HIV-1 Tat and heparan sulfate proteoglycans: 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 BlymphoidNamalwacells
but onlywhenthese
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/
HSPGquaternary 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.