Gammaherpesvirus interactions with host tumor suppressor p53

描述(由申请人提供)：伽马疱疹病毒(GHV)建立终身慢性感染，使宿主面临多种癌症的风险。在慢性感染期间，GHV表达刺激宿主细胞增殖和分化的病毒基因产物，被认为有助于长期潜伏持续并有助于肿瘤形成的过程。然而，GHV不会急剧转化，鉴于成人感染的高发病率，癌症也很少见，据估计，爱泼斯坦-巴尔病毒的感染率超过90%。这表明宿主细胞对GHV驱动的增殖和细胞永生化具有内在的抵抗力，但能够介导这种作用的宿主分子很少，而且这些分子是否在功能上限制了GHV在体内的持久性和疾病还没有确定。这项建议中描述的实验试图确定和确认宿主分子在体内与限制GHV慢性感染和疾病的能力在三个特定目标中的相关性。在利用小鼠GHV-68感染小鼠的初步研究的基础上，在特定目的1中描述的实验测试了宿主肿瘤抑制蛋白P53的功能，它是预防肿瘤疾病的关键分子，是MHV-68潜伏持续和细胞转化的天然屏障。在《特定目的2》中提出的实验试图确定P53限制MHV68潜伏感染的机制。特定目标3的实验将为长期存在的假设提供第一次体内测试，即潜伏期相关核抗原是克服p53介导的限制以实现长期潜伏感染所必需的。潜伏期相关核抗原是一种保守的GHV疾病决定因素，能够在组织培养中抑制P53的功能。这些实验利用强大的小鼠和MHV68遗传系统来解决一个问题，这个问题对于我们理解GHV宿主的动态是至关重要的。此外，我们预计，这项工作的结果将为旨在增强p53功能的新的治疗方法提供参考，以限制或预防与GHV相关的癌症，特别是在艾滋病毒感染者或实体器官移植接受者等高危患者中。

DESCRIPTION (provided by applicant): Gammaherpesviruses (GHVs) establish lifelong chronic infections that place the host at risk for numerous cancers. During chronic infection, GHVs express viral gene products that stimulate host-cell proliferation and differentiation, processes thought to facilitate long-term latent persistence and contribute to tumorigenesis. However, GHVs are not acutely transforming, and cancer is rare given the high incidence of infection among adult humans, estimated at more than 90% for Epstein-Barr virus. This suggests that host cells are equipped with an intrinsic resistance to GHV-driven proliferation and cellular immortalization, but few host molecules capable of mediating this effect are known and whether these molecules functionally restrict GHV persistence and disease in vivo has not been established. Experiments described in this proposal seek to identify and confirm the in vivo relevance of host molecules with the capacity to limit GHV chronic infection and disease in three Specific Aims. Based on preliminary studies that employed murine gammaherpesvirus-68 (MHV68) infection of mice, experiments described in Specific Aim 1 test the function of host tumor suppressor protein p53, a critical molecule for preventing neoplastic disease, as an innate barrier to MHV68 latent persistence and cellular transformation. Experiments presented in Specific Aim 2 seek to define mechanisms whereby p53 limits MHV68 latent infection. Experiments in Specific Aim 3 will provide the first in vivo test of the long- standing hypothesis that latency-associated nuclear antigen, a conserved GHV disease determinant capable of inhibiting p53 functions in tissue culture, is necessary to overcome a p53-mediated restriction to enable long- term latent infection. These experiments harness the powerful mouse and MHV68 genetic systems to address a question that is fundamental to our understanding of the GHV-host dynamic. Further, we anticipate that results of this work will inform new therapeutic approaches aimed at enhancing p53 functions to limit or prevent GHV-related cancers, especially in high-risk patients such as HIV-infected individuals or solid-organ transplant recipients.