HIV-1 infection is often associated with damage to the central nervous system (CNS). The precise molecular and cellular processes that cause this damage are still unknown. Increasing evidence suggests that HIV-1-derived proteins, particularly envelope proteins and Nef, may play important causal roles in the development of AIDS dementia. To study their effects on the CNS in vivo, we propose to express proteins of the neuroinvasive HIV-1 isolate YU-2 (including gp160 with and without cleavage site mutation, gp120, Flag'ed gp120, gp41 and Nef) in astrocytes or macrophages/microglia of transgenic mice. This will be accomplished with the help of fusion gene constructs which allow the prolonged, reproducible delivery of selected proteins (devoid of any contaminations) to specific areas/cells of the intact CNS. Regulatory sequences from the glial fibrillary acidic protein gene will be used to express the above HIV-1 proteins in astrocytes and sequences from genes encoding the high-affinity Fc receptor or lysozyme to express gp120 in macrophages. Fusion genes will be microinjected individually into fertilized mouse oocytes. The resulting transgenic mice will be bred and the expresssion of transgenes in their offspring characterized. Mice from transgenic expressor lines are expected to show structural and molecular alterations of the CNS, which will be quantitated with a well established battery of tests, including laser confocal microscopy of in situ hybridized/immunolabeled brain sections, electron microscopy, RNAse protection assays, Western blots, and bioassays. To assess the relevance of these models to human disease, alterations in the CNS of transgenic mice will be compared with those in HIV-1 infected human brain tissue, obtained postmortem. Mechanisms of HIV-1-induced CNS damage will also be analyzed in vitro by exposing neurons from nontransgenic mice to HIV-1 protein-expressing transgenic astrocytes/microglia and by testing which pharmacologic reagents block the resulting neurotoxic effects. Well characterized transgenic models will then be used to assess in vivo the effectiveness of drugs aimed at detrimental HIV-CNS interactions. By characterizing the CNS effects of different HIV-1 proteins, this project will further our understanding of HIV-1 associated neurologic disease and help identify important targets for therapeutic interventions. By providing models for the preclinical assessment of drugs, this study will facilitate the evaluation and development of therapeutic strategies for the treatment and prevention of AIDS dementia.
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