EVASION OF ANTIGEN PRESENTATION BY RHESUS CYTOMEGALOVIRUS

恒河猴巨细胞病毒逃避抗原呈递

• 批准号: 8357750
• 负责人: Klaus J Fruh
• 金额: $ 9.74万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357750
• 关键词: Antibodies; Antigen Presentation; CD8B1 gene; Cytomegalovirus; Cytomegalovirus Vaccines; Development; Funding; Glycoproteins; Goals; Grant; Immune; Individual; Infection; Life; Macaca mulatta; Major Histocompatibility Complex; Monitor; National Center for Research Resources; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Source; Subunit Vaccines; T cell response; T-Lymphocyte; Testing; United States National Institutes of Health; Viral; Viremia; Virus; Work; base; cost; improved; vaccine development; vector; vector-based vaccine

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 CMV 疫苗开发的主要挑战之一是，尽管存在显着的抗体和 T 细胞反应，但 CMV 仍会在 CMV 免疫个体中建立继发性持续感染。我们最近证明，CMV 的超级感染是由病毒 US2-11 糖蛋白（US2、US3、US6 和 US11）实现的，所有这些糖蛋白都会抑制 I 类主要组织相容性复合体 (MHC-I) 向 CD8+ T 细胞的抗原呈递。这些观察结果表明，缺乏 US2-11 区域的 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观察到的原发性病毒血症。因此，该提案的一个目标是定义针对 US2-11 缺失病毒的保护所需的 CD8+ T 细胞反应，并将这些结果与针对野生型病毒初次感染的保护联系起来。进一步的目标是确定 US2-11 区域编码的每个免疫血管素在促进重复感染中的贡献。这项工作将挑战现有的范式，特别是活 CMV 疫苗需要基于复制 CMV 以及单亚单位疫苗赋予保护性 T 细胞反应的假设。我们进一步期望开发新的和改进的方法来测试 CMV 疫苗并改进基于 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。