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Glycoprotein 120 Binding to CXCR4 Causes p38-Dependent Primary T Cell Death That Is Facilitated by, but Does Not Require Cell-Associated CD4

Sergey A. Trushin^*, Alicia Algeciras-Schimnich^*, Stacey R. Vlahakis^*,, Gary D. Bren^*, Sarah Warren^*, David J. Schnepple^* and Andrew D. Badley^1,*,

^* Division of Infectious Diseases and Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN 55905

HIV-1 infection causes the depletion of host CD4 T cells through direct and indirect (bystander) mechanisms. Although HIV Env has been implicated in apoptosis of uninfected CD4 T cells via gp120 binding to either CD4 and/or the chemokine receptor 4 (CXCR4), conflicting data exist concerning the molecular mechanisms involved. Using primary human CD4 T cells, we demonstrate that gp120 binding to CD4 T cells activates proapoptotic p38, but does not activate antiapoptotic Akt. Because ligation of the CD4 receptor alone or the CXCR4 receptor alone causes p38 activation and apoptosis, we used the soluble inhibitors, soluble CD4 (sCD4) or AMD3100, to delineate the role of CD4 and CXCR4 receptors, respectively, in gp120-induced p38 activation and death. sCD4 alone augments gp120-induced death, suggesting that CXCR4 signaling is principally responsible. Supporting that model, AMD3100 reduces death caused by gp120 or by gp120/sCD4. Finally, prevention of gp120-CXCR4 interaction with 12G5 Abs blocks p38 activation and apoptosis, whereas inhibition of CD4-gp120 interaction with Leu-3a has no effect. Consequently, we conclude that gp120 interaction with CXCR4 is required for gp120 apoptotic effects in primary human T cells.

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 Address correspondence and reprint requests to Dr. Andrew D. Badley, Mayo Clinic, 200 First Street Southwest, Guggenheim 501, Rochester, MN 55905. E-mail address: badley{at}mayo.edu

² Abbreviations used in this paper: sCD4, soluble CD4; SDF-1, stromal cell-derived factor.

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