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J. Biol. Chem., Vol. 281, Issue 11, 6940-6954, March 17, 2006

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Activation of p21-activated Kinase 2 and Its Association with Nef Are Conserved in Murine Cells but Are Not Sufficient to Induce an AIDS-like Disease in CD4C/HIV Transgenic Mice^*

Patrick Vincent, Elena Priceputu, Denis Kay, Kalle Saksela^¶, Paul Jolicoeur^||**1, and Zaher Hanna^**2

From the Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada, the Department of Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, FIN-0014, Helsinki, Finland, the ^¶Institute of Medical Technology, University of Tampere and Tampere University Hospital, FIN-33014, Tampere, Finland, the Departments of Medicine and ^||Microbiology and Immunology, Université de Montréal, Montreal, Quebec H3C 3J7, Canada, and the ^**Department of Experimental Medicine, McGill University, Montreal, Quebec H3G 1A4, Canada

A well conserved feature of human immunodeficiency virus, type 1 (HIV-1) and simian immunodeficiency virus (SIV) Nef is the interaction with and activation of the human p21-activated kinase 2 (PAK2). The conservation of this interaction in other species and its significance for Nef pathogenesis in vivo are poorly documented. In the present study, we measured these parameters in Nef-expressing thymocytes, macrophages, and dendritic cells of a transgenic (Tg) mouse model of AIDS (CD4C/HIV). We found that Nef binds to and activates PAK2, but not PAK1 and -3, in these three cell subsets. Nef associates with only a small fraction of PAK2. The Nef-PAK2 complex also comprises -PIX-COOL. The impact of the Nef-PAK2 association on disease development was also analyzed in Tg mice expressing 10 different Nef mutant alleles. CD4C/HIV Tg mice expressing Nef alleles defective in Nef-PAK2 association (P69A, P72A/P75A, R105A/R106A, 56–66, or G2A (myristoylation site)) failed to develop disease of the non-lymphoid organs (kidneys and lungs). Among these, only Tg mice expressing Nef^P69A and Nef^G2A showed some depletion of CD4⁺ T cells, although a down-regulation of the CD4 surface protein was documented in all these Tg lines, except those expressing Nef^56–66. Among other Tg mice expressing Nef mutants having conserved the Nef-PAK2 association (RD35AA, D174K, P147A/P150A, 8–17, and 25–65), only Tg mice expressing Nef^8–17 develop kidney and lung diseases, but all showed partial CD4⁺ T cell depletion despite some being defective for CD4 down-regulation (RD35AA and D174K). Therefore, Nef can activate murine PAK2 and associate with a small fraction of it, as in human cells. Such activation and binding of PAK2 is clearly not sufficient but may be required to induce a multiorgan AIDS-like disease in Tg mice.

Received for publication, November 28, 2005

^* This work was supported by grants from the Canadian Institutes of Health Research, HIV/AIDS Research Program (to P. J. and Z. H.). 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 To whom correspondence may be addressed: Dept. of Molecular Biology, Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, Quebec H2W 1R7, Canada. Tel.: 514-987-5569; Fax: 514-987-5794; E-mail: jolicop{at}ircm.qc.ca. ² To whom correspondence may be addressed: Dept. of Molecular Biology, Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, Quebec H2W IR7, Canada. Tel.: 514-987-5571; Fax: 514-987-5794; E-mail: hannaz{at}ircm.umontreal.ca.

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