Discovery of novel immunoevasins from HHV-6 and -7

描述(申请人提供)：HHV-6和HHV-7是两种密切相关的2-疱疹病毒，感染超过90%的人口。这些机会性病毒不会对健康人造成严重疾病，但在免疫功能受损的人中，这些病毒会重新激活，并导致危及生命的脑炎和巨细胞病毒病。像所有其他疱疹病毒一样，HHV-6和HHV-7在宿主体内终生存活或潜伏。在这样做的过程中，疱疹病毒进化出了许多策略来逃避免疫系统的检测。值得注意的是，到目前为止所检测的所有疱疹病毒都通过从受感染的细胞表面移除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如此广泛的一系列机制来从细胞表面移除I类MHC分子，这一策略很好地服务于它们。然而，当自然杀伤(NK)细胞检测到细胞表面不存在I类MHC分子时(即“缺失自我”)，它们就会被激活，以杀死该细胞。这一应用的重点是发现HHV-6和HHV-7如何逃避NK和CTL细胞对病毒感染的反应。将采用几种策略来鉴定允许HHV-6/-7感染细胞逃脱检测的新型病毒免疫转录素：1)我们将探索HHV-6和-7中与免疫分子有明显同源性的开放阅读框的功能。2)我们将筛选感染HHV-6和-7的抗原提呈细胞，以寻找参与启动对感染细胞的细胞溶解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，通过了解这些分子如何发挥作用来颠覆免疫反应所获得的知识，可能会导致确定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.