Disorders of the central nervous system (CNS), including dementia, are common complications of HIV infection. Although the advent of HAART therapy initially decreased morbidity and mortality due to HIV infection, including CNS abnormalities, the incidence of CNS disease has increased in recent years. This increase may in part represent the diminishing effectiveness of HAART therapy due to the prevalence of resistant strains as well as the relatively poor distribution of anti-virals in the CNS compartment. The current increase in HIV -induced neurological disorders as co-morbid conditions in HIV infection suggests the importance of developing additional strategies for the treatment and/or prevention of viral induced injury to the CNS. The studies proposed here focus on a major pathway promoting neuro-protection, the insulin-like growth factor I (IGF-I). Several lines of evidence suggest that this protective pathway is impaired in HlV infection, presumably leaving neuronal cells, as well as other cell types, vulnerable to the pro-apoptotic effects of induced cytokines and toxic metabolites. In our preliminary studies we demonstrate the ability of the IGF-I system to counteract the deleterious effects of TNF-alpha on the survival of differentiated neurons. We further show that the IGF-I receptor (IGF-IR) is activated in patients with HIV associated dementia (HAD) as determined by immunohistochemical analysis of tissue specimens with antibody specific for the phosphorylated (active) form of the receptor. The studies proposed here will test the hypothesis that the cross-talk between the IGF-IR and TNF-alpha receptor signaling pathways is important in determining the extent of neuronal injury in the context of HIV infection. We will examine this hypothesis in the context of two Specific Aims. In the first Specific Aim we will identify the threshold level of IGF-I receptor necessary for neuro-protection, and the receptor signaling domaids required for this effect. In the second Specific Aim, we will examine the interplay between the IGF-I and TNF-alpha signaling pathways and the specific signaling molecules responsible for IGF-I mediated neuro-protection. It is anticipated that the studies performed within the context of this application will contribute to the development of a novel therapeutic strategy based on the utilization and/or mobilization of the IGF-I signaling pathway.
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