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: 8312638
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312638
• 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(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。健康人的循环淋巴细胞有很强的昼夜节律振荡，在夜间达到峰值，但在HIV感染的患者中这种昼夜节律减弱。事实上，睡眠模式和昼夜节律的紊乱是艾滋病毒感染早期最常见的障碍之一。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。我们推测，HIV感染患者的睡眠模式和昼夜节律的改变可能是由于扰乱了这一中心生物钟造成的。HIV-1感染与多种神经疾病有关。虽然HIV-1的神经发病机制很复杂，但病毒蛋白Tat似乎扮演着重要的角色。SCN位于第三脑室底部，周围环绕着下丘脑室周器官(CVO)。CVO是大脑中最具渗透性的结构之一。由于TAT可以从感染细胞分泌到循环中，而且TAT很容易通过血脑屏障，我们推测SCN可能是TAT最早的靶点之一。虽然HIV-1感染影响神经功能的确切机制尚不清楚，但Tat可能在HIV感染过程中昼夜节律和睡眠的改变中发挥关键作用。我们先前的研究表明，在体外和体内将TAT直接应用于SCN可以重置生物钟(Clark等人，2005年)。为了评估TAT对睡眠和昼夜节律系统的长期影响，我们使用了四环素依赖和脑(GFAP)特异性TAT转基因小鼠。RT-PCR证实了多西环素饮食后SCN中TAT的表达。表达TAT的小鼠的昼夜节律和睡眠模式的改变与临床结果相似，其特征是运动活动减少，与环境光暗周期的同步性受损。脑电分析显示，TAT小鼠的Delta功率发生了变化。从TAT小鼠记录的脑电数据与艾滋病患者的发现相似(Darko等人，1995年；Polich等人，2000年)。由于在细胞和分子水平上对病毒诱导的昼夜节律和睡眠的改变知之甚少，这项研究可能会对病毒的神经发病机制产生新的理解，并可能导致治疗艾滋病毒感染患者经历的昼夜节律紊乱的方法。 公共卫生相关性：不同疾病阶段的艾滋病患者的昼夜节律和睡眠发生改变，且CD4计数范围很大。虽然HIV-1神经发病的确切机制尚不清楚，但病毒蛋白(gp41、gp120和Tat)被认为在神经性艾滋病中起主要作用。在这些病毒蛋白中，TAT很重要，因为它可以从感染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可以重置大脑中的生物钟-视交叉上核(SCN)，我们假设在HIV感染期间昼夜节律和睡眠的中断可能是SCN上的TAT的结果。为了验证我们的假设，我们使用了一个转基因小鼠模型，当给动物注射多西环素时，该模型可以选择性地诱导大脑中TAT的表达。用多西环素饲料喂养小鼠两周后，RT-PCR证实了小鼠SCN中TAT的表达。有趣的是，表达TAT的小鼠的昼夜节律变化与HIV感染患者的相似，特征是运动活动减少，与环境光暗周期的同步性受损。脑电分析显示，与野生型小鼠相比，TAT转基因小鼠的Delta功率降低。