This project will further define the mechanisms for the age-dependent neuropathogenesis of lentiviral infection of the brain using the neurotropic Maryland isolate of the feline immunodeficiency virus (FIV-MD) as a model in experimentally infected cats. Neurologic impairment is a persistent, debilitating problem for many people infected with human immunodeficiency virus (HIV-1). A distinct difference in time course, clinical signs, and neuropathogenesis is present in pediatric as compared to adult HIV-1 infection. Adult AIDS dementia complex is seen later in the course of the disease compared to a more rapid onset of progressive encephalopathy in children. A member of the lentivirus family, FIV-MD causes AIDS in cats that can induce quantifiable, subacute neurologic disease as demonstrated first in our laboratory. Studies of experimental FIV infection in cats indicate that an age-dependent neurologic disease process is present. The central hypothesis is that FIV-MD induces age- dependent neurologic impairment in cats that is influenced by changes in immunocompetence and blood-brain barrier (BBB) integrity. Increased severity of these changes would lead to an increased viral burden of the brain, resulting in either direct or indirect mediated neurotoxicity. The same three groups of cats will be used for all objectives of this project, each representing distinct stages of BBB and brain maturation. Cats will be infected intravenously with FIV-MD either at the start of the post- natal sensitive development period of the brain and before closure of the BBB (newborn), during the sensitive development period but after closure of the BBB (8 weeks old), and in adult cats. The first objective is to compare the serial progression of immunodeficiency and neurologic impairment. Neurologic function will be quantified using a vigilance task paradigm, quantitative electroencephalography and multimodality evoked potentials. The second objective is to determine if FIV-MD infection prior to post-natal closure of the BBB in neonatal cats correlates to a preferential loss of neurologic function, persistent alteration of the BBB after infection, and the presence of selected cellular neurotoxic products. The third objective is to determine how predilection sites of viral localization, anatomic changes in the brain, and overall viral burden in the brain correlate to the results of objectives 1 and 2. The expected results from this project are that: 1) FIV-MD causes age- dependent neurologic disease that parallels HIV-1 infection in people; 2) BBB integrity is an important component in delaying the onset and severity of neurologic impairment with lentiviral infection; and 3) Viral localization and overall viral burden in the brain is predicted by immunocompetence and BBB maturation but not by the degree of pathologic changes. From this work, future studies can concentrate on therapeutic intervention that targets precise mediators of viral entry into the brain and subsequent viral neurotoxicity to delay HIV-1-induced encephalopathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH054939-03
Application #
2445570
Study Section
Psychobiological, Biological, and Neurosciences Subcommittee (MHAI)
Project Start
1995-07-01
Project End
2000-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Podell, M; March, P A; Buck, W R et al. (2000) The feline model of neuroAIDS: understanding the progression towards AIDS dementia. J Psychopharmacol 14:205-13
Steigerwald, E S; Sarter, M; March, P et al. (1999) Effects of feline immunodeficiency virus on cognition and behavioral function in cats. J Acquir Immune Defic Syndr Hum Retrovirol 20:411-9
Podell, M; Maruyama, K; Smith, M et al. (1999) Frontal lobe neuronal injury correlates to altered function in FIV-infected cats. J Acquir Immune Defic Syndr 22:10-8
Buck, W R; Podell, M (1998) Neuronal loss in FIV-MD infected cats. J NeuroAIDS 2:69-77
Podell, M; Chen, E; Shelton, G D (1998) Feline immunodeficiency virus associated myopathy in the adult cat. Muscle Nerve 21:1680-5
Podell, M; Hayes, K; Oglesbee, M et al. (1997) Progressive encephalopathy associated with CD4/CD8 inversion in adult FIV-infected cats. J Acquir Immune Defic Syndr Hum Retrovirol 15:332-40