The long term objective of this research proposal is to understand the cellular and molecular mechanisms of the cardiac lesions observed in HIV-1 transgenic mice that the applicants have recently constructed. In these mice, the HIV-1 gene products are expressed in cells which are the target of HIV-1 infection in humans, namely CD4+T cells and cells of the dendritic/macrophage lineage. The cardiac lesions are similar to those described in HIV-1-infected individuals. The investigators would like to understand the pathogenesis of these cardiac lesions and more specifically, intend; 1) To identify the HIV-1 gene product(s) responsible for this cardiac phenotype by constructing HIV-1 mutants; 2) To characterize changes in the pattern of gene expression in the heart of HIV-1 transgenic mice; 3) To identify the cells expression HIV-1 in the heart by in situ hybridization and immunocyto-chemistry; 4) To determine the contributions of each cell type (T lymphocytes and cells of the dendritic/macrophage lineage) to the development of cardiac lesions; 5) To determine whether the ablation of specific host genes (IL-6,TNF,R, iNOS, ICE) prevents the appearance of cardiac lesions; 6) To determine the role of monocytes/macrophages derived cytokines in cardiotoxicity using cocultures of normal of HIV-1 transgenic macrophages and cardiomyocytes; and 7) To determine whether apoptosis of cardiomyocytes is a major feature of cardiomyopathy observed in these mice.
|Poudrier, Johanne; Weng, Xiaoduan; Kay, Denis G et al. (2003) The AIDS-like disease of CD4C/human immunodeficiency virus transgenic mice is associated with accumulation of immature CD11bHi dendritic cells. J Virol 77:11733-44|
|Kay, Denis G; Yue, Ping; Hanna, Zaher et al. (2002) Cardiac disease in transgenic mice expressing human immunodeficiency virus-1 nef in cells of the immune system. Am J Pathol 161:321-35|
|Poudrier, J; Weng, X; Kay, D G et al. (2001) The AIDS disease of CD4C/HIV transgenic mice shows impaired germinal centers and autoantibodies and develops in the absence of IFN-gamma and IL-6. Immunity 15:173-85|