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J. Biol. Chem., Vol. 280, Issue 4, 3029-3042, January 28, 2005

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Antiviral Activity of CYC202 in HIV-1-infected Cells^*

Emmanuel Agbottah, Cynthia de La Fuente, Sergie Nekhai, Anna Barnett¶, Athos Gianella-Borradori¶, Anne Pumfery, and Fatah Kashanchi||**

From the Department of Biochemistry and Molecular Biology, The George Washington University, School of Medicine, Washington, D. C. 20037, the Center for Sickle Cell Disease, Howard University, Washington, D. C. 20059, ^¶Cyclacel Ltd., Dundee Technopole, James Lindsay Place, Dundee DD1 5JJ, Scotland, United Kingdom, and the ^||Institute for Genomic Research, Rockville, Maryland 20850

There are currently 40 million individuals in the world infected with human immunodeficiency virus (HIV). The introduction of highly active antiretroviral therapy (HAART) has led to a significant reduction in AIDS-related morbidity and mortality. Unfortunately, up to 25% of patients discontinue their initial HAART regimen. Current HIV-1 inhibitors target the fusion of the virus to the cell and two viral proteins, reverse transcriptase and protease. Here, we examined whether other targets, such as an activated transcription factor, could be targeted to block HIV-1 replication. We specifically asked whether we could target a cellular kinase needed for HIV-1 transcription using CYC202 (R-roscovitine), a pharmacological cyclin-dependent kinase inhibitor. We targeted the cdk2-cyclin E complex in HIV-1-infected cells because both cdk2 and cyclin E are nonessential during mammalian development and are likely replaced by other kinases. We found that CYC202 effectively inhibits wild type and resistant HIV-1 mutants in T-cells, monocytes, and peripheral blood mononuclear cells at a low IC₅₀ and sensitizes these cells to enhanced apoptosis resulting in a dramatic drop in viral titers. Interestingly, the effect of CYC202 is independent of cell cycle stage and more specific for the cdk2-cyclin E complex. Finally, we show that cdk2-cyclin E is loaded onto the HIV-1 genome in vivo and that CYC202 is able to inhibit the uploading of this cdk-cyclin complex onto HIV-1 DNA. Therefore, targeting cellular enzymes necessary for HIV-1 transcription, which are not needed for cell survival, is a compelling strategy to inhibit wild type and mutant HIV-1 strains.

Received for publication, June 9, 2004 , and in revised form, September 23, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: George Washington University, 2300 Eye St., NW, Ross Hall, Rm. 551, Washington, D. C. 20037. Tel.: 202-994-1781; Fax: 202-994-1780; E-mail: bcmfxk{at}gwumc.edu.

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