Individuals infected with the human immunodeficiency virus (HIV) frequently exhibit serious, progressive behavioral, cognitive and motor deficits (termed AIDS Dementia Complex - ADC) in association with pathological changes (including gliosis, encephalitis and vacuolar myelopathy in the brain. Despite widespread neurological deficits, the virus is restricted in distribution to neural cells having a monocyte/macrophage lineage and is thought not to infect neuronal cells, implying that the mechanism of HIV-associated disease is probably indirect, mediated by toxic factors produced as a result of or in response to the viral infection. In this context an attractive hypothesis is that cytokines, produced either by infiltrating immunoinflammatory cells or by resident brain cells, via their ability to regulate the growth and functions of glial and neuronal cells are key mediators of pathology in ADC. This proposal will investigate the effects of three such cytokines - interleukin-6(IL-6), tumor necrosis factor - alpha(TNF-alpha) and interleukin-3(IL-3) to induce CNS pathology in vivo. We will use the transgenic approach to target the expression of IL-6, TNF-alpha proteins to CNS astrocytes in the mouse using a glial fibrillary acidic protein (GFAP) based expression vector. Through this approach we aim to reproduce aspects of the pathology seen in ADC and correlate these with clinical changes. In addition, interactions between pathogenetic factors will be examined in transgenic lines of mice by inducing further CNS insults e.g. stab wound injury or infection with neurotropic agents, as well as crossing lines of mice expressing different transgenes. Finally in order to gain an understanding of the neurological and behavioral impact of over-expressing cytokines in the CNS, transgenic mice will be subject to electrophysiological and behavioral testing. The studies outlined in this proposal will establish murine models to examine the pathophysiological consequences of inappropriately expressing cytokines in the CNS. They should provide important insights into what currently remains a mystery i.e. the molecular basis for ADC.
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