Evasion of Antigen Presentation by Rhesus Cytomegalovirus

描述(申请人提供)：我们研究的最终目标是了解巨细胞病毒(CMV)免疫刺激和免疫逃避之间的平衡，并利用这一理解开发新的治疗方法和疫苗。CMV疫苗开发的主要挑战之一是，尽管存在显著的抗体和T细胞反应，CMV仍会在CMV免疫的个体中建立继发性持续性感染。然而，这种独特的能力也为设计基于CMV的疫苗载体提供了机会，这种载体可以重复使用，尽管对该载体已有免疫力。我们最近证实，CMV的超级感染是通过病毒的US2-11糖蛋白-US2、US3、US6和US11实现的，所有这些糖蛋白都能抑制主要组织相容性复合体I类(MHC-I)向CD8+T细胞递呈抗原。这些观察表明，缺乏US2-11区的CMV可用于监测CMV特异性CD8+T细胞反应是否具有“保护性”，即能够控制血清阳性个体的原发病毒血症。因此，这项建议的一个目标是确定对US2-11缺失病毒的保护所需的CD8+T细胞反应，并将这些结果与对野生型病毒的初次感染的保护相关联。另一个目标是确定在US2-11区域编码的每个个体免疫球蛋白在促进超级感染中的作用。这些目标将在三个具体目标中实现：在目标1中，我们将确定单周期病毒是否能够诱导T细胞效应器记忆反应，以防止US2-11缺失病毒的双重感染，并限制对野生型病毒的攻击时的病毒血症。在目标2中，我们将确定针对CMV单一开放阅读框架的CD8+T细胞反应是否足以防止缺少US2-11的CMV的重复感染。在目标3中，我们将确定在US2-11区域重复较小缺失的CMV是否能够克服先前存在的免疫。这项工作将挑战现有的范式，特别是CMV活疫苗需要建立在复制CMV的基础上，以及单亚单位疫苗提供保护性T细胞反应的假设。我们还期望开发新的和改进的方法来测试CMV疫苗和改进基于CMV的载体。因此，我们相信我们的研究将对CMV疫苗和基于CMV的疫苗载体的发展产生重大而持久的影响。

DESCRIPTION (provided by applicant): The ultimate goal of our research is to understand the balance between immune stimulation and immune evasion of cytomegalovirus (CMV) and to use this understanding for the development of new treatments and vaccines. One of the major challenges for CMV vaccine development is the fact that CMV establishes secondary persistent infections in CMV-immune individuals despite the presence of significant antibody and T cell responses. However, this unique ability also represents an opportunity for the design of CMV-based vaccine vectors that can be used repeatedly despite pre-existing immunity to the vector. We recently demonstrated that super-infection by CMV is enabled by the viral US2-11 glycoproteins -US2, US3, US6 and US11- all of which inhibiting antigen presentation by major histocompatibility complex class I (MHC-I) to CD8+ T cells. These observations suggest that CMV lacking the US2-11 region can be used to monitor whether a CMV-specific CD8+ T cell response is "protective", i.e. able to control primary viremia as observed for sero- positive individuals. A goal of this proposal is therefore to define the CD8+ T cell response required for protection against US2-11-deleted virus and to correlate these results with protection against primary infection with wildtype virus. A further goal is to determine the contribution of each individual immunevasin encoded in the US2-11 region in promoting super-infection. These goals will be achieved in three specific aims: In aim 1 we will determine whether a single-cycle virus can induce a T cell effector memory response that protects against super-infection with US2-11 deleted virus and limits viremia upon challenge with wildtype virus. In aim 2, we will determine whether CD8+ T cell responses directed against a single open reading frame of CMV are sufficient to prevent super-infection by CMV lacking US2-11. In aim 3, we will determine whether CMV with iteratively smaller deletions in the US2-11 region is able to overcome pre-existing immunity. This work will challenge existing paradigms, specifically the assumptions that live CMV vaccines need to be based on replicating CMV and that single subunit vaccines confer protective T cell responses. We further anticipate to develop new and improved ways to test CMV vaccines and to improve CMV-based vectors. Therefore, we believe that our research will have a significant and lasting impact on the development of CMV vaccines and CMV-based vaccine vectors.