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Vol. 12, Issue 10, 2934-2946, October 2001
*Laboratory of Virology, Istituto Superiore di Sanità, 00161 Rome, Italy; Previous studies indicated that the Tat protein of human
immunodeficiency virus type-1 (HIV-1) is a progression factor for Kaposi's sarcoma (KS). Specifically, extracellular Tat
cooperates with basic fibroblast growth factor (bFGF) in promoting KS
and endothelial cell growth and locomotion and in inducing KS-like lesions in vivo. Here we show that Tat and bFGF combined increase matrix-metalloproteinase-2 (MMP-2) secretion and activation in endothelial cells in an additive/synergistic manner. These effects are
due to the activation of the
membrane-type-1-matrix-metalloproteinase and to the induction of
the membrane-bound tissue inhibitor of metalloproteinase-2 (TIMP-2) by
Tat and bFGF combined, but also to Tat-mediated inhibition of both
basal or bFGF-induced TIMP-1 and -2 secretion. Consistent with this,
Tat and bFGF promote vascular permeability and edema in vivo that are
blocked by a synthetic MMP inhibitor. Finally, high MMP-2 expression is
detected in acquired immunodeficiency virus syndrome (AIDS)-KS lesions,
and increased levels of MMP-2 are found in plasma from patients with
AIDS-KS compared with HIV-uninfected individuals with classic KS,
indicating that these mechanisms are operative in AIDS-KS. This
suggests a novel pathway by which Tat can increase KS aggressiveness or induce vasculopathy in the setting of HIV-1 infection.
GSF-National Research Center for Environment
and Health GmbH, Institute of Molecular Virology, D-85764 Neuherberg,
Germany; and Technical University of Munich, Institute
of Virology, 81675 Munich, Germany
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