Role of cell cycle protein in HIV encephalitis

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Neuronal death in HIV encephalitis is mediated by activated, HIV-infected macrophage-secreted products including chemokines, cytokines, neurotrophic factors (NTF), reactive oxygen species, and viral proteins. Most of these factors stimulate changes in cell cycle regulatory machinery which determnes cellular outcomes in non-neuronal systems. This has led us to propose that cell cycle proteins exhibit altered activity in neurons of patients with HIVE and this activity determines neuronal survival in response to the onslaught of macrophage secreted factors present in the extracellular milieu. We have observed increased inactivation of pRb by phosphorylation (ppRb) and increased cytoplasmic E2F1 in HIVE and SIVE. Using in vitro cultures, NTF and chemokiens stimulate increased ppRb and cytoplaasmic E2F1, but hydrogen peroxide does not. Because the changes in E2F1 distribution and pRb phosphorylation occur in cells responding to neurotrophic/survival signals, but not in cells responding to oxidative stress, we propose that neurons in the disease with increased ppRb and cytoplasmic E2F1 are "surviving" neurons. This has led us to hypothesize that E2F1 and ppRb determine neuronal viability dependent on their subcellular distribution and interaction partners which is determined by the prevailing signaling cues in the extracellular milieu. The following aims are proposed: 1) To determine whether cytoplasmic E2F1 provides neuroprotection from HIVE-associated toxins, 2) To determine the role of MDMx in regulating cell survival and E2F1 subcellular localization in neurons responding to neuroprotective versus neurotoxic factors, and 3) To determine if post-translational modification of pRb in response to trophic factors occurs on different amino acids as compared to those residues modified in response to toxic factors. These stuidies will elucidate the role of cell cycle proteins in determining neuronal survival in HIVE and other neurodegenerative diseases with inflammatory components.