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: 8286324
• 负责人: BASSEL E SAWAYA
• 金额: $ 29.23万
• 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/8286324
• 关键词: 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与HIF-1信号通路的正反馈相互作用。