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vß3 Integrin1
*
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy;
Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy;
Department of Pathology and Laboratory Medicine, Tulane Cancer Center, Tulane University Medical Center, New Orleans, LA 70112;
§
Advanced BioScience Laboratories, Kensington, MD 20895;
¶
Department of Medicine, Division of Clinical Immunology and Allergy, Los Angeles, CA 90024; and
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Gesellschaft für Strahlung und Umweltforschung-National Research Center for Environment and Health, Institute for Molecular Virology, Neuherberg, Germany
The Tat protein of HIV-1, a transactivator of viral gene
expression, is released by acutely infected T cells and, in this form,
exerts angiogenic activities. These have linked the protein to the
pathogenesis of Kaposi’s sarcoma (KS), a vascular tumor frequent and
aggressive in HIV-1-infected individuals (AIDS-KS). In this study, we
show that a combination of the same inflammatory cytokines increased in
KS lesions, namely IL-1ß, TNF-
, and IFN-
, synergizes with Tat
to promote in nude mice the development of angioproliferative KS-like
lesions that are not observed with each factor alone. Inflammatory
cytokines induce the tissue expression of both basic fibroblast growth
factor (bFGF) and vascular endothelial growth factor (VEGF), two
angiogenic molecules highly produced in primary KS lesions. However,
bFGF, but not VEGF, synergizes with Tat in vivo and induces endothelial
cells to migrate, to adhere, and to grow in response to Tat in vitro.
Tat angiogenic effects correlate with the expression of the
vß3 integrin that is induced by bFGF and
binds the arginine-glycine-aspartic acid (RGD) region of Tat. In
contrast, no correlation is observed with the expression of
vß5, which is promoted by VEGF and binds
Tat basic region. Finally, KS lesion formation induced by bFGF and Tat
in nude mice is blocked by antagonists of RGD-binding integrins.
Because vß3 is an RGD-binding integrin
that is highly expressed in primary KS lesions, where it colocalizes
with extracellular Tat on vessels and spindle cells, these results
suggest that vß3 competitors may represent
a new strategy for the treatment of AIDS-KS.
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