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Journal of Virology, November 2002, p. 10873-10881, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.10873-10881.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Optimized Chimeras between Kinase-Inactive Mutant Cdk9 and Truncated Cyclin T1 Proteins Efficiently Inhibit Tat Transactivation and Human Immunodeficiency Virus Gene Expression

Koh Fujinaga, Dan Irwin, Matthias Geyer, and B. Matija Peterlin*

Departments of Medicine, Microbiology, and Immunology, University of California at San Francisco, San Francisco, California 94143-0703

Received 29 April 2002/ Accepted 19 July 2002

The human cyclin T1 (hCycT1) protein from the positive transcription elongation factor b (P-TEFb) binds the transactivator Tat and the transactivation response (TAR) RNA stem loop from human immunodeficiency virus type 1 (HIV). This complex activates the elongation of viral transcription. To create effective inhibitors of Tat and thus HIV replication, we constructed mutant hCycT1 proteins that are defective in binding its kinase partner, Cdk9, or TAR. Although these mutant hCycT1 proteins did not increase Tat transactivation in murine cells, their dominant-negative effects were small in human cells. Higher inhibitory effects were obtained when hCycT1 was fused with the mutant Cdk9 protein. Since the autophosphorylation of the C terminus of Cdk9 is required for the formation of the stable complex between P-TEFb, Tat, and TAR, these serines and threonines were changed to glutamate in a kinase-inactive Cdk9 protein. This chimera inhibited Tat transactivation and HIV gene expression in human cells. Therefore, this dominant-negative kinase-inactive mutant Cdk9.hCycT1 chimera could be used for antiviral gene therapy.

* Corresponding author. Mailing address: Rm. N225, UCSF-Mt. Zion Cancer Center, 2340 Sutter St., San Francisco, CA 94115. Phone: (415) 502-1902. Fax: (415) 502-1901. E-mail: matija{at}itsa.ucsf.edu.

Journal of Virology, November 2002, p. 10873-10881, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.10873-10881.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Jadlowsky, J. K., Nojima, M., Okamoto, T., Fujinaga, K. (2008). Dominant negative mutant cyclin T1 proteins that inhibit HIV transcription by forming a kinase inactive complex with Tat. J. Gen. Virol. 89: 2783-2787 [Abstract] [Full Text]  
  • Mahlknecht, U., Dichamp, I., Varin, A., Van Lint, C., Herbein, G. (2008). NF-{kappa}B-dependent control of HIV-1 transcription by the second coding exon of Tat in T cells. J. Leukoc. Biol. 83: 718-727 [Abstract] [Full Text]  
  • Rohr, O., Marban, C., Aunis, D., Schaeffer, E. (2003). Regulation of HIV-1 gene transcription: from lymphocytes to microglial cells. J. Leukoc. Biol. 74: 736-749 [Abstract] [Full Text]  
  • Lin, X., Irwin, D., Kanazawa, S., Huang, L., Romeo, J., Yen, T. S. B., Peterlin, B. M. (2003). Transcriptional Profiles of Latent Human Immunodeficiency Virus in Infected Individuals: Effects of Tat on the Host and Reservoir. J. Virol. 77: 8227-8236 [Abstract] [Full Text]  


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