HSV-1-specific T-cell responses in human sensory ganglia

1R21AI081060-01A1 Koelle，David M. HSV-1是一种重要的人类病原体，会导致角膜、视网膜和大脑的严重感染 组织、面部和口腔组织，还造成围产期发病率和死亡率。没有 获得许可的HSV-1疫苗。慢性HSV-1感染的部位在感觉神经节的神经元内， 尤其是三叉神经节(TG)，它支配面部、角膜和脑膜。大鼠的动物模型 HSV-1感染最近证明TG是与HSV-1感染有关的免疫活性器官。 存在神经节驻留的HSV-1特异性CD8和CD4T细胞，并且这些细胞具有 在外植体和移植系统中很重要。甘油三酯-单纯疱疹病毒1型慢性期免疫学研究 与HSV-1共同进化了数百万年的自然宿主，本申请关注的是 无名人身体组织对HSV-1的TG免疫应答。长期目标 HSV-1研究计划的关键是合理设计HSV-1亚单位疫苗和 人TG中抗原处理和呈递给HSV-1特异性T细胞的理解。这笔赠款 代表着有计划的持续关注HSV-1免疫学的开始。第一个目标是 确定人类HSV-1特异性CD8 T细胞识别哪些HSV-1表位和抗原 单纯疱疹病毒1型感染三叉神经节。我们将使用虚拟HSV-1OFeome和人工抗原 呈现细胞解剖甘油三酯组织中HSV-1特异性CD8 T细胞反应。第二个目标是 确定人类HSV-1特异性CD4T细胞识别哪些HSV-1表位和抗原 TG组织。供体内含有多个表位的抗原，可由来自 多个供体，并被CD4和CD8 T细胞识别，如果检测到这些，将是合理的 HSV-1亚单位或载体疫苗的候选者。

1R21AI081060-01A1 Koelle, David M. HSV-1 is a significant human pathogen, causing serious infections of the cornea, retina, brain parenchyma, and facial and oral tissues, and also causing perinatal morbidity and mortality. There is no licensed vaccine for HSV-1. The locus of chronic HSV-1 infection is within neurons in sensory ganglia, particularly the trigeminal ganglia (TG) that enervate that face, cornea, and meninges. Animal models of HSV-1 infection have recently proven that the TG is an immunocompetent organ with regard to the presence of ganglia-resident, HSV-1-specific CD8 and CD4 T-cells, and that these cells are functionally important in explant and transplant systems. To study chronic phase TG HSV-1 immunology in the natural host that HSV-1 has been co-evolving with for millions of years, the present application focuses on the TG immune response to HSV-1 in tissue from anonymous human cadavers. The long term goals of the HSV-1 research program are the rational design of an HSV-1 subunit vaccine and an understanding of antigen processing and presentation to HSV-1-specific T-cells in human TG. This grant represents the beginning of a planned sustained focus on HSV-1 immunology. The first Aim is to determine which HSV-1 epitopes and antigens are recognized by HSV-1-specific CD8 T-cells in human HSV-1-infected trigeminal ganglia. We will use a virtual HSV-1 ORFeome and artificial antigen presenting cells to dissect the HSV-1-specific CD8 T-cell response in TG tissues. The second Aim is to determine which HSV-1 epitopes and antigens are recognized by HSV-1-specific CD4 T-cells in human TG tissues. Antigens that contain multiple epitopes within-donor, that are recognized by T-cells from multiple donors, and are recognized by both CD4 and CD8 T-cells, if these are detected, will be rational candidates for HSV-1 subunit or vectored vaccines.