Sirt-1-mediated regulation of NeuroAIDS

Sirt-1介导的神经艾滋病调控 在后抗逆转录病毒(ART)时代，人类免疫缺陷病毒(HIV)感染不再是 一种致命的情况。相反，艾滋病毒感染者会随着慢性感染而变老。因此， HIV感染的后果与正常衰老在不同的人群中重叠并协同作用 器官，尤其是大脑。人们普遍认为，艾滋病毒感染是由中枢神经系统触发的 中枢神经系统(CNS)衰老的几个特征，如认知和运动障碍以及痴呆， 不考虑CD4水平1。然而，这种加速衰老的分子方面 人们对感染艾滋病毒的大脑中的过程知之甚少。在这里，使用非人类灵长类动物模型 对于神经艾滋病、SIV感染猕猴的研究，我们将提供初步证据 感染会触发以前与人类衰老有关的分子标记。我们 建议探索病毒导致表观遗传途径中断的假设 它调节衰老和寿命，这可能是负责增强分子 最终加重与中枢神经系统功能衰退相关的炎症表型 以脑炎为代表。在这个提案中，我们将解决一个重要的问题，即艾滋病毒如何 通过潜在的转录失调促进大脑的快速老化， 并由Sirt-1的水平和功能编排，Sirt-1是一种具有深远意义的分子 对寿命和老化模型的影响。我们研究了Sirt-1与 在对照组和SIV感染猕猴的小胶质细胞中的染色质，并鉴定了一个网络 受Sirt-1调控的基因。将我们的分析范围缩小到启动子内的Sirt-1结合部位，我们 生成了一份可能在炎症性疾病的发展中起关键作用的分子的清单 大脑中的表型。在本应用程序中，我们旨在检查此网络的角色 深入分子，结合中枢神经系统功能障碍和年龄，了解分子和 衰老常见的炎性环境发生深刻变化的机制基础 以及艾滋病毒感染，并协同作用加剧神经综合征，即使在- 艺术时代。

Sirt-1-mediated regulation of NeuroAIDS In the post anti-retrovirals (ART) era, human immunodeficiency virus (HIV) infection is no longer a deadly condition. Rather, HIV+ individuals age with the chronic infection. Therefore, the consequences of HIV infection overlap and synergize with normal senescence in various organs, especially the brain. It is accepted that HIV infection triggers in the Central Nervous System (CNS) several hallmarks of aging, such as cognitive and motor disorders and dementia, regardless of CD4 levels1. However, the molecular aspects underlining this accelerated aging process in HIV-infected brains are poorly understood. Here, using the non-human primate model of neuroAIDS, SIV infection of rhesus macaques, we will provide preliminary evidence that the infection triggers molecular markers that were previously associated to aging in humans. We propose to explore the hypothesis that the virus causes a disruption of an epigenetic pathway that regulates aging and lifespan, which can be responsible for enhancing molecules that aggravate the inflammatory phenotype associated with CNS functional decay, ultimately represented by encephalitis. In this proposal we will address an important problem of how HIV promotes a rapid aging of the brain though a potential dysregulation of transcription, centered and orchestrated by the levels and function of Sirt-1, which is a molecule with profound implications to lifespan and in aging models. We studied the dynamics of Sirt-1 binding to chromatin in microglia from control and SIV-infected macaques, and identified a network of genes regulated by Sirt-1. Narrowing our analysis to in-promoter Sirt-1 binding sites, we generated a list of molecules that may have a critical role in the development of an inflammatory phenotype in the brain. In this application, we aim at examining the role of this network of molecules in depth, integrating CNS dysfunction and age, to understand the molecular and mechanistic basis for deep changes in the inflammatory environment that are common to aging and to HIV infection, and that synergize to aggravate neurological syndromes, even in the post- ART era.