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

第三个项目。HIV-1和HIF-1 a信号通路之间的正反馈相互作用。 脑的HIV-1感染通常导致慢性炎症、毒素分泌和 氧化应激氧化应激因素，如过氧化氢，超氧化物，最值得注意的是，缺氧 诱导因子1 α（HIF-1 a）可通过激活HIV-1而加速疾病发展和进展 复制和细胞功能失调。缺氧诱导因子-1a是一种转录激活因子，在转录过程中发挥主要作用 细胞和全身氧平衡的调节剂。艾滋病脑组织学评价 脑炎揭示了包括小胶质细胞、巨噬细胞和星形胶质细胞在内的几种细胞中HIF-1 α的活化， 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，委员会认为， 来自细胞培养研究的结果显示在感染原代小胶质细胞后HIF-1 a水平升高 HIV-1进一步检测HIF-1a在HIV-1蛋白存在下的表达，提示HIF-1a在HIV-1蛋白存在下的主要表达是由HIF-1a的表达决定的。 Vpr在转录和转录后水平诱导HIF-1 α的作用。同时分子 Vpr升高HIF-1 a的事件仍有待研究，我们的初步观察 提示Vpr通过与Sp1和NF-κ B转录的协同作用激活HIF-1 α的转录 因子，并通过一系列涉及TNF α、反应性TNF α和TNF α的反应器增强HIF-1 α蛋白的稳定性。 氧自由基（ROS）和MAPK。有趣的是，HIF-1a水平的增加对HIV-1有影响 基因表达和几种其它宿主细胞功能。例如，通过与p65进行交叉通信， NF-κ B亚基HIF-1 α可刺激LTR转录。此外，通过影响几种细胞的表达， 包括p21、HIF-1a在内的细胞周期控制因子可使细胞周期进程失调，影响DMA修复， 诱导细胞异常，包括线粒体，可能是细胞色素c释放。由此可见， HIF-1 α和HIV-1调节蛋白Vpr之间的相互作用及其与几种HIV-1调节蛋白的协同作用， 关键细胞蛋白，在宿主体内平衡和病毒基因表达和复制中起着重要作用， CNS。本项目的实验设计将包括一系列的分子学、病毒学和组织学研究。 本发明的目的是提供一种方法来阐明HIF-1 α参与HIV-1诱导的CNS疾病的机制。成果 这些研究将阐明HIV-1利用细胞机制进行其免疫的未定义的途径。 自己的优势。 一

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