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Role and Cell Cycle Mechanisms of pp71 in HCMV Infection

pp71在HCMV感染中的作用和细胞周期机制

基本信息

批准号：
7498688
负责人：
ROBERT F KALEJTA
金额：
$ 29.4万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2009-09-29
项目状态：
已结题

项目摘要

Human cytomegalovirus (HCMV) is a significant human pathogen that infects the majority of the world's population. Primary lytic replication or reactivation of latent infections causes severe disease in patients with suppressed immune function. Furthermore, many studies link HCMV infection with proliferative diseases such as cancer, restenosis, and transplant-associated vasculopathy. Because the HCMV pp71 protein initiates the lytic replication cycle, stimulates cell cycle progression, and may control latency, it is a potential target for antiviral therapy. We plan to examine the molecular mechanisms behind the different activities of pp71, and the role that these different activities play during lytic and latent viral replication. We have already discovered and published the mechanism through which pp71 activates viral immediate early (IE) gene expression during lytic replication: it degrades the cellular transcriptional represser Daxx. Here we will generate HCMV mutants that are resistant to Daxx-mediated repression, and use them to further our understanding of IE gene expression during lytic infection, and determine if the same mechanism applies during the establishment and/or reactivation of latency. We have previously shown that pp71 stimulates cell cycle progression by degrading the Rb protein. Here we will examine how pp71 and other viral proteins cooperate to modulate the activity of Rb (and the related p130 protein) during lytic and latent infections. Recently, we discovered that pp71 degrades another cellular protein that modulates transcription, the cell cycle, and innate immunity. Here we will determine how the ability of pp71 to degrade this protein affects each of those processes in HCMV-infected cells. This proposal builds upon our published and unpublished discoveries, and will use molecular and genetic approaches to determine not only the mechanisms used by pp71 to promote viral transcription, induce cell cycle progression, and potentially evade innate immunity, but also the roles that these activities of pp71 play during both lytic and latent infections. Thus our long-term goal is to determine the molecular mechanisms behind each function of pp71 in HCMV-infected cells, and the contribution that the different activities of pp71 make during lytic and latent viral replication cycles. This information should allow us to design antiviral therapies targeted to the functions of pp71 required for viral replication to treat both proliferative and non-proliferative diseases associated with HCMV infection.

人巨细胞病毒（HCMV）是一种重要的人类病原体，感染世界上大多数人，人口原发性裂解性复制或潜伏性感染的再激活导致严重疾病，抑制免疫功能此外，许多研究将HCMV感染与增殖性疾病联系起来例如癌症、再狭窄和移植相关血管病变。因为HCMV pp 71蛋白启动裂解复制周期，刺激细胞周期进程，并可能控制潜伏期，这是一种潜在的作为抗病毒治疗靶点。我们计划研究不同活动背后的分子机制， pp 71，以及这些不同的活性在裂解和潜伏病毒复制过程中所起的作用。我们已经发现并发表了pp 71激活病毒立即早期（IE）基因的机制在裂解复制过程中表达：它降解细胞转录阻遏物Daxx。这里我们将产生对Daxx介导的抑制有抗性的HCMV突变体，并使用它们来进一步我们的研究。了解IE基因在裂解感染过程中的表达，并确定是否适用相同的机制在等待时间的建立和/或重新激活期间。我们之前已经证明pp 71刺激细胞通过降解Rb蛋白来抑制细胞周期进程。在这里，我们将研究pp 71和其他病毒蛋白如何协同调节Rb（和相关的p130蛋白）在裂解和潜伏感染期间的活性。最近，我们发现pp 71降解另一种调节转录的细胞蛋白，周期和先天免疫在这里，我们将确定pp 71降解这种蛋白质的能力如何影响每一个过程都在HCMV感染的细胞中进行。这一建议建立在我们已发表和未发表的发现，并将使用分子和遗传方法，以确定不仅使用的机制， pp 71促进病毒转录，诱导细胞周期进程，并可能逃避先天免疫，但还研究了PP 71的这些活性在溶解性感染和潜伏性感染中所起的作用。我们的长期目的是确定pp 71在HCMV感染细胞中每种功能背后的分子机制， PP 71的不同活性在裂解和潜伏病毒复制周期中的作用。这这些信息应该使我们能够设计针对病毒感染所需的pp 71功能的抗病毒疗法。复制以治疗与HCMV感染相关的增殖性和非增殖性疾病。