Reciprocal interaction of TGFB and Wnt in HIV-1 expressi

TGFB 和 Wnt 在 HIV-1 表达中的相互作用

• 批准号: 6672687
• 负责人: BASSEL E SAWAYA
• 金额: $ 26.93万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6672687
• 关键词: AIDS /HIV neuropathy; biological signal transduction; gene expression; genetic regulatory element; human immunodeficiency virus 1; neurogenetics; neurotropic virus; tissue /cell culture; transcription factor; transforming growth factors; virus genetics; virus infection mechanism; virus protein

The control region of the HIV-1 genome is composed of multiple distinct regulatory elements, each exerting their effect on viral gene transcription by interacting with various cellular proteins. Some of the participant proteins are inducible and their expressiodactivity in cells is regulated by external stimuli such as cytokines and immunomodulators. These cytokines, such as TNFalpha and TGFbeta, whose levels are increased in patients with AIDS can trigger distinct signaling pathways that modulate expression of the HIV-1 genome during the course of infection. Examination of the TGFbeta signaling pathway in human CNS cell lines has revealed that downstream regulators of this network, i.e. Smad-3 and Smad-4, can modulate transcription of the viral genome at the immediate early stage after infection, when HIV-1 Tat is the key viral protein that is produced. Evidently, Smad-3 and Smad-4, by associating with the CEBP transcription factor, a potent stimulator of HIV-1, modulates the level of viral gene expression in human astrocytes. At the early and late phases of viral infection, when the viral regulatory proteins Tat and Vpr are produced, respectively, other signaling pathways such as Wnt, which is important for neural cell development and function, may play a central role by controlling the Tat stimulatory activity of viral gene transcription. This event is mediated through the interaction of Wnt regulatory proteins, TCF-4 and beta-catenin with Tat and its cellular partner, cyclin T. These observations provide a strong basis to hypothesize that the physical and functional communication between the signaling pathways which are operative in CNS cells, along with the HIV-1 genome and its regulatory proteins, can dictate the level of viral gene expression and replication during the course of disease in the brain. In this research project we will utilize molecular biological, virological, and biochemical approaches to decipher the mechanism(s) whereby signaling pathways and their downstream regulators affect the state of viral gene expression at the immediate early, early, and late phases of CNS infection. The outcome of these studies will provide important information which can be utilized in devising molecular strategies toward inhibition of viral gene expression by inducing host factors.

HIV-1基因组的控制区由多个不同的调控元件组成，每个调控元件都通过与各种细胞蛋白相互作用来影响病毒基因转录。一些参与蛋白是可诱导的，它们在细胞中的表达活性受细胞因子和免疫调节剂等外部刺激的调节。这些细胞因子，如TNFalpha和TGFbeta，其水平在艾滋病患者中升高，可以触发不同的信号通路，在感染过程中调节HIV-1基因组的表达。对人中枢神经系统细胞系TGFbeta信号通路的研究表明，该网络的下游调节因子，即Smad-3和Smad-4，可以在感染后的早期阶段调节病毒基因组的转录，此时HIV-1 Tat是产生的关键病毒蛋白。显然，Smad-3和Smad-4通过与CEBP转录因子（一种有效的HIV-1刺激因子）相关联，调节人类星形胶质细胞中病毒基因的表达水平。在病毒感染的早期和晚期，当病毒调节蛋白Tat和Vpr分别产生时，其他信号通路，如对神经细胞发育和功能重要的Wnt，可能通过控制病毒基因转录的Tat刺激活性发挥核心作用。这一事件是通过Wnt调节蛋白、TCF-4和β -连环蛋白与Tat及其细胞伴侣细胞周期蛋白t的相互作用介导的。这些观察结果为假设中枢神经系统细胞中起作用的信号通路之间的物理和功能交流以及HIV-1基因组及其调节蛋白可以决定大脑疾病过程中病毒基因的表达和复制水平提供了强有力的基础。在本研究项目中，我们将利用分子生物学、病毒学和生化方法来破译信号通路及其下游调节因子在中枢神经系统感染的早期、早期和晚期影响病毒基因表达状态的机制。这些研究结果将为设计通过诱导宿主因子抑制病毒基因表达的分子策略提供重要信息。