The Role of US28 During HCMV Latency

US28 在 HCMV 潜伏期中的作用

• 批准号: 8948751
• 负责人: CHRISTINE M O'CONNOR
• 金额: $ 25.35万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8948751
• 关键词: Adult; Agonist; Antiviral Agents; Area; Binding; Biochemical; Biological; Biological Process; Biology; CD34 gene; CREB1 gene; Cell Culture Techniques; Cell Differentiation process; Cells; Coupled; Cytomegalovirus; Data; Development; Disease; Environment; Exhibits; Fetus; Fibroblasts; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Goals; Hematopoietic; Hematopoietic stem cells; Homologous Gene; Immunocompromised Host; Individual; Infection; Investigation; Knowledge; Lead; Life; Lytic; Lytic Phase; Maintenance; Mediating; Messenger RNA; Methodology; Methods; Molecular; Myeloid Progenitor Cells; Onset of illness; Outcome; Pathogenesis; Pathway interactions; Phase; Population; Positioning Attribute; Process; Property; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Recombinants; Regulation; Research; Role; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Testing; United States; Vaccines; Viral; Viral Pathogenesis; Virion; Virus; Virus Diseases; Virus Latency; chemokine; experience; human GPR4 protein; insight; intercellular communication; latency associated transcript; latent infection; lytic replication; monocyte; mutant; new therapeutic target; novel; prevent; progenitor; promoter; public health relevance; reactivation from latency; research and development; research study; targeted treatment; transcription factor

 DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is a significant public health concern in the United States. Most important are the effects of the virus on developing fetuses and immunocompromised individuals where it causes a variety of pathological conditions ranging in severity from mild to life-threatening. Since HCMV is present in a persistent or latent form in 50-90% of the world's adult population, the identification of virl gene products that contribute to the establishment and maintenance of a latent infection is an intense and important area of investigation. HCMV encodes 4 GPCR homologs including US28, which has been shown to exhibit both constitutive and agonist-dependent G-protein signaling activities in HCMV infected fibroblasts. Although US28 exhibits high level signaling, it is not essential for lytic viral replication and therefore its function in viral pathogenesis remains unclear. Interestingly, US28 mRNAs are expressed in latently infected hematopoietic progenitors and monocytes, prompting questions regarding the potential role of US28 during latent CMV infections. Our exciting preliminary data indicates that US28 promotes a successful latent infection as US28 null viruses spontaneously enter the lytic phase in hematopoietic cells where wild type virus establishes a latent infection. Therefore, we hypothesize that US28 directed signaling in HCMV infected hematopoietic progenitors leads to the establishment and/or maintenance of latency. To explore this hypothesis, we will take advantage of a newly constructed panel of US28 mutant viruses and recently established methodologies to examine US28 signaling in HCMV infected cells. In Aim 1, we will examine the biological parameters by which US28 drives latency using viral recombinants in primary hematopoietic progenitor cells, and in Aim 2 we will examine the molecular signaling properties of US28 and determine which pathways contribute to the establishment and/or maintenance of latency. Finally, experiments like those proposed in this application are essential for our understanding of the role of CMV GPCRs in viral pathogenesis and will open novel avenues of research for the development of unique antivirals that specifically target the latent reservoir of virus infection.

 描述（由申请人提供）：人类巨细胞病毒 (HCMV) 是美国的一个重大公共卫生问题。最重要的是病毒对发育中的胎儿和免疫功能低下的个体的影响，它会导致各种病理状况，严重程度从轻微到危及生命。由于HCMV以持续或潜伏形式存在于世界上50-90%的成年人口中，因此鉴定有助于建立和维持潜伏感染的virl基因产物是一个激烈而重要的研究领域。 HCMV 编码 4 个 GPCR 同源物，包括 US28，已证明 US28 在 HCMV 感染的成纤维细胞中表现出组成型和激动剂依赖性 G 蛋白信号传导活性。尽管 US28 表现出高水平的信号传导，但它对于裂解病毒复制并不是必需的，因此其在病毒发病机制中的功能仍不清楚。有趣的是，US28 mRNA 在潜伏感染的造血祖细胞和单核细胞中表达，这引发了关于 US28 在潜伏 CMV 感染过程中潜在作用的问题。我们令人兴奋的初步数据表明，US28 促进成功的潜伏感染，因为 US28 无效病毒在造血细胞中自发进入裂解阶段，野生型病毒在该阶段建立潜伏感染。因此，我们假设 US28 在 HCMV 感染的造血祖细胞中定向信号传导导致潜伏期的建立和/或维持。为了探索这一假设，我们将利用新构建的 US28 突变病毒组和最近建立的方法来检查 HCMV 感染细胞中的 US28 信号传导。在目标 1 中，我们将检查 US28 在原代造血祖细胞中使用病毒重组体驱动潜伏期的生物学参数，在目标 2 中，我们将检查 US28 的分子信号传导特性，并确定哪些途径有助于潜伏期的建立和/或维持。最后，像本申请中提出的实验对于我们了解 CMV GPCR 在病毒发病机制中的作用至关重要，并将为开发专门针对潜在病毒感染库的独特抗病毒药物开辟新的研究途径。