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 (HIV). Pilot studies have shown that a proportion of macaques, when experimentally infected with simian immunodeficiency virus SIV/Mne, will develop focal and segmental glomerulosclerosis with endothelial inclusions that morphologically resemble human tubulo- reticular inclusions; this lesion is virtually identical to the human HIV-associated glomerulopathy. This model provides 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 (AIDS). 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 alterations in intrinsic renal structures including the cellular expression of Class 11 histocompatibility antigens and the amounts and distribution of the principal proteins composing glomerular structures and their potential scars. 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 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 will also be studied.
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