title: An analog of the natural steroidal alkaloid cortistatin A potently suppresses Tat-dependent HIV transcription.
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.
authors: Department of Infectology, The Scripps Research Institute, Scripps Florida, Jupiter, 33458, USA.
authors: Guillaume
authors: G
authors: Mousseau
authors: Mark A
authors: MA
authors: Clementz
authors: Wendy N
authors: WN
authors: Bakeman
authors: Nisha
authors: N
authors: Nagarsheth
authors: Michael
authors: M
authors: Cameron
authors: Jun
authors: J
authors: Shi
authors: Phil
authors: P
authors: Baran
authors: Rémi
authors: R
authors: Fromentin
authors: Nicolas
authors: N
authors: Chomont
authors: Susana T
authors: ST
authors: Valente
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured / Q000187:drug effects / Q000821:virology; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016655:HIV Core Protein p24 / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects; D011083:Polycyclic Compounds / Q000737:chemistry*; D011401:Promoter Regions, Genetic; D011533:Proviruses / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D019380:Anti-HIV Agents; D016655:HIV Core Protein p24; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; D011083:Polycyclic Compounds; C576992:didehydro-cortistatin A; C514799:p24 protein, Human Immunodeficiency Virus Type 1; D054322:tat Gene Products, Human Immunodeficiency Virus; C531521:cortistatin A