Viral Pathogenesis of Neural and Behavior Injury

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DESCRIPTION (provided by applicant): Infection of the central nervous system with the human immunodeficiency virus, type 1 (HIV-1) can lead to cognitive, motor and sensory disorders that manifest as subcortical dementia. Available data suggest that viral factors and soluble neurotoxins secreted by activated resident immune system damage vulnerable neuronal populations, resulting in neurochemical (i.e., dopaminergic) alterations and behavioral deficits reminiscent of parkinsonism. Although the basal ganglia represent the major target of HIV infection, the pathophysiology of behavioral disorders secondary to HIV infection remains poorly understood. The paucity of economical rodent animal systems significantly delays the progress in this field. Thus, in this competing continuation application, we propose to use our small animal model of viral neuropathogenesis, neonatal Borna disease virus infection (BDV), to study the mechanisms by which soluble neurotoxins (e.g., glutamate and pro-inflammatory cytokines) induce a continuing loss of GABA-ergic neurons in the basal ganglia, leading to alterations in dopamine (DA) neurotransmission and associated behavioral deficits. Specific Aim 1 will evaluate BDV-associated injury to the basal ganglia by quantitatively measuring a continuing loss of GABA-ergic and DA neurons over time. Specific Aim 2 will assess alterations in GABA and DA neurotransmissions in the basal ganglia by using in vivo and in vitro neurochemical and behavioral methods. Specific Aim 3 will investigate a role of glutamate toxicity and direct effects of virus infection in neuronal injury employing molecular biology and cell culture techniques. The results of this multidisciplinary project will advance our understanding of the pathophysiology of virus-induced basal ganglia disorders, the direct and indirect mechanisms of neuronal damage and will stimulate a search for new treatments of the neurobehavioral alterations observed in HIV-infection-related and other neurodegenerative diseases.