Discovery of novel immunoevasins from HHV-6 and -7

描述（由申请方提供）：HHV-6和HHV-7是两种密切相关的2-疱疹病毒，感染超过90%的人群。这些机会性病毒在健康人群中不会引起严重疾病，但在免疫功能低下的个体中，这些病毒可以重新激活并引起危及生命的脑炎和CMV疾病。与所有其他疱疹病毒一样，HHV-6和HHV-7在宿主体内持续存在或潜伏终生。在这样做的过程中，疱疹病毒已经进化出许多策略来逃避免疫系统的检测。值得注意的是，迄今为止检查的所有疱疹病毒通过从感染的细胞表面去除I类MHC分子来干扰病毒抗原呈递给细胞毒性T淋巴细胞（CTL）。显然，由于疱疹病毒已经进化出了如此广泛的一系列机制来从细胞表面去除I类MHC分子，这种策略很好地为它们服务。然而，当自然杀伤（NK）细胞检测到细胞表面上不存在I类MHC分子时（即，“失去自我”），它们被激活杀死那个细胞。本申请的重点是发现HHV-6和HHV-7如何逃避NK和CTL细胞对病毒感染的应答。将采用几种策略来鉴定允许HHV-6/-7感染的细胞逃避检测的新型病毒免疫逃避素：1）我们将探索与免疫分子具有明显同源性的HHV-6和-7内的开放阅读框的功能。2)我们将筛选HHV-6和HHV-7感染的抗原呈递细胞，寻找参与启动针对感染细胞的溶细胞反应的候选细胞膜蛋白的表面下调。该项目的长期目标是了解HHV-6和HHV-7逃避免疫系统检测的机制。揭示这些机会性病毒逃避免疫系统的机制不仅有助于理解这些病毒及其发病机制，而且有助于理解细胞生物学的基本原理。最终，从了解这些分子如何发挥作用来破坏免疫反应中获得的知识可能会导致识别用于治疗这些机会性感染以及治疗自身免疫性疾病的潜在治疗靶点。

DESCRIPTION (provided by applicant): HHV-6 and -7 are two closely related 2-herpesviruses that infect over 90% of the population. These opportunistic viruses do not cause serious illness in healthy people, but in immunocompromised individuals, these viruses can reactivate and cause life-threatening encephalitis and CMV disease. Like all other herpesviruses, HHV-6 and -7 persist or remain latent in their hosts throughout life. In so doing, herpesviruses have evolved numerous strategies to escape detection by the immune system. Notably, all of the herpesviruses thus far examined interfere with viral antigen presentation to cytotoxic T lymphocytes (CTLs) by removing class I MHC molecules from the infected cell surface. Clearly, since the herpesviruses have evolved such an extensive array of mechanisms to remove class I MHC molecules from the cell surface, this strategy serves them well. However, when Natural Killer (NK) cells detect an absence of class I MHC molecules on the surface of a cell (i.e., "missing self"), they become activated to kill that cell. The focus of this application is to discover how HHV-6 and -7 evade the NK and CTL cell responses to viral infection. Several strategies will be employed to identify novel viral immunoevasins that allow HHV-6/-7 infected cells to escape detection: 1) we will explore the function of open reading frames within HHV-6 and -7 that have obvious homology to immune molecules. 2) We will screen HHV-6 and -7- infected antigen-presenting cells for the surface downregulation of candidate cellular membrane proteins involved in the initiation of a cytolytic response against an infected cell. The long term goal of this project is to understand the mechanisms by which HHV-6 and -7 evade detection by the immune system. Revelation of the mechanisms by which these opportunistic viruses evade the immune system will not only contribute to the understanding of these viruses and their pathogenesis, but also to the understanding of basic underlying principles of cell biology. Ultimately, the knowledge gained from understanding how these molecules function to subvert the immune response may lead to the identification of potential therapeutic targets for the treatment of these opportunistic infections, as well as for the treatment of autoimmune disorders.