The goal of the proposed study is to define and study a relevant animal model for the unique glomerulopathy that has been associated with humans infected with human immunodeficiency virus (HlV). Initial studies have shown that a proportion of macaques, when experimentally infected with simian immunodeficiency virus, will develop focal and segmentaL glomerulosclerosis; many of these also develop interstitial nephritis. This lesion is similar to the human HIV-associated nephropathy (HIVAN). Pilot studies have also demonstrated that macaques can be infected with HIV-2, the strain of HIV principally responsible for acquired immunodeficiency syndrome (AIDS) in West Africa, and that macaques so infected may develop AIDS-like disease. More recently, macaques have also been infected with strains of HIV-1. The SIV, HIV-2, and HIV-l infected primate models provide a unique opportunity to study the pathogenesis of focal and segmental glomerulosclerosis arising in the setting of an immunodeficiency state that closely resembles human acquired immunodeficiency syndrome. The goal of this project will be to define the chronology of renal injury in infected macaques by means of clinical monitoring of serum and urine for evidence of immunologic abnormality and renal dysfunction. Morphologic correlation and definition of the evolution of this nephropathy will be established by periodic renal biopsy to obtain tissue for pathologic characterization of renal injury using standard techniques of light, immunofluorescence, and transmission electron microscopy. Additional morphologic studies of renal tissue obtained by biopsy and at autopsy will include immunohistochemical probes for the presence of virus and/or viral proteins in renal parenchyma, immunophenotypic characterization of infiltrating inflammatory cell subsets potentially important to this disease process, and characterization of expression of specific mediator growth factor molecules (platelet-derived growth factor, basic fibroblast growth factor, and transforming growth factor beta that have been implicated in the glomerulosclerosis of HIVAN. In-situ hybridization studies of renal tissue will be performed to evaluate the potential role of direct renal infection by virus in the pathogenesis of glomerular injury. The experimental protocols utilized are designed to assess the effect of variations of viral inoculum dose and portal of entry on disease expression, and the effect of potential vaccines in the prevention of renal injury.
