The neurobehavioral sequelae of HIV infection arise from poorly understood pathological effects on brain structure and function; we use the term NeuroAIDS to represent this complex of brain changes. Neuropathology is observed in about 80-90% of AIDS patients at autopsy and virus can be measured in the cerebrospinal fluid of 50-70 % of HIV infected individuals. Cognitive and motor impairments may affect up to 30% of patients in the early stages of immune suppression and up to 50% of symptomatic patients, while about 10-20 % of those with AIDS develop frank dementia. These neurobehavioral disturbances severely impact social and occupational functioning in HIV+ adults and children, thereby greatly reducing their quality of life. A neuropsychological testing battery employing a touch- sensitive computer screen has been developed to detect changes in cognitive performance in rhesus monkeys. The test battery includes probes of memory (delayed non-matching to sample, spatial working memory), attention (intra- dimensional/extra-dimensional shift task) and motor performance (bimanual motor task), as well as an estimate of relative reinforcement efficacy (progressive-ratio) and reaction-time. HIV+ patients tested in the human version of this battery exhibited a specific profile of cognitive deficits suggestive of fronto-striatal dysfunction. A model is proposed in which a neurovirulent form of simian immunodeficiency virus (SIV) is hypothesized to produce CNS changes in rhesus monkeys reminiscent of those seen in NeuroAIDS and to result in analogous behavioral deficits. The time course of disease progression will be characterized using functional measures of cognition and motor skill, as well as telemetric monitoring of gross activity, temperature and EEG. Concomitant measurement of immunological and virological parameters, may reveal correspondence between behavioral performance and the physiologic state of the monkeys across measures will ultimately be correlated with neuropathology permitting a convergence of information from all levels of analysis. The utility of an animal model rests in its ability to permit the study of a disease process under controlled conditions and the evaluation of potential therapeutic agents. An animal model that recapitulates the pathogenic and functional outcomes seen with HIV infection in humans has both face and predictive validity for use in drug treatment studies. The accelerated time course of disease compared to HIV infection,a nd the sophistication with which monkeys can be tested, makes the SIV model ideal for testing new therapies aimed at preventing or arresting cognitive decline. The study of treatment drugs with known mechanisms of action in the SIV model will not only be important as a screen for therapeutic efficacy and side effects, but will also yield important clues as to the mechanisms of the behavioral impairments associated with immunodeficiency virus infections. In this component of the Center, the SIV model will be used to explore the neurobehavioral sequelae of NeuroAIDS, the viral and host factors leading to neuronal dysfunction, and to begin testing potential therapeutic agents.
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