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J. Biol. Chem., Vol. 279, Issue 38, 39520-39531, September 17, 2004

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Hyper-responsiveness to Stimulation of Human Immunodeficiency Virus-infected CD4⁺ T Cells Requires Nef and Tat Virus Gene Products and Results from Higher NFAT, NF-B, and AP-1 Induction^*

Jean-François Fortin, Corinne Barat¶, Yannick Beauséjour¶, Benoit Barbeau¶||, and Michel J. Tremblay¶**

From the Baxter Laboratory for Genetic Pharmacology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305-5175 and the ^¶Research Center in Infectious Diseases, CHUL Research Center, and Faculty of Medicine, Laval University, Quebec G1V 4G2, Canada

A chronic state of immune hyperactivation is a feature of human immunodeficiency virus type-1 (HIV-1) infection. Studies on the molecular mechanisms by which HIV-1 can modulate the activation state of T cells indicate that both Nef and Tat can alter T cell activation. However, the vast majority of data has been obtained from experiments performed with vectors encoding a single virus protein. We demonstrate that infection of human CD4⁺ T lymphocytes with fully infectious HIV-1 leads to a hyper-responsiveness of the interleukin-2 promoter. Hypersensitivity in HIV-1-infected T cells was observed upon stimulation with various agents that are engaging different signal transduction pathways. Experiments performed with recombinant heat stable antigen-encoding HIV-1 indicated that the virus-infected cells are the cells with an enhanced response. Both Nef and Tat are involved in this virus-mediated enhancing effect on interleukin-2 promoter activity. Interestingly, whereas Nef seems to be acting mainly through hyperactivation of nuclear factor of activated T cells (NFAT), Tat acts in an NFAT-independent manner. Mobility shift experiments demonstrated that the HIV-1-associated priming of human T cells for stimulation results in a greater induction of transcription factors recognized as essential players in T cell activation, i.e. NFAT, NF-B, and AP-1. A hyper-responsive state was also established upon HIV-1 infection of a more natural cellular reservoir, i.e. primary CD4⁺ T lymphocytes. Considering that the HIV-1 life cycle is tightly regulated by the T cell signaling machinery, the priming for activation of a major viral reservoir represents a means by which this retrovirus can create an ideal cellular microenvironment for its propagation and maintenance.

Received for publication, July 6, 2004

^* This work was supported in part by Canadian Institutes of Health Research HIV/AIDS Research Program Grant HOP-15575 (to M. J. T.). 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.

Both authors contributed equally to this work.

^|| Supported by a Scholarship Award (Junior 1 level) from the Fonds de la Recherche en Santé du Québec,

^** Recipient of the Canada Research Chair in Human Immuno-Retrovirology (Tier 1 level). To whom correspondence should be addressed: Laboratory of Human Immuno-Retrovirology, Research Center in Infectious Diseases, RC709, CHUL Research Center, 2705 Laurier Blvd., Quebec G1V 4G2, Canada. Tel.: 418-654-2705; Fax: 418-654-2212; E-mail: michel.j.tremblay{at}crchul.ulaval.ca.

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