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Originally published online as doi:10.1189/jlb.0409261 on July 29, 2009

Published online before print July 29, 2009
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(Journal of Leukocyte Biology. 2009;86:1171-1178.)
© 2009 Society for Leukocyte Biology

HIV-1 Nef-mediated inhibition of T cell migration and its molecular determinants

In-Woo Park1 and Johnny J. He

Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA

1. Correspondence: Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, R2 302, 950 W. Walnut St., Indianapolis, IN 46202, USA. E-mail: parki{at}iupui.edu

ABSTRACT

Lymphocyte trafficking is a multistep, intricate process and involves a number of host factors such as integrins and chemokine receptors on lymphocytes, adhesion molecules on endothelial cells, and chemokines present in the local microenvironment. Previous studies have shown that HIV-1 Nef inhibits T cell chemotaxis in response to the physiological ligand SDF-1{alpha} [1 ]. In this study, we aimed to gain a better understanding of the inhibitory mechanisms and to define the molecular determinants of HIV-1 Nef for this phenotype. We showed that HIV-1 Nef inhibited transwell and transendothelial migration of T cells. Specifically, HIV-1 Nef protein impaired T cell chemotaxis toward SDF-1{alpha} without altering CXCR4 expression. Moreover, we showed that HIV-1 Nef protein down-modulated LFA-1 expression on T lymphocytes and diminished adhesion and polarization of T lymphocytes and as a result, led to decreased migration across the endothelium. Furthermore, we showed that the myristoylation site and {Delta}SD domain played important roles in Nef-mediated inhibition of transwell and transendothelial migration and polarization of T lymphocytes; however, different sites or domains were needed for Nef-mediated LFA-1 down-modulation and impaired adhesion of T lymphocyte. Taken together, these results demonstrated that HIV-1 Nef inhibited T lymphocyte migration at multiple steps and suggest that membrane localization and intracellular signaling events likely contribute to the inhibitory effects of Nef on T cell migration and subsequently, the pathobiology of the HIV-1 Nef protein.

Key Words: CXCR4 • SDF-1{alpha} • LFA-1 • chemotaxis • signal transduction




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