Human immunodeficiency virus (HIV) rapidly penetrates the central nervous system (CNS) and can lead to varying levels of neuronal loss and neurological impairments including AIDS dementia. Because interactions of the virus with the CNS prior to the development of AIDS probably set the stage for subsequent disease progression, early intervention is likely to be important for effective treatment of the neurological and behavioral complications of HIV infection. Microglia and macrophages are thought to play a key role in the penetration of the virus into the nervous system and subsequent pathogenesis. However, our understanding of the interactions of the virus with brain microglia and macrophages is still quite limited. Specifically, little is know about the relative role of microglia and macrophages in pathogenesis, the stimuli that provoke the activation of these cells and release of putative toxins, and the mechanisms that lead to neuronal dysfunction. Using feline immunodeficiency virus (FIV) we have developed a model of viral infection and pathogenesis that may help to explain how each cell might contribute to evolving pathogenesis. This model suggests that the macrophage population within the choroid plexus could maintain a virus reservoir capable of infecting T-cells locally and perhaps contribute to the trafficking of macrophages and secretion of neurotoxins. Using primary cultures of brain microglia, choroid plexus macrophages and neurons, we will determine the viral and non-viral stimuli that induce microglial and macrophage activation and secretion of toxins. Microglial/macrophage activation will be assessed by evaluating increases in intracellular calcium in vitro, production of cytokine and chemokine mRNA and the accumulation of substances toxic to cortical cat neurons in primary culture. In addition, we will pharmacologically characterize the actions of the secreted toxins on neurons that lead to the destabilization of intracellular calcium. Microglia, macrophages or T-cells infected in vitro will then be infused into the brain ventricles to generate an in vivo model of central nervous system pathogenesis. These studies will clarify the role of microglia, macrophages and T-cells in the inflammatory response that develops in the brain following lentivirus infection and help to generate an animal model of macrophage-induced toxicity that can be used for identification and evaluation of improved strategies for early therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063646-03
Application #
6703715
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Joseph, Jeymohan
Project Start
2002-03-11
Project End
2006-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
3
Fiscal Year
2004
Total Cost
$223,230
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Neurology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Meeker, Rick B; Poulton, Winona; Clary, Gillian et al. (2016) Novel p75 neurotrophin receptor ligand stabilizes neuronal calcium, preserves mitochondrial movement and protects against HIV associated neuropathogenesis. Exp Neurol 275 Pt 1:182-98
Sherman, Barbara L; Gruen, Margaret E; Meeker, Rick B et al. (2013) The use of a T-maze to measure cognitive-motor function in cats (Felis catus). J Vet Behav 8:32-39
Meeker, Rick B; Bragg, D C; Poulton, Winona et al. (2012) Transmigration of macrophages across the choroid plexus epithelium in response to the feline immunodeficiency virus. Cell Tissue Res 347:443-55
Meeker, Rick B; Poulton, Winona; Feng, Wen-hai et al. (2012) Suppression of immunodeficiency virus-associated neural damage by the p75 neurotrophin receptor ligand, LM11A-31, in an in vitro feline model. J Neuroimmune Pharmacol 7:388-400
Meeker, Rick B; Williams, Kimberly; Killebrew, Deirdre A et al. (2012) Cell trafficking through the choroid plexus. Cell Adh Migr 6:390-6
Fletcher, Nicola F; Meeker, Rick B; Hudson, Lola C et al. (2011) The neuropathogenesis of feline immunodeficiency virus infection: barriers to overcome. Vet J 188:260-9
Hudson, Lola C; Tompkins, Mary B; Meeker, Rick B (2008) Endothelial cell suppression of peripheral blood mononuclear cell trafficking in vitro during acute exposure to feline immunodeficiency virus. Cell Tissue Res 334:55-65
Meeker, Rick B (2007) Feline immunodeficiency virus neuropathogenesis: from cats to calcium. J Neuroimmune Pharmacol 2:154-70
Liu, Pinghuang; Hudson, Lola C; Tompkins, Mary B et al. (2006) Compartmentalization and evolution of feline immunodeficiency virus between the central nervous system and periphery following intracerebroventricular or systemic inoculation. J Neurovirol 12:307-21
Liu, Pinghuang; Hudson, Lola C; Tompkins, Mary B et al. (2006) Cerebrospinal fluid is an efficient route for establishing brain infection with feline immunodeficiency virus and transfering infectious virus to the periphery. J Neurovirol 12:294-306

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