Human immunodeficiency virus (HIV) rapidly penetrates into and infects the central nervous system (CNS). Inflammatory activity resulting from the interaction of HIV with macrophages and microglia in the nervous system leads to varying levels of neuronal loss and neurological impairments. While disease severity has been reduced with the advent of highly active antiretroviral therapy, CNS disease persists. The progression of CNS disease, although slowed, is expected to exert an increasingly heavy toll as patients with HIV live longer. The development of therapeutic strategies designed to protect against neuronal damage have been hindered by a lack of animal models that recapitulate the conditions that lead to neuropathogenesis in HIV infection. While simian immunodeficiency virus (SIV) models have been quite valuable, animals are costly and in short supply. Feline immunodeficiency virus (FIV) offers an alternative model of lentiviral neuropathogenesis which recapitulates all essential aspects of HIV infection in humans. However, a rapid model of FIV-induced CNS disease has not yet been developed. Our recent data have indicated that FIV introduced directly into the cerebral ventricles can produce greater CNS infection and increased viral RNA in the cerebrospinal fluid (CSF). In these studies a unique variant of FIV was identified in CSF which correlated with the onset of neurological disease. The proposed studies will grow this neurovirulent virus from CSF and introduce it into the brain of naive cats to encourage the development of a neurotropic strain which can be used to more effectively study CNS disease progression. Viral titers will be closely tracked in the plasma and CSF in conjunction with the analysis of viral genotype diversity using the heteroduplex tracking assay. This data should provide significant insights into the processes that control the development and evolution of viral reservoirs within the CNS. In addition, choroid plexus macrophages infected with FIV were found to encourage the trafficking of monocytes into the brain. A paradigm has been developed to assess the contribution of these cells to immune cell trafficking across the blood-brain barrier. This new in vivo model offers the potential to define the mechanisms that control the early penetration of monocytes into the brain. This infiltration is thought to trigger the inflammatory processes that lead to neuronal dysfunction and death. Thus, the model will be ideally suited for the development and testing of therapeutic strategies designed to control monocyte invasion and inflammation in the brain. Together, these studies will provide a a much needed model of HIV infection that will foster the development of therapies that restrict entry of the virus into the brain and minimize the brain damage associated with HIV infection. ? ?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AARR-A (95))
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Joseph, Jeymohan
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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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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