Autonomic nervous system control of HIV-1 replication

自主神经系统控制 HIV-1 复制

• 批准号: 6889974
• 负责人: STEVE W COLE
• 金额: $ 26.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889974
• 关键词: Macaca mulatta; T lymphocyte; antiviral agents; autonomic nervous system; biological signal transduction; clinical research; cytokine; enzyme linked immunosorbent assay; gel mobility shift assay; genetic transcription; human immunodeficiency virus 1; human tissue; immunocytochemistry; lymph; microarray technology; neuroregulation; norepinephrine; polymerase chain reaction; simian immunodeficiency virus; stress; transcription factor; transfection /expression vector; virus genetics; virus infection mechanism; virus load; virus replication

Antiretroviral medications currently represent the only effective means for controlling HIV pathogenesis, but existing drug regimens cannot fully stop viral replication in vivo. It is thus critical to identify physiologic processes that support residual HIV replication during highly active antiretroviral therapy (HAART). Recent data indicate that high levels of activity in the sympathetic division of the autonomic nervous system (ANS) represent an in vivo risk factor for elevated plasma viral load in untreated patients and those receiving HAART. The nervous system has long been known to regulate the activity of certain viral pathogens (e.g., herpes viruses), but little is known about its impact on lentiviruses such as HIV or SIV. ANS neurons innervate the lymphoid organs that serve as major sites of HIV-1 replication in vivo, and T lymphocytes bear beta adrenoreceptors that allow neural modulation of cellular activation, cytokine production, and cell trafficking. In previous studies, we found that the ANS neurotransmitter norepinephrine accelerates HIV-1 replication in vitro by altering cellular vulnerability to infection and enhancing viral gene expression. The proposed studies seek to define the molecular mechanisms of these effects. Specifically, these studies aim to: 1. Identify transcriptional mediators of ANS-induced HIV-1 gene expression. 2. Define ANS effects on soluble factors that modulate HIV-1 replication. 3. Assess interactions between ANS neurons and HIV/SIV replication in lymphoid tissues. These studies will establish a virologic framework for interventions aimed at blocking ANS support of residual HIV replication during HAART. Such interventions would enhance the efficacy of current antiretroviral treatment regimens by opposing physiologic processes that support ongoing pathogenesis.

抗逆转录病毒药物目前是控制HIV发病机制的唯一有效手段，但现有的药物治疗方案不能完全阻止病毒在体内的复制。 因此，确定在高效抗逆转录病毒治疗（HAART）期间支持残留HIV复制的生理过程至关重要。 最近的数据表明，在自主神经系统（ANS）的交感神经分支的高水平的活动代表了在未经治疗的患者和那些接受HAART的血浆病毒载量升高的体内危险因素。 长期以来，人们已经知道神经系统调节某些病毒病原体的活性（例如，疱疹病毒），但很少有人知道它对慢病毒如HIV或SIV的影响。 ANS神经元支配充当体内HIV-1复制的主要位点的淋巴器官，并且T淋巴细胞具有允许细胞活化、细胞因子产生和细胞运输的神经调节的β肾上腺素受体。 在以前的研究中，我们发现ANS神经递质去甲肾上腺素通过改变细胞对感染的脆弱性和增强病毒基因表达来加速HIV-1的体外复制。 拟议的研究旨在确定这些影响的分子机制。 具体而言，这些研究旨在：1。确定ANS诱导的HIV-1基因表达的转录介质。2.确定ANS对调节HIV-1复制的可溶性因子的影响。3.评估ANS神经元与淋巴组织中HIV/SIV复制之间的相互作用。这些研究将建立一个病毒学框架的干预措施，旨在阻止ANS支持残留的艾滋病毒复制在HAART。 这种干预措施将通过对抗支持持续发病的生理过程来提高目前抗逆转录病毒治疗方案的功效。

项目成果

Social regulation of gene expression in human leukocytes.

• DOI: 10.1186/gb-2007-8-9-r189
• 发表时间: 2007
• 期刊: GENOME BIOLOGY
• 影响因子: 12.3
• 作者: Cole, Steve W;Hawkley, Louise C;Arevalo, Jesusa M;Sung, Caroline Y;Rose, Robert M;Cacioppo, John T
• 通讯作者: Cacioppo, John T