Induction of cell-cycle regulators in simian immunodeficiency virus encephalitis

Neuronal degeneration associated with human immunodeficiency virus encephal itis has been attributed to neurotoxicity of signaling molecules secreted b y activated, infected macrophages. We hypothesized that the barrage of sign als present in the extracellular milieu of human immunodeficiency virus-inf iltrated brain causes inappropriate activation of neuronal cell-cycle machi nery. We examined the presence of three members of the cell-cycle control m achinery: pRb, E2F1, and p53 in the simian immunodeficiency virus encephali tis (SIVE) model. Compared to noninfected and simian immunodeficiency virus -infected, nonencephalitic controls, we observed increased protein expressi on of E2F1 and p53 and aberrant cellular localization of E2F1 and pRb, In S IVE, E2F1 was abundant in the cytoplasm of neurons in both neurons and astr ocytes proximal to SIVE pathology in the basal ganglia, pRb staining was nu clear and cytoplasmic in cortical neurons of SIVE cases. Antibodies to phos phorylated pRb also labeled the cytoplasm of cortical neurons. These data s uggest that br SIVE, cell signaling results in phosphorylation of pRb which may result in subsequent alteration in E2F1 activity. As increased E2F1 an d p53 activities have been linked to cell death, these data suggest that th e neurodegeneration in SIVE could In. part be because of changes in express ion and activity of cell-cycle machinery.