Antiviral responses of host mediated S-nitrosylation of viral proteins.

人类巨细胞病毒(HCMV)是一种常见的病原体，已感染了大多数人类人口。虽然巨细胞病毒的症状通常在具有免疫能力的个体中得到解决，但随着在造血干细胞中建立潜伏感染，病毒在宿主体内终生保留。人巨细胞病毒与人类共同进化，因此，该病毒适应于破坏宿主细胞的抗病毒反应。人类巨细胞病毒是如何破坏这些反应的尚不完全清楚。我们的研究发现，一种研究较少的蛋白质修饰，S-亚硝化，在巨细胞病毒与抗病毒反应的相互作用中发挥了作用。我们发现，对有效裂解复制至关重要的病毒蛋白被一氧化氮基团翻译后修饰，由此产生的修饰改变了病毒蛋白限制抗病毒反应的能力。我们建议从机制上研究这些修饰如何影响巨细胞病毒蛋白的功能，并确定S亚硝化对巨细胞病毒复制的影响。上述目标的完成将大大有助于我们了解关键病毒因子的生物学功能的调节，以及确定病毒削弱宿主抵抗感染的机制。这项工作将为为缺乏疫苗或治愈方法的病原体确定新的治疗靶点奠定基础。

Human cytomegalovirus (HCMV) is a common pathogen that has infected a majority of the human population. While symptoms of HCMV are generally resolved in immunocompetent individuals, the virus remains for the lifetime within the host as a latent infection is established in the hematopoietic stem cells. HCMV has co- evolved with humans and as such, the virus as adapted to undermine host cell antiviral responses. How HCMV undermines these responses is not fully known. Our research has found that an understudied protein modification, S-nitrosylation, plays a role in how HCMV interacts with the antiviral response. We found that viral proteins critical for efficient lytic replication are post translationally modified with nitric oxide groups and that the resulting modifications alter the viral proteins ability to limit antiviral responses. We propose to mechanistically investigate how these modifications impact HCMV protein functions and to identify the impact of S-nitrosylation on HCMV replication. Completion of the aims above will contribute significantly to our knowledge the regulation of biological functions of critical viral factors as well as identify the mechanism by which viruses weaken host defenses against infection. This work will lay the foundation in identifying novel therapeutic targets for a pathogen that lacks a vaccine or a cure.