Mechanisms of immune evasion by HHV-6 and HHV-7 U21

描述（由申请方提供）：人疱疹病毒-6和-7（HHV-6，-7）是两种密切相关的β-疱疹病毒，感染超过90%的人群。这些机会性病毒通常不会在健康人群中引起严重疾病，但在免疫功能低下的个体中，这些病毒可以重新激活并导致危及生命的脑炎，CMV疾病和肝炎。HHV-6也被认为是多发性硬化症的一种可能的病毒病原体。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。许多病毒，包括疱疹病毒家族的大多数成员，已经进化出通过I类MHC分子干扰病毒抗原呈递的机制，作为逃避细胞毒性T淋巴细胞检测的手段。HHV- 7编码一种这样的基因产物U21，其结合I类MHC分子并将其转移到溶酶体区室。本提案的重点是确定HHV-7 U21逃避免疫系统检测的机制。HHV-6中密切相关的U21基因产物的功能也将被检查。最近的研究表明，U21的内腔结构域对于I类分子转移到溶酶体隔室是至关重要的。将采用几种策略来确定HHV-7 U21内腔结构域的机制。1)将检查I类分子转移到其中的隔室的生物化学和形态学性质，2）将确定负责I类分子转移到该隔室的细胞蛋白的身份。3)将在HHV-7感染的细胞中检测U21和负责转向的细胞蛋白的作用，和4）将绘制U21结合所必需的I类分子的结构域。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。揭示这些机会病毒逃避免疫系统的机制不仅有助于了解这些病毒及其发病机制，而且有助于了解溶酶体运输的基本原理。最终，从了解这些分子如何下调免疫反应中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): Human herpesvirus-6 and -7 (HHV-6,-7) are two closely related beta-herpesviruses that infect over 90% of the population. These opportunistic viruses do not usually cause serious illness in healthy people, but in immunocompromised individuals, these viruses can reactivate and cause life-threatening encephalitis, CMV disease, and hepatitis. HHV-6 is also considered a possible viral causative agent of Multiple Sclerosis. 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. Many viruses, including most members of the herpesvirus family, have evolved mechanisms to interfere with viral antigen presentation by class I MHC molecules as a means of escaping detection by cytotoxic T lymphocytes. HHV- 7 encodes one such gene product, U21, that binds to and diverts class I MHC molecules to a lysosomal compartment. The focus of this proposal is to determine the mechanism employed by HHV-7 U21 to escape detection by the immune system. The function of the closely related U21 gene product in HHV-6 will also be examined. Recent work has shown that the lumenal domain of U21 is critical for diversion of class I molecules to the lysosomal compartment. Several strategies will be employed to ascertain the mechanism of the lumenal domain of HHV-7 U21. 1) the biochemical and morphological nature of the compartment to which class I molecules are diverted will be examined, 2) the identity of cellular proteins responsible for diversion of class I molecules to this compartment will be determined. 3) the effect of U21 and the cellular proteins responsible for diversion will be examined in HHV-7 infected cells and 4) the domains of the class I molecule essential for U21 binding will be mapped. 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 the basic underlying principles of lysosomal trafficking. Ultimately, the knowledge gained from understanding how these molecules function to downregulate the immune response may lead to the identification of potential therapeutic targets for treatment of these opportunistic infections, as well as for the treatment of autoimmune disorders.