Gammaherpesvirus interactions with host tumor suppressor p53

描述（由申请方提供）：γ疱疹病毒（GHV）可导致终身慢性感染，使宿主面临多种癌症风险。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，这一过程被认为有助于长期潜伏并有助于肿瘤发生。然而，GHV不会急性转化，并且鉴于成年人中感染率高，癌症是罕见的，估计EB病毒的感染率超过90%。这表明，宿主细胞具有对GHV驱动的增殖和细胞永生化的内在抗性，但已知很少有能够介导这种效应的宿主分子，并且这些分子是否在体内功能上限制GHV持久性和疾病尚未确定。本提案中描述的实验旨在确定和确认宿主分子在体内的相关性，这些分子具有限制GHV慢性感染和疾病的能力，具体目标有三个。基于采用鼠γ疱疹病毒-68（MHV 68）感染小鼠的初步研究，特定目标1中描述的实验检测了宿主肿瘤抑制蛋白p53（预防肿瘤疾病的关键分子）作为MHV 68潜伏持久性和细胞转化的先天屏障的功能。具体目标2中提出的实验试图确定p53限制MHV 68潜伏感染的机制。特定目标3中的实验将提供对长期存在的假设的首次体内测试，即潜伏相关核抗原（一种能够在组织培养中抑制p53功能的保守GHV疾病决定因子）对于克服p53介导的限制以实现长期潜伏感染是必要的。这些实验利用强大的小鼠和MHV 68遗传系统来解决一个对我们理解GHV-宿主动态至关重要的问题。此外，我们预计这项工作的结果将为旨在增强p53功能以限制或预防GHV相关癌症的新治疗方法提供信息，特别是在高危患者中，如HIV感染者或实体器官移植受者。

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.