Mechanisms of HSV egress

单纯疱疹病毒1型（HSV-1）是一种人类病原体，感染粘膜组织的上皮细胞，病毒在粘膜组织中进入、复制、组装和出口，导致生产性感染。在初级复制之后，病毒侵入感觉神经元建立潜伏期。潜伏期的再激活是周期性发生的，这是导致反复感染的终生病毒来源。作为一种大型DNA病毒，HSV-1在感染细胞的细胞核中组装子代衣壳。为了离开，单纯疱疹病毒-1穿过核质，穿过层蛋白细丝密集网络的层，芽穿过核膜，这一过程分为两步，称为“包膜和脱包膜”。因此，病毒驱动核膜的囊泡，并在核周空间形成包膜病毒粒子。初级病毒粒子随后与外核膜融合，释放出裸露的衣壳，以进一步成熟。在这一过程中，由病毒蛋白UL31和UL34组成的核出口复合体起着至关重要的作用。虽然UL31/UL34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，额外的病毒和宿主因素可能协同工作，这与病毒复制的时间或细胞类型特异性调节特别相关。本研究将探讨HSV核出口的机制，重点研究毒力因子γ134.5。首先，将进行遗传分析，以确定将宿主p32/gC1qR和蛋白激酶C引导到核出芽位点的病毒决定因素。此外，还将进行研究，以检查宿主因子招募的性质。其次，系统分析研究134.5与核出口复合物的相互作用。目的是确定在病毒感染时控制核膜局部溶解和核质衣壳转运的途径。总之，这些研究将为了解与疱疹病毒复制和成熟相关的核膜重塑提供见解。

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.