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J. Biol. Chem., Vol. 279, Issue 51, 52949-52960, December 17, 2004

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T-cell Activation Leads to Poor Activation of the HIV-1 Clade E Long Terminal Repeat and Weak Association of Nuclear Factor-B and NFAT with Its Enhancer Region^*

Anne-Marie Lemieux, Marie-Ève Paré, Brigitte Audet, Éric Legault, Sylvain Lefort, Nancy Boucher, Sébastien Landry, Tim van Opijnen, Ben Berkhout, Mojgan H. Naghavi||, Michel J. Tremblay**, and Benoit Barbeau¶

From the Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, and the Département de Biologie Médicale, Faculté de Médecine, Université Laval, Sainte-Foy, Quebec G1V 4G2, Canada, the Department of Human Retrovirology, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands, and the ^||Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, New York 10032

The enhancer region in the human immunodeficiency virus type 1 (HIV-1) 5'-long terminal repeat (LTR) is very important for viral transcription. This promoter sequence binds both nuclear factor-B and NFAT, two important modulators of HIV-1 gene expression. Previous studies have indicated that the enhancer regions of the different HIV-1 clade LTRs differ in their number of NF-B-binding sites. In this study, we have compared the activation potential of the different HIV-1 clade and HIV-2 LTRs and assessed their interaction with NFAT and NF-B. In T-cell lines and primary CD4⁺ T-cells, the results showed that the HIV-1 clade E LTR (with a single NF-B-binding site) was the weakest LTR regardless of the tested activators, whereas the HIV-2 LTR was the most responsive LTR. The clade E enhancer region was also demonstrated to be the weakest enhancer region in transfection experiments with luciferase reporter-based vectors. Electrophoretic mobility shift assays with extracts from activated CD4⁺ T-cells indicated that, although NF-B and NFAT bound all enhancers, HIV-1 clade E and HIV-2 LTR enhancers were poor binding targets for these two factors. Weak NFAT binding to clade E enhancers was also confirmed using NFAT1-expressing 293T cells in competition experiments. We have also shown the absence of interaction of NF-B or NFAT with the third NF-B repeat present in clade C. However, the clade C enhancer bound NFAT more efficiently than all other enhancer regions tested. Our results hence demonstrate for the first time that differences in the binding of NF-B and NFAT to the enhancer regions could be responsible for some of the observed variation in HIV-1 clade LTR activation, whereas HIV-2 LTR activation seems mostly independent of these interactions.

Received for publication, August 27, 2004 , and in revised form, September 29, 2004.

^* This work was supported in part by Have a Heart Grant 507-0154 from the Canadian Foundation for AIDS Research and Grant 003318 from the Fonds de la Recherche en Santé du Québec (to B. Barbeau). 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.

^** Recipient of a Senior Canada Research Chair in Human Immunoretrovirology.

^¶ Supported by a scholarship (Junior 2 level) from the Fonds de la Recherche en Santé du Québec.

To whom correspondence should be addressed: Centre de Recherche en Infectiologie, RC709, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, 2705 Blvd. Laurier, Sainte-Foy, Quebec G1V 4G2, Canada. Tel.: 418-654-2705; Fax: 418-654-2196; E-mail: benoit. barbeau{at}crchul.ulaval.ca.

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