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，它受到以下因素的相互作用的调节： 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， 个体经历使人衰弱的白天疲劳和困倦。 在 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改变。 这些变化发生在 在艾滋病发作之前，在没有 药物滥用或与焦虑相关的精神症状，或 萧条 HIV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 证明了啮齿动物模型用于研究细胞因子作用的实用性 和神经系统的影响 研究人员发现，在一个老鼠模型中， 睡眠，HIV产物以类似于 在艾滋病毒感染期间观察到的。 此外，在调查人员的 模型中，HIV产物增加大鼠中枢神经系统中细胞因子mRNA的表达。 神经系统（CNS）。 HIV在感染后不久进入CNS;细胞因子 浓度，包括促睡眠细胞因子白细胞介素-1（IL-1）和 肿瘤坏死因子（TNF）在所有阶段的CNS内均升高 艾滋病毒感染。 研究人员假设， HIV感染的部分原因是HIV诱导的CNS内 增强睡眠的细胞因子（例如IL-1、TNF）的浓度以及 抑制睡眠的那些（例如IL-1受体拮抗剂（IL-1 ra）和 IL-10）。 研究人员将通过以下方式检验这一工作假设： 确定能够改变睡眠的HIV组分（即HIV 包膜糖蛋白[GPS]），并通过阐明IL-1，TNF， IL-1 ra和IL-10对HIV和HIV gps的应答。 最后，他们会 确定脑区细胞因子mRNA表达的变化， 睡眠的调节，以应对艾滋病全球定位系统。 他们会用老鼠 使用EEG电极和慢性引导插管插入 侧脑室 睡眠-觉醒活动和细胞因子的变化 将在给予HIV后测定CNS中的mRNA表达 或者艾滋病全球定位系统 这些实验不仅应该表明 CNS内的细胞因子有助于HIV诱导的睡眠改变， 也可能提出新的治疗方法， 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.