Alteration of circadian rhythm and sleep by HIV protein Tat

HIV 蛋白 Tat 改变昼夜节律和睡眠

• 批准号: 8136005
• 负责人: JIAN M DING
• 金额: $ 30.57万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136005
• 关键词: Acquired Immunodeficiency Syndrome; Action Potentials; Acute; Affect; Animal Feed; Animals; Astrocytes; Attention; Blood - brain barrier anatomy; Blood Circulation; Body Temperature; Brain; Breeding; CD4 Lymphocyte Count; Calcium; Cardiovascular system; Cells; Circadian Dysregulation; Circadian Rhythms; Clinical; Complex; Corpus striatum structure; Data; Diet; Disease; Dose; Doxycycline; Electroencephalography; Endocrine; Exhibits; Extracellular Space; Glial Fibrillary Acidic Protein; Gliosis; Glutamate Receptor; Glutamates; HIV; HIV Envelope Protein gp120; HIV Infections; HIV tat Protein; HIV-1; Hippocampus (Brain); Hormones; Hour; Human; Hydrocortisone; Hypothalamic structure; In Vitro; Indiana; Individual; Infection; Interruption; Lead; Light; Long-Term Effects; Lymphocyte; Lymphocyte Count; Microglia; Modeling; Molecular; Motor Activity; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Neuropathogenesis; Neurosecretory Systems; Organ; Patients; Pattern; Performance; Phase; Physical activity; Physiological; Play; Process; Production; Property; Regulation; Research; Retinal; Reverse Transcriptase Polymerase Chain Reaction; Role; Route; Series; Severities; Signal Transduction; Sleep; Sleep Wake Cycle; Slice; Staging; Structural Protein; Structure; System; TNF gene; Testing; Tetracyclines; Therapeutic; Third ventricle structure; Time; Transgenes; Transgenic Mice; Universities; Viral; Viral Proteins; Wild Type Mouse; Work; base; body system; circadian pacemaker; cytokine; experience; gp-120 Antigen; immune function; in vivo; light entrainment; monocyte; mouse model; nervous system disorder; neurotransmission; neutralizing antibody; novel; particle; public health relevance; relating to nervous system; repaired; suprachiasmatic nucleus; tat Protein

DESCRIPTION (provided by applicant): Circadian rhythms are physiological functions that manifest a 24-hr period, including sleep-wake cycle, body temperature, neuroendocrine and neuroimmune interactions. Healthy individuals have a robust circadian oscillation of circulating lymphocytes with the peak at night, but this circadian rhythm is diminished in HIV-infected patients. In fact, disruption of sleep patterns and circadian rhythms are among the most common disorders in the early stages of HIV infection. A circadian clock located in the suprachiasmaticnucleus (SCN) of the hypothalamus regulates the circadian rhythms of all organ systems. We hypothesize that the alteration of sleep patterns and circadian rhythms in HIV infected patients may be caused by disrupting this central circadian clock. HIV-1 infection has been associated with a variety of neurological disorders. Although the neuropathogenesis of HIV-1 is complex, the viral protein Tat appears to play an important role. The SCN is located in the base on the third cerebral ventricle surrounded by the hypothalamic circumventricular organs (CVO). The CVOs are among the most permeable structures in the brain. Since Tat can be secreted to the circulation from infected cells and Tat can readily cross the blood brain barrier, we hypothesize that the SCN may be among the earliest target of Tat. Although the exact mechanism by which HIV-1 infection affects neuronal function remains unknown, Tat may play a pivotal role in the alteration of circadian rhythms and sleep during HIV infection. Our previous study showed that acute application of Tat directly to the SCN both in vitro and in vivo could reset the circadian clock (Clark et al 2005). To assess the long term effect of Tat to the sleep and circadian timing system, we used the tetracycline-dependent and brain (GFAP) specific Tat transgenic mice. RT-PCR confirmed Tat expression in the SCN following doxycycline diet. The alteration of circadian rhythm and sleep pattern in the Tat-expressing mouse is comparable to clinical findings, characterized with reduced motor activity and impaired synchronization to the environmental light dark cycle. EEG analysis showed altered delta power in the Tat mice. The EEG data recorded from the Tat mice are similar to findings in AIDS patients (Darko et al 1995; Polich et al 2000). Since little is known about viral- induced alteration of circadian rhythm and sleep at a cellular and molecular level, this research may yield novel understanding of viral neuropathogenesis and potentially lead to therapeutic approaches to circadian rhythm disorders experienced by HIV-infected patients. PUBLIC HEALTH RELEVANCE: Alteration of circadian rhythm and sleep occurs in AIDS patients with different disease stages and with a wide range of CD4 counts. Although the exact mechanism of HIV-1 neuropathogenesis remains poorly understood, viral proteins (gp41, gp120, and Tat) are thought to play a major role in the neural AIDS. Among these viral proteins, Tat is important because it can be secreted from infected cells to the extracellular space, subsequently affecting nearby neurons. Since our previous study demonstrated that Tat could reset the circadian clock in the brain, the suprachiasmatic nucleus (SCN), we hypothesize that the disruption of circadian rhythm and sleep during HIV infection could be a consequence of Tat on the SCN. To test our hypothesis, we used a transgenic mouse model that can selectively induce the expression of Tat in the brain when doxycycline is administered to the animals. RT-PCR confirmed Tat expression in the mouse SCN two weeks after feeding the animals with the doxycycline diet. Interestingly, the alteration of circadian rhythm in the Tat-expressing mouse is comparable to that found in the HIV-infected patients, characterized with reduced motor activity and impaired synchronization to the environmental light dark cycle. EEG analysis showed decreased delta power in the Tat transgenic mice compared to wild type mice.

描述（由申请人提供）：昼夜节律是表现为 24 小时周期的生理功能，包括睡眠-觉醒周期、体温、神经内分泌和神经免疫相互作用。健康个体的循环淋巴细胞具有强烈的昼夜节律振荡，在夜间达到峰值，但这种昼夜节律在艾滋病毒感染者中减弱。事实上，睡眠模式和昼夜节律的破坏是艾滋病毒感染早期最常见的疾病之一。位于下丘脑视交叉上核（SCN）的生物钟调节所有器官系统的昼夜节律。我们假设艾滋病毒感染者睡眠模式和昼夜节律的改变可能是由于这个中央生物钟被扰乱引起的。 HIV-1 感染与多种神经系统疾病有关。尽管 HIV-1 的神经发病机制很复杂，但病毒蛋白 Tat 似乎发挥着重要作用。 SCN 位于第三脑室的基部，被下丘脑室周器官 (CVO) 包围。 CVO 是大脑中渗透性最强的结构之一。由于Tat可以从受感染的细胞分泌到循环中，并且Tat可以很容易地穿过血脑屏障，因此我们假设SCN可能是Tat最早的靶标之一。尽管 HIV-1 感染影响神经元功能的确切机制仍不清楚，但 Tat 可能在 HIV 感染期间昼夜节律和睡眠的改变中发挥关键作用。我们之前的研究表明，在体外和体内直接将 Tat 直接作用于 SCN 可以重置生物钟 (Clark et al 2005)。为了评估 Tat 对睡眠和昼夜节律计时系统的长期影响，我们使用了四环素依赖性脑 (GFAP) 特异性 Tat 转基因小鼠。 RT-PCR 证实了强力霉素饮食后 SCN 中 Tat 的表达。表达 Tat 的小鼠昼夜节律和睡眠模式的改变与临床发现相当，其特征是运动活动减少和与环境明暗周期的同步性受损。脑电图分析显示 Tat 小鼠的 delta 功率发生了变化。 Tat 小鼠记录的脑电图数据与艾滋病患者的结果相似（Darko 等人 1995 年；Polich 等人 2000 年）。由于人们对病毒引起的昼夜节律和睡眠在细胞和分子水平上的改变知之甚少，这项研究可能会对病毒神经发病机制产生新的理解，并有可能为艾滋病毒感染者所经历的昼夜节律紊乱提供治疗方法。 公共卫生相关性：不同疾病阶段和不同 CD4 计数的艾滋病患者会出现昼夜节律和睡眠的改变。尽管 HIV-1 神经发病机制的确切机制仍知之甚少，但病毒蛋白（gp41、gp120 和 Tat）被认为在神经 AIDS 中发挥着重要作用。在这些病毒蛋白中，Tat 很重要，因为它可以从受感染的细胞分泌到细胞外空间，随后影响附近的神经元。由于我们之前的研究表明 Tat 可以重置大脑视交叉上核 (SCN) 的生物钟，因此我们推测 HIV 感染期间昼夜节律和睡眠的破坏可能是 Tat 对 SCN 的影响。为了检验我们的假设，我们使用了转基因小鼠模型，当给动物施用多西环素时，该模型可以选择性诱导大脑中 Tat 的表达。 RT-PCR 证实在给小鼠喂食强力霉素饮食两周后，小鼠 SCN 中存在 Tat 表达。有趣的是，表达 Tat 的小鼠昼夜节律的改变与 HIV 感染患者的昼夜节律改变相当，其特点是运动活动减少和与环境明暗周期的同步受损。脑电图分析显示，与野生型小鼠相比，Tat 转基因小鼠的 delta 功率降低。