HIV-1 Tat and heparan sulfate proteoglycan interaction: a novel mechanism of lymphocyte adhesion and migration across the endothelium.
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.
Urbinati
Chiara
C
Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, Medical School, University of Brescia, Brescia, Italy.
Nicoli
Stefania
S
Giacca
Mauro
M
David
Guido
G
Fiorentini
Simona
S
Caruso
Arnaldo
A
Alfano
Massimo
M
Cassetta
Luca
L
Presta
Marco
M
Rusnati
Marco
M
D000818:Animals; D002417:Cattle; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D018946:Chemokine CCL5 / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000494:pharmacology; D004625:Embryo, Nonmammalian / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D055503:Protein Multimerization; D053668:Syndecan-1; D014162:Transfection; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
C483024:CCL5 protein, human; C515255:CXCL12 protein, human; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D019812:Heparan Sulfate Proteoglycans; C508241:SDC1 protein, human; D053668:Syndecan-1; D054322:tat Gene Products, Human Immunodeficiency Virus