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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids / chemical synthesis
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Alkaloids / chemistry
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Alkaloids / pharmacokinetics
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Alkaloids / pharmacology*
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Animals
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Anti-HIV Agents / pharmacology*
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Antiretroviral Therapy, Highly Active
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Binding Sites
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CD4-Positive T-Lymphocytes / virology
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Cells, Cultured / drug effects
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Cells, Cultured / virology
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Female
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Gene Expression Regulation, Viral / drug effects
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HIV Core Protein p24 / metabolism
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HIV Infections / drug therapy
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HIV Infections / virology
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HIV-1 / drug effects
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HIV-1 / genetics*
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HIV-1 / physiology
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Heterocyclic Compounds, 4 or More Rings / pharmacology*
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Humans
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Isoquinolines / pharmacology*
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Male
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Mice
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Mice, Inbred C57BL
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Microsomes, Liver / drug effects
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Polycyclic Compounds / chemistry*
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Promoter Regions, Genetic
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Proviruses / drug effects
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Proviruses / genetics
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Transcription, Genetic / drug effects
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Virus Replication / drug effects
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tat Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors
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tat Gene Products, Human Immunodeficiency Virus / genetics
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tat Gene Products, Human Immunodeficiency Virus / metabolism*
Substances
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Alkaloids
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Anti-HIV Agents
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HIV Core Protein p24
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Heterocyclic Compounds, 4 or More Rings
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Isoquinolines
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Polycyclic Compounds
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didehydro-cortistatin A
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p24 protein, Human Immunodeficiency Virus Type 1
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tat Gene Products, Human Immunodeficiency Virus
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cortistatin A