During the first grant period we have shown that basic Fibroblast Growth Factor (bFGF) and its low affinity receptors play a relevant role in the pathogenesis of HIV-nephropathy (HIVAN) both in HIV-infected children and HIV-transgenic mice. This study is based on our following novel results: i) high levels of bFGF are found in the plasma of children with HIVAN; ii) bFGF increases the adhesion of HIV-infected peripheral blood mononuclear cells (PBMCs) to renal tubular epithelial cells (RTEc);iii) HIV-1 isolates derived from children with HIVAN are capable of infecting human RTEc); iv) HIV-infected PBMC's and RTEc express a novel bFGF- binding protein (BP-FGF) which potentiates bFGF mitogenic and fibrogenic activity; v) injection of bFGF into HIV-transgenic mice (HIV-Tg) accelerates the progression of renal disease. The goal of this application is to test the hypothesis that an increased number of heparan sulfate proteoglycans (HSPG) located on renal epithelial cells (REc) and the renal extracellular matrix facilitate the accumulation of bFGF and other chemokines, increasing the recruitment of HIV-infected PBMC's and the induction of renal epithelial injury.
Three specific aims are proposed: 1. Determine the mechanisms by which bFGF and HSPG modulate the ability of HIV-1 to adhere, infect and/or injure REc. Cultured primary HIV-1 isolates and RTEc corresponding to the same children will e used to test the hypothesis that bFGF induces the formation of focal adhesion contacts and facilitates the transfer of HIV-1 to RTEc. The effects of bFGF will be studied in comparison with RANTES and MIP-1 beta, two chemokines which are also stored bound to renal proteoglycans. 2. Define how a novel bFGF binding protein (BP-FGF) produced by HIV-infected PBMC's and RTEc modulates bFGF activity and the pathogenesis of HIVAN. We expect to determine how HIV-1 regulates the expression, activity, and release of BP-FGF; investigate ow BP-FGF effects on cultured human RTEc; and define whether by blocking BF-FGF activity we could prevent bFGF-induced progression of HIVAN in HIV-Tg mice. 3. Determine the mechanisms by which gp120 modulates bFGF activity and the pathogenesis of HIVAN. Studies will be done using RTEc from HIV- infected children and HIV-Tg rats, the first small animal model showing high levels circulating gp120 in association with renal disease). We will define how gp120 modulates bFGF/HSPG activity and induces renal injury. All these studies will provide new knowledge that could be applied clinically to develop new treatments to prevent the progression of HIVAN in children.
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