HIV-1 Tat protein, released from HIV-infected cells, may act as a pleiotrop
ic heparin-binding growth factor. From this observation, extracellular Tat
has been implicated in the pathogenesis of AIDS and of AIDS-associated path
ologies. Here we demonstrate that the heparin analog pentosan polysulfate (
PPS) inhibits the interaction of glutathione S-transferase (GST)-Tat protei
n with heparin immobilized to a BIAcore sensor chip. Competition experiment
s showed that Tat-PPS interaction occurs with high affinity (K-d = 9.0 nM).
Also, GST.Tat prevents the binding of [H-3]heparin to GST Tat immobilized
to glutathione-agarose beads. In vitro, PPS inhibits GST Tat internalizatio
n and, consequently, HIV-1 long terminal repeat transactivation in HL3T1 ce
lls. Also, PPS inhibits cell surface interaction and mitogenic activity of
GST Tat in murine adenocarcinoma T53 Tat-less cells. In all assays, PPS exe
rts its Tat antagonist activity with an ID50 equal to similar to1.0 nM. In
vivo, PPS inhibits the neovascularization induced by GST Tat or by Tat over
expressing T53 cells in the chick embryo chorioallantoic membrane. In concl
usion, PPS binds Tat protein and inhibits its cell surface interaction, int
ernalization, and biological activity in vitro and in vivo. PPS may represe
nt a prototypic molecule for the development of novel Tat antagonists with
therapeutic implications in AIDS and AIDS-associated pathologies, including
Kaposi's sarcoma.