The human acquired immunodeficiency dementia complex syndrome has been recently reclassified into two categories: 1. HIV-1-associated dementia complex or HIV-1-associated myelopathy, and; 2. HIV-1-associated minor cognitive/motor disorder (HMCD). Both classes, previously termed Aids Dementia Complex (ADC) are characterized by progressively compromised mental capacities in affected people including a complex collection of neuropsychological and cognitive signs of varying severity, pathognomonc of HIV-1 CNS viral infection. The relentless decline in neuropsychological performance remains as one of the most devastating aspects of this as yet incurable disease and it yet remains refractory to conventional treatment strategies. This research component of the Center application proposes to continue electrophysiological, and initiate behavioral studies in vivo that begin to analyze the potential role of specific neural processes that may underlie the early loss of attention, motivation, and memory functions in the feline model of neuroAIDS, FIV. Brainstem and cortical sensory- and cognitive evoked potentials will be analyzed in control cats and those inoculated with a molecularly cloned strain of FIV, FIV-PPR. In addition, we will continue comprehensive evaluation of sleep/wake parameters in animals implanted with cortical leads to complement the studies currently being undertaken by the human sleep studies. Using these approaches more precise knowledge will be gained regarding the effects of persistent viral infection on the alteration in cellular responsiveness and actions on synaptic circuitry that we believe is the major consequence of direct and indirect and indirect viral action in the CNS. The feline immunodeficiency virus (FIV) infection will be studied as an example of an indirect virus affecting neuronal function (similar to HIV-1). The hypothesis stating that effects of viral infection on neuronal activity and functional circuitry can be assessed by neurophysiological and neuropharmacological methods will be evaluated in the following Specific Aim: 1. We will characterize the temporal pattern and sequence of neurological, physiological, and behavioral changes in cats infected with molecularly cloned isolates of FIV, by employing a battery of measures providing biological endpoints relevant for cognitive performance; 2. We will investigate the effects of several classes of promising treatment agents (Pentoxifylline, Thalidomide, and Memantine) on the above measures in an attempt to restore to restore or prevent further decline in these functional endpoints; 3. We will evaluate, in vivo, the neuropharmacological actions of a variety of neuroactive agents (e.g. cytokines, viral envelope glycoproteins i.e. gp120, quinolinate etc.) hypothesized to be critical factors involved in cognitive decline in neuroAIDS. Taken together these studies will provide a comprehensive neurophysiological approach to the investigation of the critical cellular substrates and circuits in a small animal model of human lentivirus infection of the CNS and will provide clues as to the mechanisms leading to the neuropsychological decline in neuroAIDS.
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