Pathogenesis of HIV-Associated HUS in Children

Children'S Research Institute, Washington DC

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Abstract

DESCRIPTION: (provided by applicant) The Hemolytic Uremic Syndrome (HUS) is an important cause of acute renal failure in children. In the first period of the grant, we have shown that HIV-infected children can develop an atypical clinical form of HUS characterized by a significant renal angiogenic-fibrogenic response, rapid progression of the renal disease, and high mortality. We found elevated urine concentrations of the angiogenic growth factors, bFGF, HIV-Tat protein, and a Fibroblast Growth Factor binding protein (BP-FGF), in children with HIV-HUS. Very little is known about the role that these angiogenic factors and HIV-1 play in the pathogenesis of childhood HIV-HUS. We hypothesize that HIV-1 causes renal glomemla about endothelial (RGEc) and tubular epithelial cell (RTEc) injury and induces an an aboutogenic, pro-coagulant renal O/tokine miljen that accelerates the progression of the renal disease in children with HIV-HUS. To test this hypothesis we will:/) Determine the basic mechanisms by which HIV-1 induces renal injury m the context of HIV-HUS, and define how ang aboutogenic factors accumulated in the/gdney modulate the cytopathic effects of HIV-1. The specific pathogenic roles of HIV-1 isolates and plasma samples fi, om children with or without HIV-HUS, HIV-HELPP (an incomplete form of HIV-HUS), HIV-1 proteins and co-receptors, the glycolipid Gb3, and FGF's/Tat, will be determined in cultured human RGEc and urinary RTEc isolated fi'om children with HIV-HUS, using fusion, attachment, and cytopathic assays 2) Define how HIV-1 and Tat modulate the synthesis and release of BP-FGF in PBMC percent and the mitogenic-fibrinolytic activity of BP-FGF/FGF's in cultured human RGEc. We will define a novel mechanism by which HIV-1 could modulate the activity of FGF's in peripheral blood mononuclear cells (PBMC's) and RGEc, mainly by regulating the synthesis, release, and/or the mitogenic-fibrinolytic activity of BP-FGF. 3) Explore the in vivo role of HIV-1 and Tat in HIV-HUS, using young rats carrying a deletion gag-poi mutant of the hybrid HIV-1 virus pNL4-3, or infected with rAd vectors carrying the human CD4 antigen or Tat m renal glomerular cells. An HIV-HUS-like syndrome, similar to that seen in children with HIV-HUS, will be induced by injecting the toxin ricin (which mimics a Shiga toxin) in HIV-Tg rats. These studies will determine whether the presence of HIV-1/Tat in the kidney, increases the accumulation of renal angiogenic factors and fibrin, and accelerates the progression of the tubulointerstitial lesions in comparison to control rats, and define whether HIV-1 can cause a cytopathic infection in rat RGEc expressing CD4 and induce an HUS-like syndrome. These studies should generate new fundamental knowledge to define the role of HIV-1 in the pathogenesis of childhood HIV-HUS and other AIDS related angiogenic clinical conditions, and generate a small animal model system of HIV-HUS.