BRAIN INFECTION WITH NEUROVIRULENT SIV IN MACAQUES

我们之前的研究表明，恒河猴接种骨髓传代的具有神经毒性的SIVmac会导致脑部感染、典型的慢病毒相关神经病理、运动技能、反应时间和工作记忆任务的行为缺陷，以及运动和感觉唤起电位的明显异常。事实上，这些神经系统损伤与HIV-1感染者的报告相似，并且在没有中枢神经系统机会性感染的情况下，它们的发病率相对较高（9只猴子中有7只），这使得它成为进一步研究大脑慢病毒感染神经元损伤机制的最佳模型。我们提出了三个具体的目标，利用我们之前的神经毒性SIVmac模型的工作来验证艾滋病中的神经元损伤是由涉及NMDA受体的兴奋毒性过程作为最终共同途径引起的假设。SIV/HIV介导的兴奋性毒性反映在一种以神经元活动和信号异常为特征的病理生理状态中，这种异常可能在临床艾滋病发病之前就开始了，并在神经元实际死亡之前持续很长一段时间。在这种情况下，神经元功能障碍和损伤可能表现为与过度去极化相关的异常放电模式（例如，爆裂），这已在体外研究中得到证实，并直接从兴奋毒性假说中得到预测。电生理异常也与癫痫发作是HIV-1感染者的常见发现这一事实相一致，甚至可能是首发症状。在没有艾滋病相关神经病理的情况下，功能失调的神经元状态的发展可以解释与HIV-1感染相关的痴呆病例。我们将在SIVmac感染的恒河猴模型中验证这一假设，利用最新的多电极阵列植入技术记录疾病进展过程中来自初级运动皮层的多通道神经元峰值数据。将使用各种测量方法分析多通道神经元活动，并与从未感染的对照猴子获得的数据进行比较。与此同时，我们将通过MDA非竞争性拮抗剂来检测NMDA受体在SIV相关神经元病理生理中的潜在作用。

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.