The overall goal of this project is to extend preliminary studies designed to develop the feline immunodeficiency virus (FIV) system as a relevant and practical experimental animal model of naturally occurring lentivirus-induced immunodeficiency -- a model both relevant to HIV progression and pathogenesis and suited to experimental pathogenesis, therapy, and vaccine studies in a compressed time frame in an accessible nonendangered species. To this end, a subset of 7 rapid/high phenotype in-vivo propagated virus isolates have been isolated from over 20 FIV field strains recovered from naturally infected cats with symptoms of immunodeficiency. Results from preliminary serial In vivo passage studies with these viruses have produced high expression infection manifested by cell-tree and cell-associated viremia, CD4 cell depletion, immune dysfunction, and clinical signs of immune dysfunction within a 3 to 4 month period. We propose here to: (1) characterize the parameters of infection and immune deficits induced by FIVs by serial assay of quantitative parameters of virus burden, immune function, and clinical disease Induction in prospective studies in specific pathogen free cats; (2) determine the genetic diversity among env genes during the natural course of in vivo-propagation of these FIV isolates and through these analyses to correlate virus genotype and env gene radiation with disease induction and progression; (3) clone molecularly defined pathogenic FIV genotypes and assess in vitro biologic activity and in vivo pathogenicity of phenotypically diverse viruses in cats; and (4) to elucidate the cell and tissue tropism of FIV in vivo by use of in situ hybridization to detect viral RNA-bearing cells, immunohistochemistry to define viral protein producing cells, and assess provirus burden via quantitative PCR on sorted serially diluted blood and lymphoid cell phenotypes. This information should reveal significant information about the pathogenesis of FIV infection, it also should provide definitive information regarding the relevance and utility of the FIV infection as an experimental model of HIV infection, and in the process provide lead insights into HIV pathogenesis and immunity.
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