MECHANISMS OF HIV-INDUCED ALTERATIONS IN SLEEP

描述(改编自申请人的摘要)：免疫组织和 神经系统是人类免疫缺陷病毒的主要目标。 (艾滋病毒)。睡眠是一种可定义的行为，由两种行为之间的相互作用调节 神经和生化机制，并在病毒感染期间改变， 包括艾滋病毒。据估计，在所有艾滋病毒感染者中，多达60%的人 个体会经历令人虚弱的白天疲劳和困倦。在……里面 此外，对艾滋病毒感染者进行的多导睡眠图研究 表明夜间睡眠发生了变化。这些变化发生在 慢性艾滋病毒感染，在艾滋病发作之前，以及在没有 与焦虑或焦虑有关的药物滥用或精神症状 抑郁症。艾滋病毒改变睡眠的确切机制尚不清楚。 尽管艾滋病毒无法感染啮齿动物细胞，但其他实验室已经 展示了啮齿动物模型在细胞因子作用研究中的应用 以及神经效应。研究人员发现，在一种大鼠模型中 睡眠，HIV产品以一种类似于 在HIV感染期间观察到的那些。此外，在调查人员的 模型中，HIV产物增加了大鼠中枢神经系统细胞因子mRNA的表达 神经系统(CNS)。HIV在感染后不久进入中枢神经系统；细胞因子 浓度，包括催眠细胞因子白介素1(IL-1)和 肿瘤坏死因子(TNF)在中枢神经系统各阶段均升高 艾滋病毒感染的可能性。研究人员假设，在睡眠过程中 艾滋病毒感染的部分原因是艾滋病毒在中枢神经系统内引起的增加 促进睡眠的细胞因子浓度(如IL-1、肿瘤坏死因子)以及 抑制睡眠的药物(如IL-1受体拮抗剂(IL-1ra)和 IL-10)。研究人员将通过以下方式检验这一工作假说： 确定能够改变睡眠的艾滋病毒成分(即艾滋病毒 包膜糖蛋白[GPS])，并通过阐明IL-1、肿瘤坏死因子、 IL-1ra和IL-10在HIV和HIV GPS反应中的作用。最后，他们会 确定脑内重要区域细胞因子mRNA表达的变化 对睡眠的调节，以应对艾滋病毒全球定位系统。他们会用老鼠 用脑电电极和慢性导尿管插入 侧脑室。睡眠-觉醒活动和细胞因子的变化 中枢神经系统的信使核糖核酸的表达将在给药后被测定 或者艾滋病全球定位系统。这些实验不仅应该显示出 中枢神经系统内的细胞因子有助于艾滋病毒诱导的睡眠变化，但 也可能建议新的治疗方法，以治疗 在艾滋病期间出现的疲劳和嗜睡。

DESCRIPTION (Adapted from applicant's abstract): Tissues of the immune and nervous systems are the primary targets of the human immunodeficiency virus (HIV). Sleep, a definable behavior, is regulated by interactions between neural and biochemical mechanisms, and is altered during viral infections, including HIV. It is estimated that as many as 60% of all HIV-infected individuals experience debilitating daytime fatigue and sleepiness. In addition, polysomnographic studies conducted on HIV-infected individuals indicate that nighttime sleep is altered. These alterations occur during chronic HIV infection, prior to the onset of AIDS, and in the absence of substance abuse or psychiatric symptoms associated with anxiety or depression. The precise mechanisms whereby HIV alters sleep are not known. In spite of HIV's inability to infect rodent cells, other laboratories have demonstrated the utility of rodent models for the study of cytokine actions and neurologic effects. The investigators have found, in a rat model of sleep, that HIV products induce alterations in sleep in a manner resembling those observed during HIV infection. Furthermore, in the investigators' model, HIV products increase cytokine mRNA expression within the rat central nervous system (CNS). HIV enters the CNS shortly after infection; cytokine concentrations, including the somnogenic cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF), are elevated within the CNS during all stages of HIV infection. The investigators hypothesize that altered sleep during HIV infection is due, in part, to HIV-induced increases within the CNS in concentrations of cytokines that enhance sleep (e.g. IL-1, TNF) as well as those that suppress sleep (e.g. IL-1 receptor antagonist (IL-1ra) and IL-10). The investigators will test this working hypothesis by: determining the components of HIV capable of altering sleep (i.e. HIV envelope glycoproteins [gps]), and by elucidating the roles of IL-1, TNF, IL-1ra, and IL-10 in responses to HIV and HIV gps. Finally, they will determine changes in cytokine mRNA expression in brain regions important for the regulation of sleep, in response to the HIV gps. They will use rats instrumented with EEG electrodes, and chronic guide cannulae directed into lateral cerebral ventricles. Sleep-wake activity, and changes in cytokine mRNA expression in the CNS, will be determined after administration of HIV or HIV gps. These experiments should show not only the extent to which cytokines within the CNS contribute to HIV-induced alterations in sleep, but may also suggest new therapeutic approaches for the debilitating symptoms of fatigue and sleepiness that occur during AIDS.