This study will investigate the role of HIV-encoded Tat protein in the central nervous system pathology and behavioral impairment associated with NeuroAIDS. The goal of this project is to contribute to the understanding of NeuroAIDS etiology and pathology by focusing on HIV-Tat protein as a possible contributing factor to the neurological deficits and neurodegeneration seen in HIV infection. Although Tat protein is a single component of HIV infection, previous research demonstrating the neurotoxic and neuromodulatory effects of Tat support its involvement in NeuroAIDS. This study will test the hypothesis that HIV-Tat protein induces neurodegeneration and learning and memory deficits. The hypothesis will be tested using a transgenic mouse with inducible and brain-selective Tat protein expression. Brains will be excised from Tat-induced, uninduced, and C57BI/6 mice for anatomical and diffusion tensor magnetic resonance imaging using a 9.4 T magnet. Reductions in volume and the integrity white matter axonal tracts will be evaluated in the hippocampus and prefrontal cortex and other brain regions considered essential for intact learning and memory. This technology will allow for identification of brain regions and circuitry damaged by Tat protein. Also, mice induced to express Tat will be tested in behavioral assays assessing learning and memory and will be compared to uninduced littermates and C57BI/6 mice. The novel object recognition task will be used to assess recognition memory. The Barnes maze will be used to assess spatial learning and memory by testing the ability of the mice to use spatial cues to locate an escape hole. Overall, this research aims to identify the contribution of HIV-Tat protein to neurodegeneration and behavioral impairment associated with NeuroAIDS.
Evaluating the consequences of HIV-Tat protein activity in the brain could improve our understanding of NeuroAIDS and help identify a target for development of therapeutics to prevent or treat the neurodegeneration and cognitive dysfunction associated with HIV infection. This is particularly important given that antiretroviral drugs are less effective at allaying the effects of HIV in the brain.
