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J. Biol. Chem., Vol. 282, Issue 23, 16981-16988, June 8, 2007

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Negative Elongation Factor NELF Represses Human Immunodeficiency Virus Transcription by Pausing the RNA Polymerase II Complex^*

Zhiqiang Zhang¹, Alicia Klatt^¶1, David S. Gilmour, and Andrew J. Henderson^¶2

From the Center of Molecular Immunology and Infectious Diseases, Department of Veterinary and Biomedical Sciences, the Center for Gene Regulation, Department of Biochemistry and Molecular Biology, and the ^¶Graduate Program in Pathobiology, Pennsylvania State University, University Park, Pennsylvania 16802

Human immunodeficiency virus (HIV) transcription requires virally encoded Tat and the P-TEFb protein complex, which together associate with the Tat-activating region, a structured region in the nascent transcript. P-TEFb phosphorylates Proteins in the transcription elongation complex, including RNA polymerase II (pol II), to stimulate elongation and to overcome premature termination. However, the status of the elongation complex on the HIV long terminal repeat (LTR) in a repressed state is not known. Chromatin immunoprecipitation demonstrated that NELF, a negative transcription elongation factor, was associated with the LTR. Depleting NELF increased processive HIV transcription and replication. Mapping pol II on the LTR showed that pol II was paused and that NELF depletion released pol II. Decreasing NELF also correlated with displacement of a positioned nucleosome and increased acetylation of histone H4, suggesting coupling of transcription elongation and chromatin remodeling. Previous work has indicated that the Tat-activating region plays a critical role in regulating transcription from the LTR. Our results reveal an earlier stage, mediated by NELF, when repression occurs at the HIV LTR.

Received for publication, November 17, 2006 , and in revised form, March 14, 2007.

^* This work was supported by Pennsylvania State Tobacco Formula Funds and National Institutes of Health Grants AI62467 (to A. J. H.) and GM47477 (to D. S. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Medicine, Section of Infectious Diseases, Center for HIV/AIDS Care and Research, Boston University School of Medicine, EBRC, 650 Albany St., Boston, MA 02118-2393. Tel.: 617-414-5240; Fax: 617-414-3561; E-mail: andrew.henderson{at}bmc.org.

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