Neuronal Regulation of HSV Lytic and Latent Infection

描述(申请人提供)：单纯疱疹病毒感染是全球散发性致死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，生殖器单纯疱疹病毒感染者感染艾滋病毒的可能性是前者的2-3倍。一旦感染，目前没有办法消除潜伏的病毒基因组，它在宿主的一生中持续存在，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。考虑到目前世界上70%以上的人口感染了HSV，这种病毒对人类健康的直接和间接影响是深远的。尽管这很重要，但我们对HSV体内致病的核心方面，即潜伏期的建立和重新激活的病毒/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设计。这项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重新激活，以及长期相关的病理。在识别涉及调节潜伏期的关键病毒基因方面取得了进展，但颠覆或加强潜伏期进入和退出的神经元的生理变化尚不清楚。在这个方案中，我们将继续我们的重要新观察，即在体内神经元中早幼粒细胞白血病蛋白(PML)和PML核体(PML-NB)的形成在潜伏期和再激活的建立中起核心作用。利用体内最先进的定量方法，特定的敲除小鼠和HSV突变体，我们将：(1)确定体内PML和PML-NB的形成对HSV的作用：(I)裂解感染，(Ii)建立和维持潜伏感染，(Iii)退出潜伏期和再激活；(2)确定ICP0在体内的生物学意义：(I)在急性神经节感染期间；(Ii)在从潜伏期重新激活的感觉神经元中。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定期进入裂解复制周期的病毒/宿主相互作用。这些知识将直接导致改进疫苗、基因转移载体、溶瘤病毒治疗癌症的设计，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.