BRAIN EFFECTS OF INTERFERON ALPHA

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The behavioral effects of HIV infection are more extensive than would be predicted from the nature and extent of the infection of the central nervous system, therefore, the possible role of cytokines must be examined. Because an acid-labile interferon-alpha (IFN-alpha) is seen in the serum of HIV infected individuals, and because exogenous IFN given to treat virus infections or tumors has neuropsychological effects, this cytokine is the focus of the proposed studies. We have established in a mouse model that exogenous IFN-alpha produces some of the symptoms of HIV infection and IFN treatment; decreased activity and anorexia. This proposal is concerned with the problem of how this peripherally produced cytokine can have CNS effects. Peripherally administered IFN-alpha enters the brain in small amounts. This proposal seeks to accurately determine the exact amounts and location of entry of IFN-alpha into the CNS and to determine whether it is concentrated around the circumventricular organs where the blood brain barrier is weak. First, the IFN-alpha assay will be optimized by removing factors that interfere with IFN detection. Second, the time course of IFN- alpha titers in a variety of organs, including brain will be determined. Third, using the results of the previous two experiments, the regional distribution of IFN-alpha in the brain will be determined to assess the hypothesis that it acts at the circumventricular organs (CVO) lacking a blood-brain barrier. Fourth, should IFN-alpha be localized to the CVOs it should be concentrated enough to enable detection using silver enhanced colloidal gold-labeled IFN to localize the exact sites of entry of IFN- alpha into the brain. Fifth, we will determine whether the amounts of IFN- alpha that enter the brain are sufficient to have the typical IFN effects upon the brain. mRNA from an IFN-specific gene (guanylate binding protein) will be detected by polymerase chain reaction amplification in areas of the brain found to contain IFN. Sixth, in situ hybridization will be used to localize the GBP-1 gene expression in conjunction with gold labeling of IFN. Having determined the sites of entry of IFN-alpha into the CNS and its ability to act there, we will be able to design future studies on the interaction between IFN-alpha, IFN regulated products and brain systems that produce the behavioral effects due to exogenous IFN or virus infection.