EVASION OF ANTIGEN PRESENTATION BY RHESUS CYTOMEGALOVIRUS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 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。我们最近证实，CMV的超级感染是由病毒的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CD8T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。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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. We recently demonstrated that super-infection by CMV is enabled by the viral US2-11 glycoproteins -US2, US3, US6 and US11- all of which inhibit 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. 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.