BRAIN INFECTION WITH NEUROVIRULENT SIV IN MACAQUES

我们以前的工作表明，用骨髓传代的、神经毒力强的SIVmac接种恒河猴会产生生产性脑感染，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，以及运动和感觉诱发电位的显著异常。这些神经损伤与已报道的HIV-1感染者相似，并且已报道HIV-1感染者，而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)，这使这成为进一步研究慢病毒感染脑部神经元损伤机制的最佳模型。我们提出了三个具体的目标，利用我们之前使用神经毒力SIVmac模型所做的工作来检验这一假设，即艾滋病中的神经元损伤是由NMDA受体作为最终共同途径的兴奋性毒性过程造成的。SIV/HIV介导的兴奋性毒性反映在一种病理生理状态，其特征是神经元活动和信号的异常，这种异常可能早在临床艾滋病发作之前就开始了，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，爆发性放电)，这已在体外研究中得到证实，并直接从兴奋毒性假说中预测出来。电生理异常也符合这样一个事实，即癫痫是HIV-1感染者的常见发现，甚至可能是主要症状。在没有艾滋病相关神经病理的情况下，神经功能障碍状态的发展可能解释与HIV-1感染相关的痴呆症。我们将利用多电极阵列植入技术的最新进展，在SIVmac感染恒河猴的模型中测试这一假设，以记录疾病进展过程中初级运动皮质的多个通道的神经元棘波数据。多通道神经元活动将使用各种测量方法进行分析，并与从未感染的对照猴子获得的数据进行比较。同时，NMDA受体在介导SIV相关神经元病理生理中的潜在作用将通过丙二醛非竞争性拮抗剂的治疗来检验。

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.