Indirubin-3'-monoxime, a derivative of a Chinese antileukemia medicine, inhibits P-TEFb function and HIV-1 replication

• Published in: AIDS (London) Vol. 19; no. 18; pp. 2087 - 2095
• Main Authors: HEREDIA, Alonso, DAVIS, Charles, BAMBA, Douty, LE, Nhut, GWARZO, Muhammad Y, SADOWSKA, Mariola, GALLO, Robert C, REDFIELD, Robert R
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 02-12-2005
• Subjects: Biological and medical sciences; Cyclin-Dependent Kinases - antagonists & inhibitors; Drug Evaluation; Flavonoids - pharmacology; HIV-1 - physiology; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Indoles - pharmacology; Infectious diseases; Inhibitory Concentration 50; Leukocytes, Mononuclear - virology; Macrophages - virology; Medical sciences; Oximes - pharmacology; Piperidines - pharmacology; Positive Transcriptional Elongation Factor B - antagonists & inhibitors; Protein Kinase Inhibitors - pharmacology; Purines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction - methods; Roscovitine; U937 Cells; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Virus Replication - drug effects; Immunopathology; Treatment resistance; HIV-1 virus; Tat; Retroviridae; AIDS; Immune deficiency; Lentivirus; P-TEFb; Infection; Virus; Chinese medicine; Viral disease; Replication; Human immunodeficiency virus; drug resistance
• ISSN: 0269-9370; 1473-5571
• DOI: 10.1097/01.aids.0000194805.74293.11

To evaluate the effects of the cyclin dependent kinase (CDK) inhibitor Indirubin-3'-monoxime (IM) on Tat-mediated transactivation function, a step of the HIV-1 cycle that is not currently targeted in antiviral therapy.
The effects of IM on CDK implicated in HIV-1 Tat transactivation function were evaluated by kinase assays, transfection experiments, RNase protection assay and RT-PCR analysis of viral transcripts. The antiviral effect of IM was investigated in cells from HIV-1 infected individuals as well as in cell lines, primary lymphocytes and monocyte-derived macrophages. The antiviral activity of IM was also tested against drug-resistant HIV-1.
IM inhibits the kinase activity of CDK9 [50% inhibitory concentration (IC50) of 0.05 microM], the catalytic subunit of Positive transcription elongation factor b (P-TEFb). Inhibition of CDK9 activity by IM results in abrogation of Tat-induced expression of HIV-1 RNA in cell lines. In addition, IM inhibits the replication of HIV-1 in both peripheral blood mononuclear cells (IC50 of 1 microM) and macrophages (IC50 of 0.5 microM). IM is effective against primary and drug-resistant strains of HIV-1. Importantly, the antiviral effects of the drug were seen at concentrations that did not affect cell proliferation.
Non-toxic concentrations of IM inhibit HIV-1 by blocking viral gene expression mediated by the cellular factor P-TEFb. The drug is effective against wild-type and drug-resistant strains of HIV-1. IM may help control replication of HIV-1 in patients by disrupting a step of the HIV-1 cycle that is not being targeted in current antiretroviral treatments.