ROLE FOR CELL CYCLE PROTEINS IN HIV ENCEPHALITIS

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DESCRIPTION: HIV encephalitis is remarkable for neuronal damage and loss in the absence of significant HIV infection of neuroglial cells. Neuronal cell death is believed to be mediated by activated, HIV-infected macrophagesecreted products including chemokines, cytokines, neurotrophic factors (NTF), and quinolinic acid. Several of these factors including NTF have the ability to induce changes in the cell cycle regulatory machinery. We have observed changes in expression and subcellular localization of three key regulators of the cell cycle, pRb. E2F1, and p53, in models for HIV encephalitis (HIVE). This has led us to propose the hypothesis that neuronal degeneration observed in HIVE is caused by changes in activity of cell cycle machinery in terminally differentiated neurons. Activation of cytokine, chemokine, and neurotrophic factor receptors in non-neuronal systems results in second messenger cascade, which result in phosphorylation of pocket proteins like the retinoblastoma susceptibility gene product, pRb. Phosphorylation of these proteins leads to deregulation of proteins controlling gene expression, most notably E2F1. Since pRb, E2F1 and p53 control the two key pathways determining cell survival, we hypothesize that changes in activity of these proteins will alter neuronal viability. Using both retrospective autopsy studies and an in vitro model of HIVE, we will study the activity and expression of members of these two pathways and their effects on survival of neuronal and glial elements. Our first aim focuses on determining the regulation of pRb and its family members by phosphorylation in response to macrophage secreted factors. Specific Aim 2 will determine if E2F1 activity is altered by macrophage secreted factor signaling and study the impact of activated E2F1 on neuronal and glial survival. Finally specific aim 3 will address the contribution of p53 to neuronal and glial survival in response to macrophage secreted factors. These specific aims will help define the role of cell cycle regulators in neuronal and glial survival during HIVE and define therapeutic targets to disrupt the molecular cascade leading to the associated neurodegenerative disease.