HUMAN IMMUNE RESPONSES TO YELLOW FEVER VIRUS

描述（改编自应用摘要）：黄热病病毒（YF） 感染是非洲和南部非洲一个重要的新出现的健康问题， 美国，尽管获得了许可，安全和免疫原性YF 17 D 株疫苗。 关于对YF的细胞免疫应答或 人类的发病机制。 相关的T淋巴细胞研究 人黄病毒登革热已经证明了CD 4+和CD 8+记忆T细胞 用非结构性NS 3蛋白作为免疫显性蛋白产生。 最近，嵌合黄病毒已被开发出具有YF非结构 基因作为日本脑炎（JE）结构基因的骨架。 这些新 疫苗将很快进入I期临床试验，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 提出的主要目标 人类免疫反应的培训和研究 黄热病病毒 为了实现第一个目标 培训 两年 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教学研究。 学生将学习（1）构建疫苗/YF NS 3重组病毒; (2)设计引物建立巢式RT-PCR定性检测方法 （3）在人类灵长类动物标本中产生YF RNA的竞争者; 建立YF RNA定量竞争RT-PCR方法; (4)设计了一种YF/登革热嵌合病毒 我们研制的分子试剂 上述内容将在研究计划中使用。具体目标是：（1） 定义TF中T淋巴细胞识别的免疫显性蛋白- （2）通过定量RT-PCR检测病毒复制， 初次感染/接种期间的PCR及其与临床的关系 和/或免疫学结果;（3）确定是否存在相关性， 预先存在的记忆细胞毒性T淋巴细胞应答水平，或 中和抗体反应和随后病毒血症的发展， 中和抗体应答和/或细胞免疫应答 施用第二剂量的YF或嵌合YF/JE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.