Evasion of Antigen Presentation by Rhesus Cytomegalovirus

描述（由申请人提供）：我们研究的最终目标是了解巨细胞病毒（CMV）的免疫刺激和免疫逃避之间的平衡，并将这种理解用于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细胞应答，但CMV在CMV免疫个体中建立继发性持续感染。然而，这种独特的能力也代表了一个机会，设计的CMV为基础的疫苗载体，可以重复使用，尽管预先存在的免疫力的载体。我们最近证明，CMV的超感染是由病毒US 2 -11糖蛋白-US 2，US 3，US 6和US 11-所有这些抑制抗原呈递的主要组织相容性复合物I类（MHC-I）的CD 8 + T细胞。这些观察结果表明，缺乏US 2 -11区域的CMV可用于监测CMV特异性CD 8 + T细胞应答是否是“保护性的”，即能够控制如对血清阳性个体观察到的原发性病毒血症。因此，本提案的目标是定义针对US 2 -11缺失病毒的保护所需的CD 8 + T细胞应答，并将这些结果与针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US 2 -11区域中编码的每个单独的免疫消失素在促进超感染中的贡献。这些目标将在三个具体目标中实现：在目标1中，我们将确定单循环病毒是否可以诱导T细胞效应记忆应答，其保护免受US 2 -11缺失病毒的超感染并限制野生型病毒攻击后的病毒血症。在目标2中，我们将确定针对CMV单个开放阅读框架的CD 8 + T细胞反应是否足以预防缺乏US 2 -11的CMV的超级感染。在目标3中，我们将确定在US 2 -11区域中具有迭代较小缺失的CMV是否能够克服预先存在的免疫性。这项工作将挑战现有的范例，特别是假设活CMV疫苗需要基于复制CMV和单亚单位疫苗赋予保护性T细胞反应。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的疫苗载体的开发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.