Alpha-herpesvirus assembly, egress and viral particle heterogeneity

α-疱疹病毒组装、流出和病毒颗粒异质性

• 批准号: 7878985
• 负责人: Gregory Allan Smith
• 金额: $ 6.56万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878985
• 关键词: Acyclovir; Address; Antiviral Agents; Blindness; Capsid; Capsid Proteins; Cell Nucleus; Cells; Comparative Study; Country; Coupled; Cytoplasm; Disease; Disease Progression; Encephalitis; Goals; Herpes zoster disease; Herpesviridae; Herpesvirus 1; Herpesvirus Type 3; Heterogeneity; Human; Human Herpesvirus 2; Individual; Infection; Intervention; Keratitis; Life; Link; Measures; Molecular; Morbidity - disease rate; Mutagenesis; Neonatal; Newborn Infant; Nuclear; Nuclear Envelope; Pathway interactions; Process; Property; Proteins; Role; Series; Simplexvirus; Staging; Structure; Study models; Subgroup; Suid Herpesvirus 1; Varicellovirus; Viral; Viral Pathogenesis; Viral Proteins; Virus; Virus Diseases; Viviparous-1 protein; X-Ray Crystallography; base; domain mapping; fluorescence imaging; imaging modality; member; mortality; mutant; novel strategies; particle; pathogen

The neuroinvasive herpesviruses are a highly-prevalent group of the alpha-herpesvirus subfamily that includes the human pathogens: herpes simplex virus types 1 and 2 (HSV-1, HSV-2), and varicella zoster virus (VZV). An additional member of this group is a virus of veterinary significance, pseudorabies virus (PRV), which historically has provided models for studying viral pathogenesis. Despite the availability of the antiviral compound acyclovir, several severe forms of disease caused by these viruses remain prevalent in this country and world wide. Infections associated with high rates of morbidity or mortality include encephalitis, keratitis, shingles and disseminated infections in newborns. Novel strategies to interfere with the assembly and egress of these viruses could prove valuable to treatment of infections, yet much of the herpesvirus infectious cycle remains undefined. In this application we leverage our expertise in infectious clone mutagenesis and single viral particle fluorescence imaging methods to dissect viral structural composition in living-cells and extracellularly, and to address the molecular pathways guiding viral assembly and egress. New evidence is provided indicating that the very large herpesvirus tegument protein, VP1/2, is a key effector of viral assembly during distinct stages of assembly in the nucleus and cytoplasm of infected cells. This proposal is based on the hypothesis that herpesvirus assembly and egress are coupled processes that occur through a series of sequential steps both in the nucleus and cytoplasm of infected cells, and that each of these steps are effected in part by the VP1/2 protein. Our goal is to refine our understanding of these steps at the level of the protein interactions that contribute to the dynamics of viral egress. This proposal includes comparative studies of model viruses from the two neuroinvasive herpesviruses subgroups, the simplexviruses (represented by HSV-1) and the varicelloviruses (represented by PRV), to develop a comprehensive analysis of the properties of these viruses.

神经性疱疹病毒是α-疱疹病毒亚家族的一组高度降低的群体 包括人类病原体：单纯疱疹病毒类型1和2（HSV-1，HSV-2）和Varicella 带状线病毒（VZV）。该组的其他成员是具有兽医意义的病毒， 伪酸病毒（PRV），历史上为研究病毒发病机理提供了模型。 尽管有抗病毒化合物阿西洛韦的可用性，但 这些病毒在这个国家和世界范围内仍然很普遍。高率相关的感染 发病率或死亡率包括新生儿中的脑炎，角膜炎，带状疱疹和传播感染。 干扰这些病毒的组装和出口的新型策略可能被证明是有价值的 感染的治疗，但是许多疱疹病毒感染周期仍然不确定。在这个 应用我们利用我们在传染性克隆诱变和单个病毒颗粒方面的专业知识 荧光成像方法以在活细胞和细胞外剖析病毒结构组成， 并解决指导病毒组装和出口的分子途径。提供了新的证据 表明非常大的疱疹病毒tegument蛋白VP1/2是病毒组装的关键效应器 在被感染细胞的细胞核和细胞质的不同阶段。该提议是 基于以下假设：疱疹病毒组装和出口是发生的耦合过程 通过一系列的顺序步骤 这些步骤部分由VP1/2蛋白进行部分影响。我们的目标是完善我们对这些的理解 蛋白质相互作用水平的步骤有助于病毒出口的动力学。这 提案包括对两个神经侵袭性疱疹病毒的模型病毒的比较研究 亚组，单纯病毒（由HSV-1代表）和Varicellovires（由PRV代表）， 为这些病毒的特性进行全面分析。