Mechanisms of HSV egress

HSV 流出机制

• 批准号: 10097988
• 负责人: BIN HE
• 金额: $ 19.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-04 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10097988
• 关键词: Afferent Neurons; Antiviral Agents; Blindness; Capsid; Cell Nucleus; Cells; Complex; Crystallization; DNA Viruses; Data; Development; Disease; Encephalitis; Epithelial; Epithelial Cells; Event; Filament; Genes; Genital; Genitalia; Herpesviridae; Herpesvirus 1; Impairment; Infection; Integration Host Factors; Interferons; Invaded; Lamins; Mass Spectrum Analysis; Mediating; Membrane; Modeling; Molecular; Mucous Membrane; Multiprotein Complexes; Nature; Neurons; Nuclear; Nuclear Envelope; Nuclear Inner Membrane; Nuclear Lamina; Nuclear Outer Membrane; Nuclear Translocation; Nucleocapsid; Nucleoplasm; Pathogenesis; Pathway interactions; Phosphorylation; Play; Process; Production; Protein Kinase C; Proteins; Proteomics; Regulation; Research; Resolution; Role; Series; Simplexvirus; Site; Source; Structure; Surface; Therapeutic; Tissues; Ulcer; Vesicle; Viral; Viral Proteins; Virion; Virulence Factors; Virus; Virus Diseases; Virus Replication; Work; base; cell type; cellular protein p32; design; gene product; genetic analysis; human pathogen; insight; novel vaccines; protein activation; reactivation from latency; recruit; recurrent infection; response

Herpes simplex virus 1 (HSV-1) is a human pathogen which infects the epithelial cells of the mucosal tissues where the virus undergoes entry, replication, assembly and egress, leading to productive infection. Following primary replication, the virus invades the sensory neurons to establish latency. Reactivation from latency occurs periodically, which is a lifelong source of virus responsible for recurrent infections. As a large DNA virus, HSV-1 assembles progeny capsids in the nucleus of infected cells. To exit, HSV-1 traverses the nucleoplasm, crosses the lamina of a dense meshwork of lamin filaments, and buds through the nuclear membranes in a two-step process known as “envelopment and de-envelopment”. Therefore, the virus drives vesiculation of the inner nuclear membrane and forms enveloped virions in the perinuclear space. Primary virions then fuse with the outer nuclear membrane to release the naked capsids for further maturation. In this process the nuclear egress complex, composed of viral proteins UL31 and UL34, plays an essential role. While UL31/UL34 orchestrates a series of events, the regulatory circuit is unclear in virus-infected cells. Accumulating evidence suggests the hypothesis that additional virus and host factors may work coordinately, which is particularly relevant to temporal or cell-type specific regulation of viral replication. This research will investigate the mechanism of HSV nuclear egress, with a focus on a virulence factor γ134.5. Firstly, genetic analysis will be performed to identify viral determinants that direct host p32/gC1qR and protein kinase C to the sites of nuclear budding. Furthermore, studies will be carried out to examine the nature of host factor recruitment. Secondly, systematic analysis will be integrated to investigate the interplay of 134.5 and the nuclear egress complex. The objective is to define the pathways that control local dissolution of nuclear lamina and capsid transit in the nucleoplasm upon virus infection. Together, these studies will provide insights into the remodeling of nuclear envelope pertinent to herpesvirus replication and maturation.

单纯疱疹病毒1（HSV-1）是感染粘膜组织的上皮细胞的人类病原体，其中病毒经历进入、复制、组装和排出，导致生产性感染。初次复制后，病毒侵入感觉神经元以建立潜伏期。潜伏期的再激活周期性发生，这是导致反复感染的病毒的终身来源。作为一种大的DNA病毒，HSV-1在感染细胞的细胞核中组装后代衣壳。为了离开，HSV-1穿过核质，穿过核纤层蛋白丝的致密网状结构的层，并在称为“增殖和去增殖”的两步过程中通过核膜出芽。因此，病毒驱动内核膜的囊泡化并在核周空间中形成有包膜的病毒体。原代病毒体与外核膜融合，释放出裸露的衣壳，进一步成熟。在这个过程中，由病毒蛋白UL 31和UL 34组成的核出口复合物起着至关重要的作用。虽然UL 31/UL 34协调了一系列事件，但在病毒感染的细胞中，调控回路尚不清楚。越来越多的证据表明，假设额外的病毒和宿主因素可能会协调工作，这是特别相关的时间或细胞类型的病毒复制的特定调节。本研究将研究HSV核出口的机制，重点是毒力因子γ134.5。首先，将进行遗传分析以鉴定将宿主p32/gC 1 qR和蛋白激酶C引导至核出芽位点的病毒决定簇。此外，还将开展研究，审查东道国因素征聘的性质。其次，将系统分析整合到调查的相互作用，134.5和核出口复杂。目的是确定控制病毒感染后核纤层的局部溶解和核质中衣壳转运的途径。总之，这些研究将提供有关疱疹病毒复制和成熟的核膜重塑的见解。