The goal of this project is to contribute to the development of therapy for the neurologic effects of human immunodeficiency virus (HIV) infection. The pathogenesis of acquired immunodeficiency syndrome (AIDS) dementia (ADC) is not completely known. Replication of FUV type I in the brain and the effects of its glycoprotein(gp) 120 are associated with the brain lesions of ADC. Neuronal derangement are attributed to toxic substances produced by interaction of virus-infected macrophages with microglia or infected microglia with astrocytes, and the direct effect of gp 120 on astrocytes leading to disturbance of their fimctions of neurotransmitter uptake and maintenance of homeostasis. This proposal will address the identification of the particular portion of gp 120 that has neurotoxic effects; such a segment has not been described previously. Clones of mutants of gp 120 will be generated and overexpressed in baculovirus expression system- The response of cultured microglia and astrocytes b y expressing tumor necrosis factor (TNF) alpha, interleukin- I (IL-1), IL-6 and interccllular adhesion molecule (ICAM) 1, in response to application of the protein will be used to evaluate the activity of each mutant. The ability of the mutants to utilize signal transduction pathways in activating the cells will be determined by assaying the activities of protein kinase C isoforms. Induction if ICAM-1 will suggest involvement of the mutant in the induction of increased blood brain barrier permeability in ADC. Neuropathogenesis of HIV-1 infection is difficult to investigate becau the brain parenchyma is not accessible to sampling during the course of AIDS. This raises the need for animal models of 111V infection of CNS. No other animal species can be infected with HIV to produce similar lesions as in man. The infection of goat brain by caphine arthritis encephalitis virus(CAEV) a lentivirus just like MV is also being studied as an animal model in our laboratory. We will evaluate the re levance of this virus as a model for HIV-induced neuropathogenesis as follows: I -investigate the relationship of viral load to clinical neurological disease by analyzing in brain explants during CAE, viral load, and concentrations of gp 135, cytokines and ICAM-1; 2. analyze the activity of CAEV gp135 and its mutants on glial cbUs as described above for gp 120. Identification of neurotoxic mutants of gp 120 and gp 135 will pave the way for development of therapies for ADC.
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