BRAIN INFECTION WITH NEUROVIRULENT SIV IN MACAQUES

我们以前的工作已经表明，用骨髓传代的神经毒性SIVmac接种恒河猴产生了生产性脑感染，经典的慢病毒相关神经病理学，运动技能、反应时间和工作记忆任务的行为缺陷，以及运动和感觉诱发电位的显著异常。事实上，这些神经功能障碍与HIV-1感染的人中报道的相似，并且在没有CNS机会性感染的情况下，它们具有相对高的发病率（9只测试的猴子中有7只），这使得这成为进一步研究脑慢病毒感染引起的神经元损伤机制的最佳模型。我们提出了三个具体的目标，利用我们以前的工作与神经毒性SIVmac模型来测试艾滋病的神经元损伤的结果从兴奋性毒性过程中涉及NMDA受体作为最终的共同途径的假设。SIV/HIV介导的兴奋性毒性反映在以神经元活性和信号传导的异常为特征的病理生理状态中，其可在临床AIDS发作之前开始并在神经元实际死亡之前持续很长时间。在这种情况下，神经元功能障碍和损伤可能采取与过度去极化相关的异常放电模式（例如，爆发）的形式，这在体外研究中已经得到证实，并直接从兴奋性毒性假说中预测。电生理异常也与癫痫发作是HIV-1感染者的常见发现，甚至可能是表现症状的事实相一致。神经元功能障碍状态的发展可以解释在没有艾滋病相关神经病理学的情况下与HIV-1感染相关的痴呆病例。我们将利用多电极阵列植入技术的最新进展，在SIVmac感染的恒河猴模型中测试这一假设，以记录疾病进展过程中来自初级运动皮层的神经元锋电位数据的多个通道。将使用多种测量方法分析多通道神经元活动，并与未感染对照猴获得的数据进行比较。同时，通过MDA非竞争性拮抗剂的作用，探讨NMDA受体在介导SIV相关神经病理生理过程中的作用。

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.