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J Virol, April 1998, p. 2788-2794, Vol. 72, No. 4
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Plasma Membrane-Targeted Raf Kinase Activates NF-kappa B and Human Immunodeficiency Virus Type 1 Replication in T Lymphocytes

Egbert Flory,1 Christoph K. Weber,1 Peifeng Chen,1 Angelika Hoffmeyer,1 Christian Jassoy,2 and Ulf R. Rapp1,*

Institut für Medizinische Strahlenkunde und Zellforschung (MSZ)1 and Institut für Virologie und Immunbiologie,2 Universität Würzburg, D-97078 Würzburg, Germany

Received 8 October 1997/Accepted 31 December 1997

Increasing evidence points to a role of the mitogenic Ras/Raf/MEK/ERK signaling cascade in regulation of human immunodeficiency virus type 1 (HIV-1) gene expression. Stimulation of elements of this pathway leads to transactivation of the HIV-1 promoter. In particular, the NF-kappa B motif in the HIV long terminal repeat (LTR) represents a Raf-responsive element in fibroblasts. Regulation of the Raf kinase in T cells differs from findings with a variety of cell lines that the catalytic domain of Raf (RafDelta 26-303) shows no activity. In this study, we restored the activity of the kinase in T cells by fusing its catalytic domain to the CAAX motif (-Cx) of Ras, thus targeting the enzyme to the plasma membrane. Constitutive activity of Raf was demonstrated by phosphorylation of mitogen-activated protein kinase kinase (MEK) and endogenous mitogen-activated protein kinase 1/2 (ERK1/2) in A3.01 T cells transfected with RafDelta 26-303-Cx. Membrane-targeted Raf also stimulates NF-kappa B, as judged by kappa B-dependent reporter assays and enhanced NF-kappa B p65 binding on band shift analysis. Moreover, we found that active Raf transactivates the HIVNL4-3 LTR in A3.01 T lymphocytes and that dominant negative Raf (C4) blocked 12-O-tetradecanoylphorbol-13-acetate induced transactivation. When cotransfected with infectious HIVNL4-3 DNA, membrane-targeted Raf induces viral replication up to 10-fold over basal levels, as determined by the release of newly synthesized p24gag protein. Our study clearly demonstrates that the activity of the catalytic domain of Raf in A3.01 T cells is dependent on its cellular localization. The functional consequences of active Raf in T lymphocytes include not only NF-kappa B activation and transactivation of the HIVNL4-3 LTR but also synthesis and release of HIV particles.

* Corresponding author. Mailing address: Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Versbacherstr. 5, D-97078 Würzburg, Germany. Phone: 49-931-201-5140. Fax: 49-931-201-3835. E-mail: rappur{at}rzbox.uni-wuerzburg.de.




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