HIV-infected children can develop a severe form of Hemolytic Uremic Syndrome (HUS) characterized by rapid progression of the renal disease and/or death associated with bleeding complications. In the last grant cycle we have identified the pleotropic growth factor Fibroblast Growth Factor -2 (FGF-2), its binding protein BP-1, HIV-Tat, and VEGF- A, as potential precipitating angiogenic co-factors that can induce vascular leakage, bleeding disorders, and rapid development of chronic renal failure in children with HIV- HUS. Based on work done by others and our preliminary data, we hypothesize that an excessive renal accumulation of these angiogenic factors, in combination with HIV-1 and other inflammatory co-factors, precipitate the development of childhood HIV-HUS, and induces an aberrant renal regenerative response characterized by severe capillary permeability changes, renal recruitment of HIV-infected cells, and glomerular-tubular proliferative lesions that induce rapid renal fibrosis and chronic renal failure.
In aim 1 we will define how FGF-2, BP-1, HIV-Tat , VEGF-A, and heparin, alone or in combination, modulate the permeability of cultured human glomerular endothelial cells and determine the relative contribution of the VEGFR-2, Tie-2, Src, and ROK pathways in this process. Second, we will define how plasma or urine samples harvested from HIV-infected children with high and low FGF-2 levels, modulate the permeabilty of cultured renal endothelial cells. This assay will allow us to identify children at risk of developing endothelial dysfunction, vascular leakage, or HIV-HUS.
In aim 2, we will test the hypothesis that BP-1 accelerates the progression of the renal disease in HIV-Tg mice expressing an inducible BP-1 transgene, and determine how HIV-Tat expressed specifically in endothelial cells (EC) modulates the angiogenic and fibrinolytic activity of FGF-2 and VEGF-A in renal glomeruli. These experiments will generate two new mouse models to elucidate the mechanisms by which BP-1 and HIV-Tat accelerate the progression of childhood HIV-HUS.
Aim 3 will explore the role of Angiopoietin-1 (Ang- 1), alone or in combination with protease inhibitors, to prevent the rapid progression of the renal disease induced by the accumulation of angiogenic-inflammatory factors in HIV-HUS . We will determine the relative contribution of the Tie-2/Src, NF-kB, and ROK signaling pathways in this process. These experiments will generate new knowledge and therapies to improve the clinical outcome of HIV-HUS.

Public Health Relevance

HIV-infected children can develop a severe type of Hemolytic Uremic Syndrome (HUS), characterized by hemolytic anemia and rapid progression of the renal disease, or death associated with infections, vascular leakage and bleeding disorders. Our studies will explore the role of angiogenic factors released into the circulation of HIV-infected children in the pathogenesis of these renal and vascular complications, and develop a new animal model system to test novel therapies against this lethal childhood disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055605-14
Application #
8274877
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Sarkar, Rita
Project Start
1995-07-01
Project End
2014-05-31
Budget Start
2012-06-05
Budget End
2014-05-31
Support Year
14
Fiscal Year
2012
Total Cost
$429,868
Indirect Cost
$179,868
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
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Ray, Patricio E; Al-Attar, Ali; Liu, Xue-Hui et al. (2014) Expression of a Secreted Fibroblast Growth Factor Binding Protein-1 (FGFBP1) in Angioproliferative Kaposi Sarcoma. J AIDS Clin Res 5:
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Debebe, Zufan; Ammosova, Tatyana; Breuer, Denitra et al. (2011) Iron chelators of the di-2-pyridylketone thiosemicarbazone and 2-benzoylpyridine thiosemicarbazone series inhibit HIV-1 transcription: identification of novel cellular targets--iron, cyclin-dependent kinase (CDK) 2, and CDK9. Mol Pharmacol 79:185-96
Xie, Hui; Ray, Patricio E; Short, Billie Lou (2010) Role of sensory C fibers in hypoxia/reoxygenation-impaired myogenic constriction of cerebral arteries. Neurol Res 32:487-91

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