Positive feedback interaction between HIV-1 and Hif-1 signaling

HIV-1 和 Hif-1 信号传导之间的正反馈相互作用

• 批准号: 7923811
• 负责人: BASSEL E SAWAYA
• 金额: $ 29.53万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7923811
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Affect; Apoptotic; Astrocytes; Binding; Biological; Biological Markers; Biology; Brain; Cell Culture Techniques; Cell Cycle; Cell Cycle Progression; Cell Nucleus; Cell physiology; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Chronic; Clinical; DNA; Data; Dementia; Detection; Development; Disease; EP300 gene; Encephalitis; Equilibrium; Evaluation; Event; Experimental Designs; Feedback; Gene Expression; Genetic Transcription; HIV-1; Homeostasis; Hydrogen Peroxide; Hypoxia; Impairment; Infection; Inflammation; Injury; Light; MAP Kinase Gene; MAPK14 gene; Mediating; Microglia; Mitochondria; Modification; Molecular; Neurologic; Neuropathogenesis; Outcome Study; Oxidative Stress; Oxidative Stress Induction; Oxygen; Pathway interactions; Patients; Permeability; Phosphorylation; Play; Production; Proteins; Reactive Oxygen Species; Role; Sampling; Seminal; Series; Services; Signal Pathway; Signal Transduction; Sp1 Transcription Factor; Stress; Superoxides; T-Lymphocyte; Testing; Therapeutic; Toxin; Transcription Coactivator; Translating; Viral Genes; Virus; Virus Replication; brain cell; brain tissue; caspase-3; cytochrome c; genetic regulatory protein; hypoxia inducible factor 1; macrophage; p65; programs; promoter; repaired; tool; transcription factor; virus host interaction

Project #3. Positive feedback interaction between HIV-1 and HIF-1 a signaling pathway. HIV-1 infection of brain usually results in chronic inflammation, secretion of toxins, and induction of oxidative stress. Oxidative stress factors such as hydrogen peroxide, superoxide, and most notably, hypoxia inducible factor 1 alpha (HIF-1 a) can accelerate disease development and progression by activating HIV-1 replication and dysregulating cell function. HIF-1 a is a transcriptional activator that functions as a chief regulator of cellular and systemic oxygen homeostasis. Histological evaluation of AIDS brains with encephalitis revealed activation of HIF-1 a in several cells including microglia, macrophages, and astrocytes, all of which are targets for infection with HIV-1 and support its replication to various degrees. Accordingly, results from cell culture studies showed elevated levels of HIF-1 a upon infection of primary microglial cells with HIV-1. Further examination of HIF-1a expression in the presence of HIV-1 proteins suggested a major role for Vpr in induction of HIF-1 a at the transcription and post-transcription levels. While the molecular events involved in the elevation of HIF-1 a by Vpr remain to be investigated, our preliminary observations pointed to the activation of HIF-1 a transcription via cooperation of Vpr with the Sp1 and NF-icB transcription factors, and enhancement of the stability of HIF-1 oc protein by a series of reactors involving TNFoc, reactive oxygen species (ROS) and MAPK. Interestingly, the increase in the level of HIF-1 a has an impact on HIV-1 gene expression and several other host cell functions. For example, by cross-communicating with the p65 subunit of NF-icB, HIF-1 a can stimulate LTR transcription. Further, by influencing expression of several cell cycle controllers, including p21, HIF-1a can dysregulate cell cycle progression, affecting DMA repair and induce cellular abnormalities including mitochondria, presumably cytochrome c release. Thus, it is evident that the interplay between HIF-1 a and the HIV-1 regulatory proteins, Vpr and its cooperativity with several key cellular proteins, plays a seminal role in host homeostasis and viral gene expression and replication in CNS. The experimental design in this project will include a series of molecular, virological and histological approaches to unravel the mechanism of HIF-1 a involvement in HIV-1 induced CNS diseases. The outcome of these studies will shed light on undefined pathways by which HIV-1 exploits the cellular machinery to its own advantage. a

项目3.HIV-1和HIF-1信号通路之间的正反馈相互作用. HIV-1感染大脑通常会导致慢性炎症、毒素分泌和诱导 氧化应激。氧化应激因素，如过氧化氢、超氧化物，最显著的是缺氧 诱导因子1α(HIF-1 a)可通过激活HIV-1来加速疾病的发生和发展 复制和细胞功能失调。HIF-1a是一种转录激活物，起着首席的作用。 细胞和全身氧平衡的调节器。艾滋病患者脑组织的组织学评价 脑炎发现HIF-1α在几个细胞中激活，包括小胶质细胞、巨噬细胞和星形胶质细胞， 所有这些都是HIV-1感染的目标，并在不同程度上支持其复制。因此， 细胞培养研究结果显示，在原代小胶质细胞感染时，HIF-1 a水平升高。 携带HIV-1病毒。在存在HIV-1蛋白的情况下进一步检测HIF-1a的表达表明 VPR在转录和转录后水平诱导HIF-1a中的作用。而分子 VPR升高HIF-1α的事件仍有待调查，我们的初步观察 指出HIF-1α转录通过VPR与Sp1和NF-ICB转录的协同作用而被激活 影响HIF-1oc蛋白稳定性的因素，以及利用一系列涉及TNFoc的反应性反应器提高HIF-1蛋白稳定性 氧物种(ROS)和MAPK。有趣的是，HIF-1a水平的增加对HIV-1有影响 基因表达和其他几种宿主细胞功能。例如，通过与P65的交叉通信 核因子-ICB亚单位HIF-1α可刺激LTR转录。此外，通过影响几个细胞的表达 包括p21、HIF-1a在内的周期调控因子可以失调细胞周期进程，影响DMA修复和 导致细胞异常，包括线粒体，可能是细胞色素c的释放。由此可见， HIF-1α与HIV-1调节蛋白、VPR之间的相互作用及其与几种 关键细胞蛋白，在宿主体内平衡和病毒基因表达和复制中发挥重要作用 中枢神经系统。该项目的实验设计将包括一系列分子、病毒学和组织学 HIF-1α参与HIV-1诱导的中枢神经系统疾病机制的研究进展结果是 这些研究将揭示HIV-1利用细胞机制达到其自身功能的未知途径 自己的优势。 一个