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Journal of Virology, June 2007, p. 6043-6056, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02074-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Sustained Induction of NF-{kappa}B Is Required for Efficient Expression of Latent Human Immunodeficiency Virus Type 1{triangledown}

Samuel A. Williams,1,2 Hakju Kwon,1,{dagger} Lin-Feng Chen,1,{ddagger} and Warner C. Greene1,3,4*

Gladstone Institute of Virology and Immunology,1 Departments of Physiology,2 Medicine,3 Microbiology and Immunology, University of California, San Francisco, San Francisco, California 941584

Received 18 September 2006/ Accepted 12 March 2007

Cells harboring infectious, but transcriptionally latent, human immunodeficiency virus type 1 (HIV-1) proviruses currently pose an insurmountable barrier to viral eradication in infected patients. To better understand the molecular basis for HIV-1 latency, we used the J-Lat model of postintegration HIV-1 latency to assess the kinetic relationship between the induction of NF-{kappa}B and the activation of latent HIV-1 gene expression. Chromatin immunoprecipitation analyses revealed an oscillating pattern of RelA recruitment to the HIV-1 long terminal repeat (LTR) during continuous tumor necrosis factor alpha (TNF-{alpha}) stimulation. RNA polymerase II (Pol II) recruitment to the HIV-1 LTR closely mirrored RelA binding. Transient stimulation of cells with TNF-{alpha} for 15 min induced only a single round of RelA and RNA Pol II binding and failed to induce robust expression of latent HIV-1. Efficient formation of elongated HIV-1 transcripts required sustained induction by NF-{kappa}B, which promoted de novo synthesis of Tat. Cyclin-dependent kinase 9 (CDK9) and serine-2-phosphorylated RNA Pol II were rapidly recruited to the HIV-1 LTR after NF-{kappa}B induction; however, these elongating polymerase complexes were progressively dephosphorylated in the absence of Tat. Okadaic acid promoted sustained serine-2 phosphorylation of the C-terminal domain of RNA Pol II and stimulated efficient transcriptional elongation and HIV-1 expression in the absence of Tat. These findings underscore important differences between NF-{kappa}B and Tat stimulation of RNA Pol II elongation. While NF-{kappa}B binding to the HIV-1 LTR induces serial waves of efficient RNA Pol II initiation, elongation is impaired by the action of an okadaic acid-sensitive phosphatase that dephosphorylates the C-terminal domain of RNA Pol II. Conversely, the action of this phosphatase is overcome in the presence of Tat, promoting very efficient RNA Pol II elongation.

* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158. Phone: (415) 734-2000. Fax: (415) 355-0153. E-mail: wgreene{at}gladstone.ucsf.edu

{triangledown} Published ahead of print on 21 March 2007.

{dagger} Present address: PDL BioPharma, Inc., 34801 Campus Drive, Fremont, CA 94555.

{ddagger} Present address: Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801.

Journal of Virology, June 2007, p. 6043-6056, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02074-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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