application s abstract): The human immunodeficiency virus type 1 (HIV-1) is a human retrovirus that causes AIDS. The exact pathogenic roles of HIV-1 in AIDS, however, are not well understood. Possible roles include apoptosis and dysregulation of cytokine expression, mediated by the viral transactivator, Tat, and synctium formation, bystander killing, and cell cycle dysregulation, mediated by binding of the envelope glycoprotein gp120 to CD4 or to one of several co-receptors, which are the chemokine receptors CCR5 and CXCR4. Most studies have focused on cell-virus interactions in cell culture. These systems, however, lack the complexity of interactions that occur in infected people. Animal model systems are needed; unfortunately, only primates are readily infected with human immunodeficiency viruses, and only chimpanzees can be infected with HIV-1. Mice trangenic for human CD4 (jCD4) are not highly susceptible to infection. Blocks to HIV-1 infection of mice include a lack of functional receptors and co-receptors and an inability to support Rev function in relevant cell types. HIV-1 has been established as a transgene in mice to circumvent problems of viral entry, but the transgene is not expressed well in peripheral blood mononuclear cells (PBMC) (in contrast to PBMC in infected humans), and the lack of functional interactions between envelope proteins and murine cell surface receptors precludes induction of pathogenic effects due to envelope-receptor binding. Rat CXCR4 has been reported to support infection of hCD4+ rat cells with some syncytium inducing (SI) strains of HIV-1. The investigators have established rats transgenic for a SI HIV-1 provirus lacking gag and pol genes. Envelope gp 120 is expressed on PBMC and in serum of transgenic rats. This application focuses on characterizing HIV-1 gene expression and pathology in the HIV-1 gene expression and pathology in the HIV-1 Tat-inducible promoter will also be established and their susceptibility to exogenous HIV-1 infection analyzed. The hCD4+ rat will be transplanted with bone marrow or peripheral blood mononuclear cells from the HIV-1 trangenic rat to provide envelope protein and elicit antibodies and CTLs against HIV-1. This may provide clues as to what role the host immune system plays in HIV-1 pathogenesis.
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