Approximately 10 percent of humans infected with HIV develop renal disease termed HIV-associated nephropathy (HIV-AN). Currently, the pathogenesis of HIV-AN is poorly understood. In this application, the investigators propose to use the SIV/macaque as a model to study the pathogenesis of HIV-AN. SIV infection of macaques results in a disease syndrome that is very similar to HIV infection in humans and is characterized by depletion of the CD4 subset of T-cells, increased opportunistic infections and neurological disease. Additional advantages of the SIV model are that pathogenic molecular clones of this virus are available and the renal tissue can be examined for morphologic alterations at different times postinfection. Preliminary data suggest that the SIV infected macaques develop lesions comparable to those observed in patients with HIV-AN. Data suggest that macaques infected with lymphocyte-tropic SIVmac239 more frequently developed nonsclerosing glomerular disease and tubulointerstitial disease.In contrast, animals that were inoculated with homogenates containing macrophage-tropic SIV developed glomerular sclerosis. Using SIV infected macaques, the investigators propose to monitor the progression of the disease by correlating morphologic alterations and virus localization (using in situ hybridization) with changes in renal function. Using techniques to fractionate renal tissue, they will separate glomeruli from tubulointerstitial fractions and use various virologic techniques to isolate and characterize the viruses from these fractions. In addition, polymerase chain reaction (PCR) technique will be used to isolate the glycoprotein genes from these fractions of renal tissue. These env genes will be cloned and the nucleic acid sequence determined. Sequences will be analyzed to determine if SIV env sequences from glomerular and tubulointerstitial fractions can be differentiated.Finally, chimeric viruses will be constructed with env sequences isolated from glomerular and tubulointerstial fraction to determine if SIV from these tissues confer lymphocyte or dualtropic properties. It is anticipated that the proposed studies will provide valuable information concerning pathogenesis of lentivirus associated nephropathy that could be directly applicable to the understanding of HIV-AN.
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