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Pharmacological Cyclin-Dependent Kinase Inhibitors Inhibit Replication of Wild-Type and Drug-Resistant Strains of Herpes Simplex Virus and Human Immunodeficiency Virus Type 1 by Targeting Cellular, Not Viral, Proteins

Luis M. Schang,^1* Andrew Bantly,^1, Marie Knockaert,² Farida Shaheen,¹ Laurent Meijer,² Michael H. Malim,^1, Nathanael S. Gray,³ and Priscilla A. Schaffer^1,

University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,¹ Station Biologique de Roscoff, CNRS, Roscoff, Bretagne, France,² Genomics Institute of the Novartis Research Foundation, San Diego, California³

Received 15 November 2001/ Accepted 29 April 2002

Pharmacological cyclin-dependent kinase (cdk) inhibitors (PCIs) block replication of several viruses, including herpes simplex virus type 1 (HSV-1) and human immunodeficiency virus type 1 (HIV-1). Yet, these antiviral effects could result from inhibition of either cellular cdks or viral enzymes. For example, in addition to cellular cdks, PCIs could inhibit any of the herpesvirus-encoded kinases, DNA replication proteins, or proteins involved in nucleotide metabolism. To address this issue, we asked whether purine-derived PCIs (P-PCIs) inhibit HSV and HIV-1 replication by targeting cellular or viral proteins. P-PCIs inhibited replication of HSV-1 and -2 and HIV-1, which require cellular cdks to replicate, but not vaccinia virus or lymphocytic choriomeningitis virus, which are not known to require cdks to replicate. P-PCIs also inhibited strains of HSV-1 and HIV-1 that are resistant to conventional antiviral drugs, which target viral proteins. In addition, the anti-HSV effects of P-PCIs and a conventional antiherpesvirus drug, acyclovir, were additive, demonstrating that the two drugs act by distinct mechanisms. Lastly, the spectrum of proteins that bound to P-PCIs in extracts of mock- and HSV-infected cells was the same. Based on these observations, we conclude that P-PCIs inhibit virus replication by targeting cellular, not viral, proteins.

Present address: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa.

Present address: Department of Infectious Diseases, Guy’s, King’s and St. Thomas’ School of Medicine, King’s College London, GKT Guy’s Hospital, London SE1 9RT, United Kingdom.

Present address: Department of Medicine, Harvard Medical School at the Beth Israel Deaconness Medical Center, Boston, MA 02215.

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