HUMAN IMMUNE RESPONSES TO YELLOW FEVER VIRUS

描述(摘自申请摘要)：黄热病病毒(YF) 在非洲和南非，感染是一个重要的和新出现的健康问题 美国，尽管有许可的、安全的和免疫原性的YF 17D 菌株疫苗。对YF或YF的细胞免疫反应知之甚少 人类的发病机制。一种相关疾病的T淋巴细胞研究 人类黄病毒登革热已经证明了CD4+和CD8+记忆T细胞 是由非结构性NS3蛋白作为免疫优势蛋白产生的。 最近，嵌合的黄病毒已经被开发出具有YF非结构的 日本脑炎(乙脑)结构基因的骨架基因。这些新的 疫苗即将进入第一阶段临床试验，并进一步强调 了解更多关于人类对YF的免疫反应的重要性。有两个 主要目标介绍了人类免疫反应方面的培训和研究 黄热病病毒。要实现第一个目标，培训两年 课程涉及生物化学、分子生物学、 细胞和分子免疫学、生物统计学和流行病学。实验室 轮换将补充分子生物学领域的说教研究。 候选人将学习(1)构建疫苗/YF NS3重组病毒； (2)设计引物，建立定性套式RT-PCR检测方法。 人类灵长类动物标本中YF RNA的含量；(3)创造一个竞争对手 YF RNA定量竞争RT-PCR滴定方法的建立 (4)研制YF/登革热嵌合病毒。发展起来的分子试剂 以上内容将在研究计划中使用。具体目标是：(1) 确定Tf-T淋巴细胞识别的免疫优势蛋白 (2)定量RT-RT检测病毒复制； 初次感染/接种过程中的聚合酶链式反应及其与临床的关系 和/或免疫结果；(3)确定之间是否存在相关性 预先存在的记忆细胞毒性T淋巴细胞反应水平或 中和抗体反应和随后的病毒血症的发展， 下列中和抗体反应和/或细胞免疫反应 接种第二剂YF或嵌合YF/乙脑疫苗。

DESCRIPTION (adapted from application abstract): Yellow fever virus (YF) infections are an important and emerging health problem in Africa and South America, despite the availability of the licensed, safe and immunogenic YF 17D strain vaccine. Little is known about the cellular immune responses to YF or the mechanism of pathogenesis in humans. T lymphocyte studies in a related human flavivirus, dengue, have demonstrated that CD4+ and CD8+ memory T cells are generated with the nonstructural NS3 protein as an immunodominant protein. Recently chimaeric flaviviruses have been developed with a YF nonstructural gene as a backbone for Japanese encephalitis (JE) structural genes. These new vaccines will soon enter Phase I clinical trials and further emphasize the importance of learning more about human immune responses to YF. There are two major goals presented training and research in human immune responses to yellow fever virus. To achieve the first goal training a two-year curriculum involving didactic training in biochemistry, molecular biology, cellular and molecular immunology, biostatistics and epidemiology. Laboratory rotations will complement didactic studies in the area of molecular biology. The candidate will learn (1) to construct a vaccines/YF NS3 recombinant virus; (2) to design primers to develop a qualitative nested RT-PCR for the detection of YF RNA in human primate specimens; (3) to create a competitor for the development of a quantitative competitor RT-PCR for the titration of YF RNA; (4) to engineer a YF/dengue chimaeric virus. The molecular reagents developed above will be utilized in the Research Plan. The specific aims are: (1) to define the immunodominant proteins recognized by T lymphocytes in TF- vaccinated individuals; (2) To examine viral replication by quantitative RT- PCR during primary infection/vaccination and its relationship to clinical and/or immunological outcome; (3) To determine if a correlation exists between the pre-existing level of memory cytotoxic T lymphocyte response or neutralizing antibody responses and the development of subsequent viremia, neutralizing antibody responses and/or cellular immune responses following administration of a second dose of YF or chimaeric YF/JE vaccine.