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J. Biol. Chem., Vol. 280, Issue 52, 42557-42567, December 30, 2005

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Synthetic Vpr Protein Activates Activator Protein-1, c-Jun N-terminal Kinase, and NF-B and Stimulates HIV-1 Transcription in Promonocytic Cells and Primary Macrophages^*

Audrey Varin, Anne-Zélie Decrion, Emmanuelle Sabbah, Vincent Quivy¶1, Joséphine Sire||, Carine Van Lint¶2, Bernard P. Roques, Bharat B. Aggarwal**3, and Georges Herbein4

From the Department of Virology, EA3186, IFR133, Franche-Comté University, F-25030 Besançon, France, ^||Pathogénie des Infections à Lentivirus, INSERM U372, F-13276 Marseille, France, ^¶Laboratoire de Virologie Moléculaire, Service de Chimie Biologique, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, B-6041 Gosselies, Belgium, Departement de Pharmacochimie Moleculaire et Structurale, U266 INSERM, UMR 8600 CNRS, F-75270 Paris, France, and the ^**Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The human immunodeficiency virus (HIV) Vpr protein plays a critical role in AIDS pathogenesis, especially by allowing viral replication within nondividing cells such as mononuclear phagocytes. Most of the data obtained so far have been in experiments with endogenous Vpr protein; therefore the effects of extracellular Vpr protein remain largely unknown. We used synthetic Vpr protein to activate nuclear transcription factors activator protein-1 (AP-1) and NF-B in the promonocytic cell line U937 and in primary macrophages. Synthetic HIV-1 Vpr protein activated AP-1, c-Jun N-terminal kinase, and MKK7 in both U937 cells and primary macrophages. Synthetic Vpr activated NF-B in primary macrophages and to a lesser extent in U937 cells. Because synthetic Vpr activated AP-1 and NF-B, which bind to the HIV-1 long terminal repeat, we investigated the effect of synthetic Vpr on HIV-1 replication. We observed that synthetic Vpr stimulated HIV-1 long terminal repeat in U937 cells and enhanced viral replication in chronically infected U1 promonocytic cells. Similarly, synthetic Vpr stimulated HIV-1 replication in acutely infected primary macrophages. Activation of transcription factors and enhancement of viral replication in U937 cells and primary macrophages were mediated by both the N-terminal and the C-terminal moieties of synthetic Vpr. Therefore, our results suggest that extracellular Vpr could fuel the progression of AIDS via stimulation of HIV-1 provirus present in such cellular reservoirs as mononuclear phagocytes in HIV-infected patients.

Received for publication, February 28, 2005 , and in revised form, October 19, 2005.

^* This research was funded by The Clayton Foundation for Research (to B. B. A.), by grants from the Franche-Comté University (to G. H.), from the Agence Nationale de la Recherche sur le SIDA (to B. P. R., E. S., V. Q., and C. V. L.), from the Fonds National de la Recherche Scientifique (Belgium), and from the Université Libre de Bruxelles (ARC program Grant 04/09-309), the Internationale Brachet Stiftung, the CGRI-INSERM cooperation, the Région Wallonne-Commission Européenne FEDER (Program Interreg III, Intergenes), the Theyskens-Mineur Foundation, the Fortis Banque Assurance, and the Région Wallonne (Programs WALEO 021/5110 and 021/5347), and the Féd-ération Belge contre le Cancer. 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 Chargé de Recherches of the Fonds National de la Recherche Scientifique.

² Maître de Recherches of the Fonds National de la Recherche Scientifique.

³ To whom correspondence may be addressed. Tel.: 713-794-1817; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org. ⁴ To whom correspondence may be addressed: Dept. of Virology, Franche-Comte School of Medicine, Hôpital Saint-Jacques, 2, place Saint-Jacques, F-25030 Besancon cedex, France. Tel.: 33-3-81-21-88-77; Fax: 33-3-81-66-56-95; E-mail: gherbein{at}chu-besancon.fr.

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