The progressive neurologic syndromes caused by the Human Immunodeficiency Virus (HIV) are a serious complication of HIV infection and give impetus to the study of mechanisms of retroviral neurovirulence. During the course of HIV infection, a variety of diseases of the central and peripheral nervous system with diverse inflammatory, demyelinating, or degenerative pathologic features can develop. Whether these diseases are due to direct effects of virus upon specific nervous system cell types, or to indirect mechanisms mediated by induction of factors, such as cytokines, are questions currently under investigation. An understanding of the pathogenesis of retrovirus-mediated neurologic diseases is crucial for the design of rational therapy. The goal of this research program is to analyze mechanisms of retroviral neurovirulence. To gain insight into the pathogenesis of one retroviral neurologic disease, a murine model system is being employed. The neurodegenerative disease produced by the murine neurotropic type C retrovirus Cas-Br-E is being analyzed. Infection of mice with Cas-Br-E can serve as a model of HIV-associated encephalopathy in which HIV infection of the brain, without inflammation, leads to progressive cognitive deficits. This murine model enables the dissection of complex issues of retroviral neurovirulence relevant to advancing the understanding of mechanisms of AIDS neurologic disease syndromes. Central to the understanding of neurovirulence is the identification of viral target cells and the exploration of the role of each type of target cell in disease production. The Cas-Br-E model enables an examination of these issues on the organismal, cellular and molecular levels.
The specific aims of this research program are: (1) to achieve a precise identification of viral target cells using in situ hybridization with two probes, one for Cas-Br-E and the other for target cell type, temporally from the time of infection to the onset of disease and (2) to examine the interaction of Cas-Br-E with specific cell types in order to determine whether Cas-Br-E neurodegenerative disease is due to direct effects of virus upon neurons or indirect, resulting from viral infection of glia or endothelial cells using the following approaches: a. Viral infection of aggregation chimeras containing virus-susceptible CNS cells and virus-resistant CNS cells in which resistant neurons can be visualized using a beta-galactosidase marker, will determine whether virus-resistant neurons degenerate as a consequence of infection of adjacent, virus-susceptible cells. b. Transgenic mouse studies will address whether neurodegenerative effects can be produced when the viral envelope gene, the primary determinant of Cas- Br-E neurovirulence, is targeted to specific DNS cell populations using cell type-specific promoters. c. A comparison of cytokine expression in the CNS of mice infected with neurovirulent Cas-Br-E and non-neurovirulent Moloney murine leukemia virus will be carried out to determine whether the expression of specific cytokines are unique to CNS tissue exhibiting neuropathologic changes. If specific cytokines are identified using this approach, then the effects of modifying disease with cytokine antagonists or using cytokine-deficient mice will be explored.
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