The broad goal of this application is a focused examination of the neuropathogenesis of the AIDS Dementia Complex (ADC). His experimental design relies on the use of a murine model of neurodegeneration in which infection of a mutant form of Moloney Murine Leukemia Virus (MoMuLV) induces a progressive neuroimmunodegenerative disease (NID) that has some clinical and pathological similarities to human immunodeficiency virus type 1 (HIV1)-associated central nervous system (CNS) disease. Similarities between this model and HIV-1 infection of the CNS include: (1) selective depletion of T cells in the immune system and neurons in the CNS; (2) infection and overactivation of CNS astrocytes and microglia; (3) elevated levels of tumor necrosis factor (TNF) in lesion areas; and (4) neuronal loss as a result of indirect mechanisms.
The specific aims of this application are: (1) to determine the expression levels of TNF, IL-1, Fas/FasL, and other cytokines in the brain stem, spinal cord, and cerebral cortex of ts1- and WT-infected mice and uninfected controls and to quantitate the concentration of TNF produced in the brain stem and cerebral cortex of ts1-infected mice at various time points postinfection; (2) to determine which cell types in the CNS express TNF, IL-1, Fas, and FasL; which cell types undergo apoptosis; and which cell types are infected by ts1 in ts1-infected mice; (3) to determine if TNF, IL-1, and Fas signal transduction is the pathway utilized in ts1-mediated neurodegeneration by comparing disease progression and neuronal loss in ts1-infected TNFR KO, TNF KO, IL-1R KO, and Fas- as well as FasL-deficient mice with those in respective uninfected KO mice and ts1-infected normal mice and by comparing disease progression and neuronal loss in ts1-infected FVB/N mice treated with soluble TNFR, soluble Fas, or soluble IL-1R; and (4) to determine if the combined action of (a) TNF and Fas or (b) TNF and IL-1 is necessary to prevent disease development in double knock out (KO) mice homozygous for disruption of both TNFR1 and Fas and in mice homozygous for disruption of both TNFR1 and IL-1R. Combined treatments of ts1-infected FVB/N mice with soluble receptors of both TNF and FasL or TNF and IL-1 will also be conducted.
