Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) occurs in a majority of acquired immune deficiency syndrome (AIDS) patients and causes a variety of neuropathologies. Memory loss, loss of motor control, and cognitive deficiencies often ensue. Highly active antiretroviral therapy (HAART) has been shown to restore immune function, ameliorate HIV-related CNS symptoms and prevent opportunistic infections. However, as the number of treated subjects with chronic HIV infection increases, the prevalence of HIV-associated cognitive and neurological impairment is actually rising despite HAART. Thus, it is becoming increasingly urgent to have a better understanding of HIV pathogenesis in the CNS and to explore neuroAIDS models and alternative strategies for developing new neuroAIDS therapeutics. We have recently developed a doxycycline (Dox)-inducible and brain-targeted HIV-1 Tat transgenic mouse model and showed that Tat expression alone is sufficient to induce some of impotrant neuropathological hallmarks observed in the brain of HIV-infected individuals. Using this small rodent model, we found that administration of EGb 761, the standardized extract from Ginkgo biloba that has been widely used for treating neurological deficits, had significant neuroprotective effects against Tat-induced neuropathologies. The immediate goals of this application are to continue to evaluate the effects of EGb 761 on Tat-induced neuropathology and to determine the underlying neuroprotective mechanism of EGb 761 against Tat-induced pathology. These goals will be addressed in the context of the unique Tat transgenic mouse model. We believe that this combined molecular, cellular, biochemical, and genetic approach will provide a better understanding of EGb 761 function against HIV-1 Tat-induced neuropathologies and yield novel clues for developing anti-HIV therapeutic strategies. Importantly, the proposed study will provide evidence for the first time to support use of this model for development of neuroAIDS therapeutics. Lack of small rodent neuroAIDS models has greatly impeded development of drugs for treating HIV neurological diseases. The proposed study is to explore the possibility of using a mouse model to develop, evaluate, and validate therapeutic strategies specifically targeted at these diseases. ? ? ?
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