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HIV-1 Tat and heparan sulfate proteoglycan interaction: a novel mechanism of lymphocyte adhesion and migration across the endothelium

By URBINATI C, NICOLI S, M. GIACCA, DAVID G, FIORENTINI S, CARUSO A, ALFANO M, CASSETTA L, PRESTA M and RUSNATI M

Abstract

The HIV-1 transactivating factor Tat accumulates on the surface of endothelium by interacting with heparan sulfate proteoglycans (HSPGs). Tat also interacts with B-lymphoid Namalwa cells but only when these overexpress HSPGs after syndecan-1 cDNA transfection (SYN-NCs). Accordingly, SYN-NCs, but not mock-transfected cells, adhere to endothelial cells (ECs) when Tat is bound to the surface of either one of the 2 cell types or when SYN-NCs are transfected with a Tat cDNA. Moreover, endogenously produced Tat bound to cell-surface HSPGs mediates cell adhesion of HIV(+) ACH-2 lymphocytes to the endothelium. This heterotypic lymphocyte-EC interaction is prevented by HSPG antagonist or heparinase treatment, but not by integrin antagonists and requires the homodimerization of Tat protein. Tat tethered to the surface of SYN-NCs or of peripheral blood monocytes from healthy donors promotes their transendothelial migration in vitro in response to CXCL12 or CCL5, respectively, and SYN-NC extravasation in vivo in a zebrafish embryo model of inflammation. In conclusion, Tat homodimers bind simultaneously to HSPGs expressed on lymphoid and EC surfaces, leading to HSPG/Tat-Tat/HSPG quaternary complexes that physically link HSPG-bearing lymphoid cells to the endothelium, promoting their extravasation. These data provide new insights about how lymphoid cells extravasate during HIV infection

Topics: Animals Cattle Cell Adhesion Cell Line, Tumor *Cell Movement Chemokine CCL5/pharmacology Chemokine CXCL12/pharmacology Embryo, Nonmammalian/metabolism Endothelium, Vascular/*metabolism HIV Infections/genetics/*metabolism HIV-1/*metabolism Heparan Sulfate Proteoglycans Humans Lymphocytes/*metabolism Protein Multimerization Syndecan-1 Transfection Zebrafish/genetics/metabolism tat Gene Products, Human Immunodeficiency Virus/genetics/*metabolism
Year: 2009
DOI identifier: 10.1182/blood-2009-01-198945
OAI identifier: oai:arts.units.it:11368/3181
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