Individuals infected with the human immunodeficiency virus (HIV-1) frequently exhibit serious, progressive behavioral cognitive and motor deficits (termed NeuroAIDS). In association with pathological changes in the brain. Evidence suggests the pathogenesis of NeuroAIDS involves a combination of neurotoxic pathways mediated by (1) products of the host response exemplified by IFNalpha, released from activated macrophages/microglia and astroglia and (2) HIV-1 products e.g. the envelope protein gp120. As demonstrated in Preliminary Results, transgenic (tg) mice with astrocyte expression of IFNalpha or gp120 recapitulate many of the structural and functional features of NeuroAIDS and will be used in the proposed studies. To determine the nature and mechanisms by with these factors as well as the CXC chemokine IP-10 influence the degree and progression of structural and functional injury in the CNS. The molecular basis for the actions of IFNalpha and gp120 in the CNS are poorly understood and will be examined in relation to the development of neuropathological changes in the tg mice. In studies designed to examine critical signal transduciton pathways, the applicant will determine the nature and role of the signal transducers and activators of transcription (STAT) and suppressors of cytokine signaling ((SOCS) in the development of the clinical, cellular and molecular alterations in the CNS of the IFNalpha and the gp120 tg mice. A multifaceted approach will be employed for these studies which will (I) define the temporal and spatial expression of the STAT and SOCS genes in the CNS and (ii) evaluate the structural consequences of the loss of STAT signaling in the IFNalpha or gp120 tg mice deficient in STAT gene expression. The potential for synergistic/additive neurotoxicity produced when IFNalpha and gp120 are co-expressed in the CNS will be assessed in bi-genic mice co-expressing IFNalpha and gp120 and the structural CNS alterations will be compared with singly tg and wild type mice. The CXC chemokine IP-10 is prominently expressed in the CNS of the IFNalpha and gp120 tg mice and in patients with NeuroAIDS. To ascertain the CNS effects of IP-10, the investigators will utilize tg mice they recently developed exhibiting astrocyte expression of the IP-10 or gene-knockout mice deficient for the expression of the IP-10- receptor CXCR3. These tg and KO mice will be cross bred with IFNalpha or gp120 mice and the structural and functional CNS alterations will be compared with singly tg and wild type mice. To determine the extent to which the structural damage produced y the host and viral factors is reflected in a change in neuronal function, hippocampal slice physiology will be analyzed in the mice described above. The results from this proposal will advance our understanding of the fundamental mechanisms of action of key host and viral factors in the pathogenesis of NeuroAIDS and may help to identify important targets for therapeutic interventions.
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