Spectrum of cdk-9 inhibitor activity against HIV-1 replication among various models of chronic and latent infection

• Published in: Antiviral chemistry & chemotherapy Vol. 12; pp. 33 - 41
• Main Authors: PISELL, T. L, HO, O, LEE, G, BUTERA, S. T
• Format: Conference Proceeding Journal Article
• Language: English
• Published: London International Medical Press 2001
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cdk9 protein; Cell Line; Cyclin-Dependent Kinase 9; Cyclin-Dependent Kinases - antagonists & inhibitors; Enzyme Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus 1; Humans; Medical sciences; Models, Biological; Pharmacology. Drug treatments; Virus Latency - drug effects; Virus Replication - drug effects; Transcription; HIV-1 virus; Enzyme; Transferases; Retroviridae; Enzyme inhibitor; Review; Lentivirus; In vitro; Biological activity; Virus; Protein kinase; Replication; Human immunodeficiency virus
• ISSN: 0956-3202; 2040-2066

The cellular transcription elongation factor, P-TEFb, and its kinase component, cdk-9, have been implicated in the regulation of HIV-1 transactivation and transcription. We tested a panel of demonstrated cdk-9 kinase inhibitors for the ability to block HIV-1 expression in a variety of cell models representing chronic and latent/inducible infection. These agents induced cellular toxicity, in accordance with their potency for cdk-9 inhibition, with more pronounced toxicity in cultures of T-cell lineage. These agents also inhibited HIV-1 expression, in accordance with their potency for cdk-9 inhibition, in several latent models tested (representing T-lymphocytic, promonocytic and promyelocytic lineages) and using various extracellular stimuli that activate HIV-1 expression via distinct intracellular pathways. Such was the case even though some of these cell models of latent/inducible HIV-1 infection harbour viral defects in the HIV-1 transactivation mechanism. Two additional cell models of latent/inducible HIV-1 infection, both derived from Jurkat T-lymphocytes, were relatively resistant to inhibition of viral expression by these agents. This apparent lack of effect was most likely due to the narrow therapeutic range of these agents in T-cell cultures. Inhibition of HIV-1 replication by these agents was also observed in two cell models representing constitutive viral expression in cells of T-lymphocytic and promyelocytic lineages. Overall, the observed pattern of viral inhibition with these compounds suggests that cdk-9 enzymatic activity is important for HIV-1 expression irrespective of cell lineage or cellular pathway of viral activation. However, because of the non-selective nature of these inhibitors, other cellular pathways must also be considered. Agents that target cellular components essential for HIV-1 expression may provide new therapeutic approaches to limit viral replication, especially when combined with potent antiretroviral regimens.