Reciprocal interaction of TGFB and Wnt in HIV-1 expressi

HIV-1基因组的控制区由多个不同的调控元件组成，每个调控元件通过与各种细胞蛋白相互作用对病毒基因转录产生影响。一些参与蛋白质是可诱导的，它们在细胞中的表达活性受外部刺激如细胞因子和免疫调节剂的调节。这些细胞因子，如TNF α和TGF β，其水平在AIDS患者中增加，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CNS细胞系中TGF β信号传导途径的研究表明，当HIV-1达特是产生的关键病毒蛋白时，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。显然，Smad-3和Smad-4通过与CEBP转录因子（HIV-1的有效刺激物）结合，调节人类星形胶质细胞中病毒基因表达的水平。在病毒感染的早期和晚期，当病毒调节蛋白达特和Vpr分别产生时，其他信号传导途径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达特刺激活性而发挥核心作用。该事件通过Wnt调节蛋白、TCF-4和β-连环蛋白与达特及其细胞伴侣细胞周期蛋白T的相互作用介导。这些观察结果提供了一个强有力的基础来假设，在CNS细胞中起作用的信号传导途径之间的物理和功能通信，沿着HIV-1基因组及其调节蛋白，可以决定在脑中疾病过程中病毒基因表达和复制的水平。在这个研究项目中，我们将利用分子生物学，病毒学和生物化学的方法来破译的机制（S），信号通路及其下游调节影响病毒基因表达的状态，在即时的早期，早期和晚期阶段的中枢神经系统感染。这些研究的结果将提供重要的信息，可用于设计通过诱导宿主因子抑制病毒基因表达的分子策略。

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.