replication, including the cardiac glycosides. Our work indicates that the entire cardiac glycoside family of drugs shows potential for antiretroviral drug development.

• Authors: Gregory M Laird, Evelyn E Eisele, S Alireza Rabi, Daria Nikolaeva, Robert F Siliciano
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 69 Issue 4 Pg. 988-94 (Apr 2014) ISSN: 1460-2091 [Electronic] England
• PMID: 24275119 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Cardiac Glycosides

Topics

• Anti-HIV Agents (pharmacology)
• Cardiac Glycosides (pharmacology)
• Drug Repositioning
• HIV-1 (physiology)
• High-Throughput Screening Assays
• Humans
• Virus Activation (drug effects)
• Virus Release (drug effects)