This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by D'Orso, I.
Right arrow Articles by Frankel, A. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by D'Orso, I.
Right arrow Articles by Frankel, A. D.

 Previous Article  |  Next Article 

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]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»