A novel cell-based high-throughput screen for inhibitors of HIV-1 gene expression and budding identifies the cardiac glycosides
GM Laird, EE Eisele, SA Rabi… - Journal of …, 2014 - academic.oup.com
Journal of Antimicrobial Chemotherapy, 2014•academic.oup.com
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 …
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 …
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 Ca2+.
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.
Oxford University Press