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

人类巨细胞病毒（HCMV）是一种常见病原体，已感染大多数人群。虽然 HCMV 的症状通常在免疫功能正常的个体中得到缓解，但由于造血干细胞中建立了潜伏感染，因此该病毒将终生保留在宿主体内。 HCMV 与人类共同进化，因此，该病毒适应破坏宿主细胞的抗病毒反应。 HCMV 如何破坏这些反应尚不完全清楚。我们的研究发现，一种正在研究的蛋白质修饰（S-亚硝基化）在 HCMV 与抗病毒反应相互作用的过程中发挥着重要作用。我们发现，对于有效裂解复制至关重要的病毒蛋白被一氧化氮基团进行翻译后修饰，并且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 HCMV 蛋白功能，并确定 S-亚硝基化对 HCMV 复制的影响。完成上述目标将极大地有助于我们了解关键病毒因子的生物学功能的调节，并确定病毒削弱宿主防御感染的机制。这项工作将为确定缺乏疫苗或治愈方法的病原体的新治疗靶点奠定基础。

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.