Spectrum of cdk-9 inhibitor activity against HIV-1 replication among various models of chronic and latent infection.
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.
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HIV and Retrovirology Branch, Division of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
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D002460:Cell Line; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D017735:Virus Latency / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
D004791:Enzyme Inhibitors; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases