BRAIN INFECTION WITH NEUROVIRULENT SIV IN MACAQUES

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Our previous work has shown that inoculation of rhesus macaques with bone marrow passaged, neurovirulent SIVmac yields productive brain infection, classic lentivirus related neuropathology, behavioral deficits on motor skill, reaction time and working memory tasks, and marked abnormalities in motor and sensory evoke potentials. The fact that these neurologic impairments are similar to those that have been reported for HIV-1 infected humans and that they have reported for HIV-1 infected humans and that they have a relative high incidence (7 out of 9 monkeys tested) in the absence of CNS opportunistic infections make this an optimal model for further studies of the mechanism of neuronal injury from lentiviral infection of the brain. We propose three specific aims that take advantage of our previous work with the neurovirulent SIVmac model to test the hypothesis that neuronal injury in AIDS results from an excitotoxic process involving NMDA receptors as a final common pathways. SIV/HIV mediated excitotoxicity is reflected in a pathophysiological state characterized by abnormalities in neuronal activity and signaling that may begin well before the onset of clinical AIDS and persist for long periods of time before the neuron actually dies. Neuronal dysfunction and impairment in this case may take the form of abnormal firing patterns (for example, bursting) related to excessive depolarization that has been demonstrated in vitro-studies and is directly predicted from the excitotoxic hypothesis. Electrophysiological abnormalities are also consistent with the fact that seizures are a common finding in people infected with HIV-1 and may even be the presenting symptom. The development of a dysfunctional neuronal state may explain cases of dementia associated with HIV-1 infection in the absence of AIDS related neuropathology. We will test this hypothesis in SIVmac infected rhesus macaque model by taking advantage of recent advances in multi-electrode array implant technology to record multiple channels of neuronal spike data from primary motor cortex over the course of disease progression. Multi-channel neuronal activity will be analyzed using a variety of measures and compared to data obtained from uninfected control monkeys. The potential role of NMDA receptors in mediating SIV related neuronal pathophysiology will be tested by treating with MDA non-competitive antagonist, meantime.