cortistatin-a and HIV-Infections

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.

Topics: Alkaloids; Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Binding Sites; CD4-Positive T-Lymphocytes; Cells, Cultured; Female; Gene Expression Regulation, Viral; Heterocyclic Compounds, 4 or More Rings; HIV Core Protein p24; HIV Infections; HIV-1; Humans; Isoquinolines; Male; Mice; Mice, Inbred C57BL; Microsomes, Liver; Polycyclic Compounds; Promoter Regions, Genetic; Proviruses; tat Gene Products, Human Immunodeficiency Virus; Transcription, Genetic; Virus Replication