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

描述(申请人提供)：人类疱疹病毒-6和-7(HHV-6，-7)是两种密切相关的β-疱疹病毒，感染人口的比例超过90%。这些机会性病毒通常不会对健康人造成严重疾病，但在免疫功能低下的人中，这些病毒会重新激活，并导致危及生命的脑炎、巨细胞病毒病和肝炎。HHV-6也被认为是多发性硬化症的可能病毒病原体。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。许多病毒，包括疱疹病毒家族的大多数成员，已经进化出机制来干扰I类MHC分子的病毒抗原提呈，作为逃避细胞毒性T淋巴细胞检测的一种手段。HHV-7编码一种这样的基因产物U21，它与I类MHC分子结合，并将其转移到溶酶体隔室。这项提案的重点是确定HHV-7U21逃避免疫系统检测的机制。与HHV-6密切相关的U21基因产物的功能也将被检测。最近的工作表明，U21的管腔结构域对于将I类分子转移到溶酶体室是至关重要的。将采用几种策略来确定HHV-7U21的管腔结构域的机制。1)将检查I类分子被转移到的间隔的生化和形态性质，2)将确定负责将I类分子转移到该间隔的细胞蛋白质的身份。3)将在HHV-7感染细胞中检测U21的作用和负责分流的细胞蛋白；4)将绘制与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致病机制，而且有助于理解溶酶体运输的基本原理。最终，通过了解这些分子如何发挥功能来下调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): 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.