Human cytomegalovirus latency in cultured monocytes

培养单核细胞中的人巨细胞病毒潜伏期

• 批准号: 8019543
• 负责人: THOMAS E SHENK
• 金额: $ 35.86万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019543
• 关键词: Antiviral Therapy; Biological; Biological Assay; CD14 gene; Cell Culture Techniques; Cell surface; Cells; Clinical; Code; Cultured Cells; Cytomegalovirus; Cytomegalovirus Infections; Dendritic Cells; Genes; Genetic; Grant; Herpesviridae; Immune; Immune system; Individual; Infection; Investigation; Laboratories; Latent Virus; Maintenance; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Biology; Monitor; Morbidity - disease rate; Myeloid Cells; Pharmaceutical Preparations; Phenotype; Play; Population; Proteomics; Role; Symptoms; System; Testing; Time; Viral; Viral Drug Resistance; Viral Genes; Viral Proteins; Virus; Virus Diseases; cell type; cytokine; design; latent infection; macrophage; monocyte; mortality; mutant; peripheral blood; programs; public health relevance

DESCRIPTION (provided by applicant): Although they reside in different cell types, all herpes viruses can enter a state of quiescence termed latency. When these viruses are latent, they are resistant to antiviral therapies that attack replicating viruses. As a result, existing drugs treat symptoms of active infections, but do not clear latent virus, and, therefore, do not cure herpes virus infections. Consequently, it is critically important to advance our understanding of the mechanisms underlying latency; indeed, this is one of the major outstanding questions in our field. Human cytomegalovirus (HCMV) resides in a latent state in cells of the myeloid lineage. Although the virus likely reactivates frequently from latency, it is readily controlled with no known consequences to healthy people. However, reactivation can cause severe morbidity and mortality when it re-emerges from latency in people with compromised or immature immune systems. Thus, it is critical to develop the ability to control and eventually eradicate latent virus, and this capability will come from a deeper understanding of latency. My long term objective is to employ a validated cell culture model of latency -- peripheral blood monocytes -- to investigate the molecular mechanisms underlying the initiation, maintenance and exit from latency. We will carry out our investigations primarily with clinical isolates of HCMV; and our technical approach will combine genetics, molecular biology and proteomics. My specific aims are designed to employ our cell culture model of latency to (i) investigate the effect of cell phenotype on HCMV latency; (ii) study the role of viral protein-coding genes with the potential to function during latency; and (iii) test the hypothesis that viral and/or cell-coded miRNAs function in HCMV latency. This is an opportune time to study HCMV latency, because we now appreciate many of the critical differences between clinical versus laboratory isolates of the virus that cause them to behave differently in experimental infections, experimental systems have been developed to investigate latency in cultured cells, and new biological components likely to play important roles in latency have been recently identified. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus, like other herpes viruses, can enter a state of quiescence or latency. As a consequence, drugs that treat symptoms of active infections, do not clear latent virus and do not cure cytomegalovirus infections. It is critically important to advance our understanding of the mechanisms underlying latency so that new, more efficacious therapies can be developed.

描述（由申请人提供）：虽然它们存在于不同的细胞类型中，但所有疱疹病毒都可以进入称为潜伏期的静止状态。当这些病毒处于潜伏状态时，它们对攻击复制病毒的抗病毒疗法具有抵抗力。因此，现有药物治疗活动性感染的症状，但不能清除潜伏病毒，因此不能治愈疱疹病毒感染。因此，增进我们对延迟背后机制的理解至关重要；事实上，这是我们领域中尚未解决的主要问题之一。人巨细胞病毒（HCMV）以潜伏状态存在于骨髓系细胞中。尽管该病毒可能会在潜伏期后频繁重新激活，但它很容易得到控制，对健康人没有已知的后果。然而，当免疫系统受损或不成熟的人从潜伏期重新激活时，重新激活可能会导致严重的发病率和死亡率。因此，发展控制并最终根除潜伏病毒的能力至关重要，而这种能力将来自对潜伏期的更深入理解。我的长期目标是采用经过验证的潜伏期细胞培养模型（外周血单核细胞）来研究潜伏期启动、维持和退出的分子机制。我们将主要利用 HCMV 的临床分离株进行研究；我们的技术方法将结合遗传学、分子生物学和蛋白质组学。我的具体目标是利用我们的细胞培养潜伏期模型来 (i) 研究细胞表型对 HCMV 潜伏期的影响； (ii) 研究病毒蛋白编码基因在潜伏期发挥作用的潜力； (iii) 检验病毒和/或细胞编码的 miRNA 在 HCMV 潜伏期发挥作用的假设。现在是研究 HCMV 潜伏期的好时机，因为我们现在认识到该病毒的临床分离株与实验室分离株之间存在许多关键差异，这些差异导致它们在实验感染中表现不同，已经开发了实验系统来研究培养细胞中的潜伏期，并且最近已经确定了可能在潜伏期中发挥重要作用的新生物成分。 公共卫生相关性：人类巨细胞病毒与其他疱疹病毒一样，可以进入静止或潜伏状态。因此，治疗活动性感染症状的药物不能清除潜伏病毒，也不能治愈巨细胞病毒感染。增进我们对潜伏期机制的理解至关重要，这样才能开发出新的、更有效的疗法。