Evasion of Antigen Presentation by Rhesus Cytomegalovirus

恒河猴巨细胞病毒逃避抗原呈递

• 批准号: 9316834
• 负责人: Klaus J Fruh
• 金额: $ 56.7万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316834
• 关键词: Animal Model; Animals; Antigen Presentation; Antigen-Presenting Cells; Benign; Biological Models; Biology; CD8B1 gene; Cell membrane; Cell surface; Cells; Cellular Immunity; Chimeric Proteins; Chronic; Complex; Cytomegalovirus; Cytomegalovirus Infections; Cytoplasmic Vesicles; Data; Development; Disease; Down-Regulation; Epitopes; Family; Fetus; Frequencies; Funding; Genes; Goals; HIV; Herpesviridae; Homologous Gene; Human; Immune; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Immunologic Monitoring; Immunology; Individual; Infection; Infectious Agent; Lead; Life; Macaca mulatta; Maintenance; Modeling; Molecular; Natural Killer Cells; Newborn Infant; Peptides; Population; Prevention; Primates; Process; Protein Family; Proteins; Proteomics; Reporting; Research; Role; Series; Specificity; Staging; Structure; T cell response; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Transplant Recipients; Vaccine Design; Vaccines; Viral; Virus; Work; adaptive immunity; base; gene product; improved; inhibitor/antagonist; insight; member; nonhuman primate; novel; prevent; public health relevance; response; secondary infection; vaccine development; vector; vector-based vaccine

 DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that persists for life. Although HCMV is generally benign in healthy individuals, the virus can cause disease in immunocompromised populations and HCMV is the leading infectious cause of congenital disease in newborns. The reasons why the immune system is able to control, but unable to eradicate HCMV are unknown. Our main hypothesis is that immunomodulatory CMV genes, particularly modulators of innate and adaptive cellular immunity, enable the establishment and maintenance of persistent infection in immunocompetent individuals. A better understanding of these immune modulatory processes will be essential for the development of vaccines against HCMV as well as for the optimization of CMV-based vaccine vectors that have recently assumed center stage in the development of vaccines against HIV. Our work in non-human primate models of CMV infection revealed a series of unexpected results that indicate a complex relationship between CMV and the innate and adaptive cellular immune response involving viral evasion, viral recruitment and viral manipulation of the host's immune response. Particularly novel is our finding that rhesus CMV-encoded genes enable the virus to control the epitope specificity of the adaptive, CD8+ T cell immune response. We discovered that while wildtype RhCMV or HCMV elicits conventional MHC-I restricted CD8+ responses, deletion of a single gene, Rh189 or US11, respectively, results in the additional induction of T cells that recognize "canonical" MHC-I epitopes, i.e. immunodominant in a non-CMV context. Since such stringent control of T cell specificity has not been observed before for any infectious agent, we will elucidate why primate CMVs prevent the induction of canonical T cells and by what molecular mechanism. In Specific Aim 1 we will determine how canonical T cells control secondary infections by RhCMV and in Specific Aim 2 we will determine the role of MHC-I- downregulation in the prevention of canonical T cell priming by Rh189 and US11. Preliminary data further demonstrate that RhCMV interferes with MHC-II cell surface expression by redistribution to cytoplasmic vesicles suggesting that RhCMV inhibits direct antigen presentation by MHC-II. Furthermore, we discovered that upon deletion of subunits of the gH/gL/UL131A/UL130/UL128 pentamer RhCMV elicits MHC-II-restricted CD8+ T cells at a high frequency, another unprecedented finding. In Specific Aim 3 we will therefore characterize the mechanism of MHC-II downmodulation by RhCMV to test the hypothesis that pentamer-intact RhCMV prevents priming of MHC-II-restricted CD8+ T cells by downregulating MHC-II in antigen presenting cells whereas pentamer-deficient RhCMV is unable to do so since the pentameric complex is essential for viral entry into non-fibroblast cells. The results of this work are expected to provide new insights into the control of unconventional CD8+ T cell targeting by CMV that will ultimately lead to improved vaccines for HCMV and improved vaccine vectors based on HCMV.

 描述(申请人提供)：人巨细胞病毒(HCMV)是一种普遍存在的疱疹病毒，可终身存在。虽然巨细胞病毒在健康个体中一般是良性的，但该病毒可在免疫功能低下的人群中引起疾病，并且巨细胞病毒是新生儿先天性疾病的主要感染原因。免疫系统能够控制，但无法根除巨细胞病毒的原因尚不清楚。我们的主要假设是，免疫调节性CMV基因，特别是天然和适应性细胞免疫的调节器，能够在具有免疫能力的个体中建立和维持持续感染。更好地了解这些免疫调节过程对于开发抗HCMV疫苗以及优化基于CMV的疫苗载体至关重要，因为CMV疫苗载体最近在抗HIV疫苗的开发中处于中心地位。我们在非人类灵长类动物CMV感染模型上的工作揭示了一系列意想不到的结果，表明CMV与先天性和获得性细胞免疫反应之间存在复杂的关系，涉及病毒逃避、病毒募集和病毒对宿主免疫反应的操纵。特别新奇的是，我们发现恒河猴巨细胞病毒编码的基因使病毒能够控制适应性CD8+T细胞免疫反应的表位特异性。我们发现，虽然野生型RhCMV或HCMV可以诱导常规的MHC-I限制性CD8+反应，但单个基因Rh189或US11的缺失会导致额外诱导识别“规范”MHC-I表位的T细胞，即在非CMV环境中免疫优势。由于以前还没有观察到对T细胞特异性的如此严格的控制，所以我们将阐明为什么灵长类CMV阻止规范T细胞的诱导以及通过什么分子机制。在特定目标1中，我们将确定规范T细胞如何控制RhCMV继发感染；在特定目标2中，我们将确定MHC-I下调在防止Rh189和US11激活规范T细胞中的作用。初步数据进一步表明，RhCMV通过重新分布到细胞质小泡来干扰MHC-II细胞表面的表达，这表明RhCMV抑制了MHC-II的直接抗原提呈。此外，我们还发现，当Gh/gl/UL131a/UL130/UL128五聚体亚基缺失时，RhCMV以高频诱导MHC-II限制性CD8+T细胞，这是另一个史无前例的发现。因此，在特定的目标3中，我们将描述RhCMV下调MHC-II的机制，以检验这样的假设：五聚体完整的RhCMV通过下调抗原提呈细胞中的MHC-II来阻止MHC-II限制性CD8+T细胞的启动，而五聚体缺陷的RhCMV无法做到这一点，因为五聚体复合体是病毒进入非成纤维细胞所必需的。这项工作的结果有望为CMV控制非常规CD8+T细胞靶向提供新的见解，最终将导致改进的HCMV疫苗和基于HCMV的疫苗载体的改进。