Determination of the mechanisms of action of a cytomegalovirus chemokine receptor homologue in pathogenesis

许多疱疹病毒编码的蛋白质与我们免疫系统的蛋白质相似。病毒利用这些盗版蛋白，使其能够在被感染的个体中复制和持续存在，通常是通过逃避或从正常的免疫反应中获得优势。该项目将研究在人类和动物疱疹病毒（特别是巨细胞病毒（CMV））中发现的一种这样的蛋白质的作用，这种蛋白质与结合免疫信号分子（趋化因子）的细胞表面蛋白（受体）保守。趋化因子是早期感染反应中的重要蛋白质。趋化因子与其受体的结合在细胞内启动一系列信号，这些信号对细胞对环境刺激的反应有深远的影响。因此，人们认为疱疹病毒获得了趋化因子受体来修饰或对免疫反应作出反应，导致受感染细胞不顾趋化因子信号或响应趋化因子信号而表现异常。该项目将确定这种巨细胞病毒特异性蛋白如何影响巨细胞病毒感染细胞的功能，以及这可能如何促进病毒在感染宿主中的复制、传播和持久性。我们还将设计cmv，其中目标蛋白的活性可以通过施用原型抗病毒药物来抑制。如果发现抑制这种蛋白的活性可以减少病毒的复制、传播或持续存在，那么这将证明这种类型的蛋白将是开发抗巨细胞病毒感染新药的合适靶点。巨细胞病毒可导致新生儿（在子宫感染后）和免疫抑制者（如新生儿）严重（可能危及生命）疾病。器官移植受者和艾滋病患者)。我们的研究将提高我们对特定巨细胞病毒蛋白对疾病的贡献的理解，从而有助于减少巨细胞病毒感染的影响。

A number of herpesviruses encode proteins that are similar to proteins of our immune system. These pirated proteins are exploited by the virus to enable it to replicate and persist in the infected individual, usually by evading or gaining advantage from the normal immune response. This project will investigate the role of one such protein found in both human and animal herpesviruses (specifically cytomegaloviruses (CMV)) that is conserved with cellular cell surface proteins (receptors) that bind immune signaling molecules (chemokines). Chemokines are important proteins in the early response to infection. Binding of chemokines to their receptors initiates a cascade of signals within the cell that has profound effects on cellular responses to environmental stimuli. Thus, it is believed that herpesviruses have acquired chemokine receptors to modify or react to the immune response, causing infected cells to behave abnormally either despite or in response to chemokine signals. This project will determine how this CMV specific protein affects the function of cells that CMV infects and how this may promote virus replication, dissemination and persistence in infected hosts. We will also engineer CMVs where the activity of the target protein can be inhibited by administration of prototype antiviral drugs. If inhibition of the activity of the protein is found to reduce virus replication, dissemination or persistence, then this will demonstrate that this type of protein would be a suitable target for the development of novel drugs active against CMV infections. CMV can cause serious (potentially life threatening) disease in newborn children (following infection in the uterus) and immunosuppressed people (eg. organ transplant recipients and people with HIV-AIDS). Our studies will improve our understanding of the contribution of a specific CMV protein to disease, thereby assisting efforts to reduce the impact of CMV infections.