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Cell Host Microbe. 2012 Jul 19;12(1):97-108. doi: 10.1016/j.chom.2012.05.016.

An analog of the natural steroidal alkaloid cortistatin A potently suppresses Tat-dependent HIV transcription.

Author information

1
Department of Infectology, The Scripps Research Institute, Scripps Florida, Jupiter, 33458, USA.

Abstract

The human immunodeficiency virus type 1 (HIV) Tat protein, a potent activator of HIV gene expression, is essential for integrated viral genome expression and represents a potential antiviral target. Tat binds the 5'-terminal region of HIV mRNA's stem-bulge-loop structure, the transactivation-responsive (TAR) element, to activate transcription. We find that didehydro-Cortistatin A (dCA), an analog of a natural steroidal alkaloid from a marine sponge, inhibits Tat-mediated transactivation of the integrated provirus by binding specifically to the TAR-binding domain of Tat. Working at subnanomolar concentrations, dCA reduces Tat-mediated transcriptional initiation/elongation from the viral promoter to inhibit HIV-1 and HIV-2 replication in acutely and chronically infected cells. Importantly, dCA abrogates spontaneous viral particle release from CD4(+)T cells from virally suppressed subjects on highly active antiretroviral therapy (HAART). Thus, dCA defines a unique class of anti-HIV drugs that may inhibit viral production from stable reservoirs and reduce residual viremia during HAART.

PMID:
22817991
PMCID:
PMC3403716
DOI:
10.1016/j.chom.2012.05.016
[Indexed for MEDLINE]
Free PMC Article

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