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

doi:10.1128/JVI.75.16.7266-7279.2001

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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. Basedon this result, we investigated the transcription of HIV-1 inthe presence of chemical drugs that specifically inhibited cdkactivity and functionally mimicked p21/Waf1 activity. HIV-1 productionin virally integrated lymphocytic and monocytic cell lines, suchas ACH₂, 8E5, and U1, as well as activated peripheral blood mononuclearcells infected with syncytium-inducing (SI) or non-syncytium-inducing(NSI) HIV-1 strains, were all inhibited by Roscovitine, a purinederivative that reversibly competes for the ATP binding site presentin cdk's. The decrease in viral progeny in the HIV-1-infectedcells was correlated with a decrease in the transcription of HIV-1RNAs in cells treated with Roscovitine and not with the non-cdkgeneral cell cycle inhibitors, such as hydroxyurea (G₁/S blocker)or nocodazole (M-phase blocker). Cyclin A- and E-associated histoneH1 kinases, as well as cdk 7 and 9 activities, were all inhibitedin the presence of Roscovitine. The 50% inhibitory concentrationof Roscovitine on cdk's 9 and 7 was determined to be ~0.6 µM.Roscovitine could selectively sensitize HIV-1-infected cells toapoptosis at concentrations that did not impede the growth andproliferation of uninfected cells. Apoptosis induced by Roscovitinewas found in both latent and activated infected cells, as evidentby Annexin V staining and the cleavage of the PARP protein bycaspase-3. More importantly, contrary to many apoptosis-inducingagents, where the apoptosis of HIV-1-infected cells accompaniesproduction and release of infectious HIV-1 viral particles, Roscovitinetreatment selectively killed HIV-1-infected cells without virionrelease. Collectively, our data suggest that cdk's are requiredfor efficient HIV-1 transcription and, therefore, we propose specificcdk inhibitors as potential antiviral agents in the treatmentofAIDS.

^* 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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