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J. Biol. Chem., Vol. 279, Issue 46, 48197-48204, November 12, 2004

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The Glutamine-rich Region of the HIV-1 Tat Protein Is Involved in T-cell Apoptosis^*

Grant R. Campbell, Eddy Pasquier, Jennifer Watkins¶, Veronique Bourgarel-Rey, Vincent Peyrot, Didier Esquieu, Pascale Barbier, Jean de Mareuil, Diane Braguer, Pontiano Kaleebu||, David L. Yirrell||**, and Erwann P. Loret

From the CNRS Formation de Recherche en Evolution 2737, Faculté de Pharmacie, Université de la Méditerranée, 27, Boulevard Jean Moulin, 13385 Marseille, France, the ^||Medical Research Council (United Kingdom) Programme on AIDS in Uganda, Uganda Virus Research Institute, P. O. Box 49, Entebbe, Uganda, and the ^**West of Scotland Specialist Virology Centre, Gartnavel General Hospital, Glasgow G12 0ZA, Scotland, United Kingdom

Human immunodeficiency virus (HIV) infection and the progression to AIDS are characterized by the depletion of CD4⁺ T-cells. HIV-1 infection leads to apoptosis of uninfected bystander cells and the direct killing of HIV-infected cells. This is mediated, in part, by the HIV-1 Tat protein, which is secreted by virally infected cells and taken up by uninfected cells. We chemically synthesized two 86-residue subtype D Tat proteins, Ug05RP and Ug11LTS, from two Ugandan patients who were clinically categorized as either rapid progressor or long-term survivor, with non-conservative mutations located essentially in the glutamine-rich region. Structural heterogeneities were revealed by CD, which translate into differing trans-activational and apoptotic effects. CD data analysis and molecular modeling indicated that the short -helix observed in subtype D Tat proteins from rapid progressor patients such as Tat Mal and Tat Ug05RP is not present in Ug11LTS. We show that Tat Ug05RP is more efficient than Tat Ug11LTS in its trans-activational role and in inducing apoptosis in binding tubulin via the mitochondrial pathway. The glutamine-rich region of Tat appears to be involved in the Tat-mediated apoptosis of T-cells.

Received for publication, June 3, 2004 , and in revised form, August 24, 2004.

^* This work was supported in part by the Conseil Régional Provence Alpes Cêtes-d'Azur, the Conseil Général des Bouches-du-Rhones (Ville de Marseille), and the Association Faire Face au Syndrome d'Immuno-Déficience Acquise. 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.

Supported by a scholarship from the Entente Cordiale Program between the United Kingdom and France and the Scottish International Education Trust.

^¶ Supported by a scholarship from the Conseil Régional Provence Alpes Cêtes-d'Azur and SYNPROSIS.

To whom correspondence should be addressed. Tel.: 33-491-835-508; Fax: 33-491-835-506; E-mail: erwann.loret{at}pharmacie.univmrs.fr.

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