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Journal of Virology, August 2001, p. 7266-7279, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7266-7279.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Inhibition of Human Immunodeficiency Virus Type 1 Transcription by Chemical Cyclin-Dependent Kinase Inhibitors

Dai Wang,1 Cynthia de la Fuente,1 Longwen Deng,1 Lai Wang,1 Irene Zilberman,1 Carolyn Eadie,1 Marlene Healey,1 Dana Stein,2 Thomas Denny,2 Lawrence E. Harrison,3 Laurent Meijer,4 and Fatah Kashanchi1,*

George Washington University School of Medicine, Washington, DC 200371; Department of Pathology and Pediatrics2 and Department of Surgery,3 UMDNJ-New Jersey Medical School, Newark, New Jersey 07103; and Station Biologique, CNRS, 29682 Roscoff, France4

Received 4 December 2000/Accepted 14 May 2001

Cyclin-dependent kinases (cdk's) have recently been suggested to regulate human immunodeficiency virus type 1 (HIV-1) transcription. Previously, we have shown that expression of one cdk inhibitor, p21/Waf1, is abrogated in HIV-1 latently infected cells. Based on this result, we investigated the transcription of HIV-1 in the presence of chemical drugs that specifically inhibited cdk activity and functionally mimicked p21/Waf1 activity. HIV-1 production in virally integrated lymphocytic and monocytic cell lines, such as ACH2, 8E5, and U1, as well as activated peripheral blood mononuclear cells infected with syncytium-inducing (SI) or non-syncytium-inducing (NSI) HIV-1 strains, were all inhibited by Roscovitine, a purine derivative that reversibly competes for the ATP binding site present in cdk's. The decrease in viral progeny in the HIV-1-infected cells was correlated with a decrease in the transcription of HIV-1 RNAs in cells treated with Roscovitine and not with the non-cdk general cell cycle inhibitors, such as hydroxyurea (G1/S blocker) or nocodazole (M-phase blocker). Cyclin A- and E-associated histone H1 kinases, as well as cdk 7 and 9 activities, were all inhibited in the presence of Roscovitine. The 50% inhibitory concentration of Roscovitine on cdk's 9 and 7 was determined to be ~0.6 µM. Roscovitine could selectively sensitize HIV-1-infected cells to apoptosis at concentrations that did not impede the growth and proliferation of uninfected cells. Apoptosis induced by Roscovitine was found in both latent and activated infected cells, as evident by Annexin V staining and the cleavage of the PARP protein by caspase-3. More importantly, contrary to many apoptosis-inducing agents, where the apoptosis of HIV-1-infected cells accompanies production and release of infectious HIV-1 viral particles, Roscovitine treatment selectively killed HIV-1-infected cells without virion release. Collectively, our data suggest that cdk's are required for efficient HIV-1 transcription and, therefore, we propose specific cdk inhibitors as potential antiviral agents in the treatment of AIDS.

* Corresponding author. Mailing address: George Washington University School of Medicine, 2300 Eye St., NW, Ross Hall, Rm. 552, Washington, DC 20037. Phone: (202) 994-1781. Fax: (202) 994-1780. E-mail: bcmfxk{at}gwumc.edu.

Journal of Virology, August 2001, p. 7266-7279, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7266-7279.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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