The investigator hypothesizes that HIV infection in the central nervous system (CNS) in AIDS patients results in astrogliosis and microglial nodule formation as the result of induction of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF alpha) and IL-6. The author suggests that binding of HIV to glial cells and triggering of brain disorders occurs through a molecule other than, or in addition to, CD4. Dr. Merrill proposes to study the interaction of HIV with both rat and human glial cells by examining binding, entry, infection (productive or latent, labile), and induction of morphological and functional changes in vitro. Induction of gliosis, microglial fusion, proliferation and cytokine production will be correlated with virus binding and either entry into glial cells or crosslinking of cell surface molecules in the absence of entry and reverse transcription. Cytokines induced by virus and responsible for morphological changes will be determined by specific bioassays, by Northern blot and by in situ hybridization analyses. If virus-induced changes correlate with specific cytokines, recombinant cytokines will be used to mimic these events and cytokine- specific antibodies will be used to inhibit the virus-induced changes. Since it is possible that HIV binding, induction of fusion, proliferation or cytokine response are governed by more than one viral epitope, the author will try to map the epitopes involved by blocking these events with a battery of monoclonal and polyclonal antibodies. The investigator proposes using hybrid constructs of high and low inducer recombinant virus isolates to map inductive epitopes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030768-03
Application #
2268727
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1992-03-16
Project End
1995-02-28
Budget Start
1994-03-01
Budget End
1995-02-28
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Other Domestic Higher Education
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Parkinson, J F; Mitrovic, B; Merrill, J E (1997) The role of nitric oxide in multiple sclerosis. J Mol Med 75:174-86
Merrill, J E; Murphy, S P; Mitrovic, B et al. (1997) Inducible nitric oxide synthase and nitric oxide production by oligodendrocytes. J Neurosci Res 48:372-84
Mitrovic, B; Ignarro, L J; Vinters, H V et al. (1995) Nitric oxide induces necrotic but not apoptotic cell death in oligodendrocytes. Neuroscience 65:531-9
Koka, P; He, K; Zack, J A et al. (1995) Human immunodeficiency virus 1 envelope proteins induce interleukin 1, tumor necrosis factor alpha, and nitric oxide in glial cultures derived from fetal, neonatal, and adult human brain. J Exp Med 182:941-51
St Pierre, B A; Granger, D A; Wong, J L et al. (1995) A study on tumor necrosis factor, tumor necrosis factor receptors, and nitric oxide in human fetal glial cultures. Adv Pharmacol 34:415-38
Merrill, J E; Jonakait, G M (1995) Interactions of the nervous and immune systems in development, normal brain homeostasis, and disease. FASEB J 9:611-8
Koka, P; He, K; Camerini, D et al. (1995) The mapping of HIV-1 gp160 epitopes required for interleukin-1 and tumor necrosis factor alpha production in glial cells. J Neuroimmunol 57:179-91
Mitrovic, B; St Pierre, B A; Mackenzie-Graham, A J et al. (1994) The role of nitric oxide in glial pathology. Ann N Y Acad Sci 738:436-46
Mackenzie-Graham, A J; Mitrovic, B; Smoll, A et al. (1994) Differential sensitivity to nitric oxide in immortalized, cloned murine oligodendrocyte cell lines. Dev Neurosci 16:162-71
Mitrovic, B; Ignarro, L J; Montestruque, S et al. (1994) Nitric oxide as a potential pathological mechanism in demyelination: its differential effects on primary glial cells in vitro. Neuroscience 61:575-85

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