Infection with human immunodeficiency virus type 1 (HIV-1) can cause dementia in greater than 30% of AIDS patients. HIV-1 enters the brain at the early stage of infection and resides primarily in a limited number of macrophages/microglia and astrocytes. Infection of these cells, however, may not explain the massive neuronal pathology which is seen in AIDS associated dementia suggesting a role for factors from HIV-1 and infected cells that trigger a cascade of events leading to neurodegeneration. One of the viral proteins which possesses a strong regulatory activity is Tat, which is secreted by infected cells and can be taken up by neighboring uninfected cells. Results from our recent studies show that Tat can influence multiple biological events that lead to neuronal injury. For example, treatment of neuronal cells with Tat affects MAPWERK1/2 activity, the downstream central component of the nerve growth factor (NGF) signaling pathway. This can affect Egr-I, a transcription factor which is regulated by MAPWEMU2 and is responsible for the stimulation of p35 protein. p35 is a neuron-specific activator of cdk5, a cyclin dependent kinase which phosphorylates several neuronal proteins including neurofilament and plays an important role in neuronal differentiation and survival. Accordingly, our data indicate that treatment of cells with Tat severely decreases p35 expression. In parallel, Tat can bind to the cellular protein, Pura, which associates with cdk5. Results from Pura knockout animals revealed a decrease in p35 activity, pointing to the importance of Pura association with cdk5 in the activity of cdk5:p35 complex. These observations provide a strong rationale for launching a comprehensive series of experiments to investigate the cooperativity between HIV- 1 Tat and the cellular protein, Puralpha, which results in de-regulation of the NGF signal transduction pathway in neuronal cells. Results from the proposed studies in this project should unravel several biological pathways which are affected by HIV- 1 leading to neurodegeneration and dementia, and assist us in devising a neuroprotective strategy toward treatment of HIV- 1 induced neuronal injury.
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