Neuronal Regulation of HSV Lytic and Latent Infection

描述（由申请人提供）：单纯疱疹病毒感染是世界范围内散发性致命性脑炎和美国传染性失明的主要原因。传播给新生儿与高发病率和死亡率有关，感染生殖器HSV的个体感染艾滋病毒的可能性高出2-3倍。一旦被感染，目前还没有办法消除潜伏的病毒基因组，潜伏的病毒基因组在宿主的生命中持续存在，并周期性地重新激活，产生传染性病毒后代，然后传播给新的宿主。考虑到目前全球70%以上的人口感染了单纯疱疹病毒，这种病毒对人类健康的直接和间接影响是深远的。尽管如此，我们对体内HSV发病机制核心方面（即潜伏期的建立和再激活）的病毒/宿主相互作用的理解仍然不足以指导预防和治疗策略的基本原理设计。拟议研究的长期目标是了解HSV与神经系统之间的相互作用，这些相互作用导致潜伏期的建立和随后的再激活以及长期相关的病理。在确定涉及调节潜伏期的关键病毒基因方面已经取得了进展，但神经元中破坏或增强进入和退出潜伏期的生理变化尚不清楚。在这篇文章中，我们将继续我们重要的新观察，即早幼粒细胞白血病蛋白（PML）和PML核小体（PML- nb）的形成在体内神经元中起着建立潜伏期和再激活的核心作用。利用最先进的体内定量方法、特异性敲除小鼠和HSV突变体，我们将：(1)确定体内PML和PML- nb形成对HSV的作用：(i)溶性感染，（ii）潜伏感染的建立和维持，（iii）从潜伏期和再激活中退出；(2)确定ICP0在体内破坏PML的生物学意义：(i)急性神经节感染期间；（ii）感觉神经元在潜伏期再激活过程中。公共卫生相关性：我们建议确定控制单纯疱疹病毒潜伏期的建立和维持以及周期性进入裂解性复制周期的病毒/宿主相互作用。这一知识将直接导致改进疫苗、基因转移载体、溶瘤病毒的设计，以治疗癌症，并可能揭示新的抗病毒靶点。

DESCRIPTION (provided by applicant): Herpes simplex virus infection is the leading cause of sporadic fatal encephalitis worldwide and infectious blindness in the US. Transmission to the neonate is associated with high morbidity and mortality and an individual with genital HSV infection is 2-3 times more likely to acquire HIV. Once infected, there is currently no way to eliminate the latent viral genome, which persists for the life of the host and periodically reactivates producing infectious viral progeny that then is transmitted to new hosts. Considering that more than 70% of the world's population is currently infected with HSV, the direct and indirect impact of this virus to human health is profound. Despite this importance, our understanding of the viral/host interactions underlying the core aspects HSV pathogenesis in vivo, namely the establishment of and reactivation from latency, remains inadequate to direct the rationale design of preventative and treatment strategies. The long term goal of the proposed research is to understand those interactions between HSV and the nervous system which result in the establishment of latency and subsequent reactivation and the long term associated pathologies. Progress has been made in identifying key viral genes involved regulating latency, but the physiological changes in neurons that subvert or enhance the entry into and exit from latency are not understood. In this proposal we will pursue our important new observations that promyelocytic leukemia protein (PML) and the formation of PML-nuclear bodies (PML-NB) in neurons in vivo plays a central role in the establishment of latency and reactivation. Using state of the art quantitative in vivo methods, specific knock out mice, and HSV mutants we will: (1) Determine the role of PML and PML-NB formation in vivo on HSV: (i) lytic infection, (ii) establishment and maintenance of latent infections, and (iii) exit from latency and reactivation; and (2) Determine the biological significance of PML disruption by ICP0 in vivo: (i) during acute ganglion infection; and (ii) in sensory neurons during reactivation from latency. PUBLIC HEALTH RELEVANCE: We propose to determine the viral/host interactions that govern the establishment and maintenance of herpes simplex virus latency and periodic entry into the lytic replicative cycle. This knowledge will lead directly to improved design of vaccines, gene transfer vectors, oncolytic viruses to treat cancer, and may reveal new anti-viral targets.