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Journal of Virology, December 2004, p. 13522-13533, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13522-13533.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Coordination of Transcription Factor Phosphorylation and Histone Methylation by the P-TEFb Kinase during Human Immunodeficiency Virus Type 1 Transcription

Meisheng Zhou,1,2 Longwen Deng,1 Vincent Lacoste,1 Hyeon Ung Park,2 Anne Pumfery,1 Fatah Kashanchi,1,3 John N. Brady,2* and Ajit Kumar1*

Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine, Washington, D.C.,1 Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda,2 The Institute for Genomic Research, Rockville, Maryland3

Received 31 March 2004/ Accepted 3 August 2004

The human immunodeficiency virus type 1 (HIV-1) Tat protein recruits positive transcription elongation factor b (P-TEFb) to the transactivation response (TAR) RNA structure to facilitate formation of processive transcription elongation complexes (TECs). Here we examine the role of the Tat/TAR-specified cyclin-dependent kinase 9 (CDK9) kinase activity in regulation of HIV-1 transcription elongation and histone methylation. In HIV-1 TECs, P-TEFb phosphorylates the RNA polymerase II (RNAP II) carboxyl-terminal domain (CTD) and the transcription elongation factors SPT5 and Tat-SF1 in a Tat/TAR-dependent manner. Using in vivo chromatin immunoprecipitation analysis, we demonstrate the following distinct properties of the HIV-1 transcription complexes. First, the RNAP II CTD is phosphorylated at Ser 2 and Ser 5 near the promoter and at downstream coding regions. Second, the stable association of SPT5 with the TECs is dependent upon P-TEFb kinase activity. Third, P-TEFb kinase activity is critical for the induction of methylation of histone H3 at lysine 4 and lysine 36 on HIV-1 genes. Flavopiridol, a potent P-TEFb kinase inhibitor, inhibits CTD phosphorylation, stable SPT5 binding, and histone methylation, suggesting that its potent antiviral activity is due to its ability to inhibit several critical and unique steps in HIV-1 transcription elongation.

* Corresponding author. Mailing address for J. N. Brady: Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, NCI/NIH, Building 41, Room B201, Bethesda, MD 20892. Phone: (301) 496-0986. Fax: (301) 496-4951. bradyj{at}exchange.nih.gov. Mailing address for A. Kumar: Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine, Ross Hall, Room 232, 2300 Eye St., NW, Washington, DC 20037. Phone: (202) 994-2919. Fax: (202) 994-8974. E-mail: akumar{at}gwu.edu.

Journal of Virology, December 2004, p. 13522-13533, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13522-13533.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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