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Journal of Virology, October 2008, p. 9492-9504, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00763-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Targeting Tat Inhibitors in the Assembly of Human Immunodeficiency Virus Type 1 Transcription Complexes{triangledown} ,{dagger}

Iván D'Orso,1 Jocelyn R. Grunwell,1 Robert L. Nakamura,2 Chandreyee Das,1,{ddagger} and Alan D. Frankel1*

Department of Biochemistry and Biophysics, University of California—San Francisco, 600 16th Street, San Francisco, California 94143-2280,1 Advanced Genetic Systems, San Francisco, California 94143-22802

Received 7 April 2008/ Accepted 21 July 2008

Human immunodeficiency virus type 1 (HIV-1) transcription is regulated by the viral Tat protein, which relieves a block to elongation by recruiting an elongation factor, P-TEFb, to the viral promoter. Here, we report the discovery of potent Tat inhibitors that utilize a localization signal to target a dominant negative protein to its site of action. Fusing the Tat activation domain to some splicing factors, particularly to the Arg-Ser (RS) domain of U2AF65, creates Tat inhibitors that localize to subnuclear speckles, sites where pre-mRNA processing factors are stored for assembly into transcription complexes. A U2AF65 fusion named T-RS interacts with the nonphosphorylated C-terminal domain of RNA polymerase II (RNAP II) via its RS domain and is loaded into RNAP II holoenzyme complexes. T-RS is recruited efficiently to the HIV-1 promoter in a TAR-independent manner before RNAP II hyperphosphorylation but not to cellular promoters. The "preloading" of T-RS into HIV-1 preinitiation complexes prevents the entry of active Tat molecules, leaving the complexes in an elongation-incompetent state and effectively suppressing HIV-1 replication. The ability to deliver inhibitors to transcription complexes through the use of targeting/localization signals may provide new avenues for designing viral and transcription inhibitors.

* Corresponding author. Mailing address: Department of Biochemistry and Biophysics, University of California—San Francisco, 600 16th St., San Francisco, CA 94143-2280. Phone: (415) 476-9994. Fax: (415) 514-4112. E-mail: frankel{at}cgl.ucsf.edu

{triangledown} Published ahead of print on 30 July 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} Present address: Dana Farber Cancer Institute, Room D728, 44 Binney St., Boston, MA 02115.

Journal of Virology, October 2008, p. 9492-9504, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00763-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • D'Orso, I., Frankel, A. D. (2009). Tat acetylation modulates assembly of a viral-host RNA-protein transcription complex. Proc. Natl. Acad. Sci. USA 106: 3101-3106 [Abstract] [Full Text]  


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