An Analog of the Natural Steroidal Alkaloid Cortistatin A Potently Suppresses Tat-Dependent HIV Transcription

• Published in: Cell host & microbe Vol. 12; no. 1; pp. 97 - 108
• Main Authors: Mousseau, Guillaume, Clementz, Mark A., Bakeman, Wendy N., Nagarsheth, Nisha, Cameron, Michael, Shi, Jun, Baran, Phil, Fromentin, Rémi, Chomont, Nicolas, Valente, Susana T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.07.2012
• Subjects: alkaloids; Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - pharmacokinetics; Alkaloids - pharmacology; Animals; Anti-HIV Agents - pharmacology; antiretroviral agents; Antiretroviral Therapy, Highly Active; Binding Sites; CD4-Positive T-Lymphocytes - virology; Cells, Cultured - drug effects; Cells, Cultured - virology; drugs; Female; gene expression; Gene Expression Regulation, Viral - drug effects; genome; Heterocyclic Compounds, 4 or More Rings - pharmacology; HIV Core Protein p24 - metabolism; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - physiology; Human immunodeficiency virus 1; Human immunodeficiency virus 2; Humans; Isoquinolines - pharmacology; Male; messenger RNA; Mice; Mice, Inbred C57BL; Microsomes, Liver - drug effects; Polycyclic Compounds - chemistry; Porifera; Promoter Regions, Genetic; proviruses; Proviruses - drug effects; Proviruses - genetics; tat Gene Products, Human Immunodeficiency Virus - antagonists & inhibitors; tat Gene Products, Human Immunodeficiency Virus - genetics; tat Gene Products, Human Immunodeficiency Virus - metabolism; therapeutics; transcription (genetics); Transcription, Genetic - drug effects; transcriptional activation; viremia; virion; Virus Replication - drug effects
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2012.05.016

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. [Display omitted] ► Didehydro-Cortistatin A (dCA) inhibits Tat-mediated HIV transactivation ► dCA binds Tat's TAR-binding domain and prevents transcriptional elongation ► No viral rebound in chronically infected cells upon termination of dCA treatment ► dCA suppresses residual viremia in CD4+T cells from virally suppressed subjects