Human immunodeficiency virus-infected and immune competent brain mononuclear phagocytes (MP;macrophages and microglia) secrete cellular and viral toxins that affect neuronal damage during advanceddisease. Methamphetamine (METH) abuse causes even more significant neuronal aberrations and thechanges can be associated with impaired cognitive functions, such as learning, problem solving, andprocessing information. Together METH abuse and HIV infection appears to result in greater impairmentthan each condition alone. Amongst a number of cues and host cell immune factors that can control suchevents, astrocytes affect such disease processes and the cells abilities to modulate the nervous system'smicroenvironment. Interestingly, little is known how astrocytes communicate with MP to curtail disease andnotably in the setting of METH abuse. Thus, this project will investigate MP-astrocyte crosstalk using state ofthe art biological analysis coupled with proteomic fingerprint tests. The microglial-astrocyte dialogue will beevaluated in the setting of METH for how abused drugs can affect microglial functions and affect astrocyteregulation of neurotoxicity. Specifically, a complete proteomic analysis will be done including thecytoskeleton, cell death, and migratory pathways linked to specific biological outcomes. How such glialcrosstalk is mediated will be uncovered with a focus on microglial affected viral growth. These processes areknown to be linked to the regulation of reactive oxygen species and other disease-modulatory factors in celland rodent models of human disease. These experimental results will be joined with projects 2 and 3 (Drs.Fox and Ciborowski) so that studies at the cellular level can be sought in relationship to focused animalmodel experimentation and clinical endpoints.The public health relevance of this work is that combined toxicity of HIV and METH on the brain can resultin substantial problems for those who are HIV infected and abuse METH. This research will uncover thebasis of the interaction of these agents on brain cells, leading to information that can be disseminated todissuade METH use, and provide targets for potential therapeutic intervention.
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