Immunologic and virologic determinants of congenital Cytomegalovirus transmission and disease in rhesus monkeys

先天性巨细胞病毒传播的免疫学和病毒学决定因素 和恒河猴的疾病。 先天性巨细胞病毒(CMV)是导致出生缺陷和婴儿神经系统疾病的主要感染原因。 缺陷，然而我们对保护性母体免疫反应的知识差距阻碍了 开发一种成功的巨细胞病毒疫苗，以消除这种导致婴儿发病的原因。的首要目标是 该计划旨在通过定义关键免疫来结束先天性CMV疫苗研究的僵局 决定胎儿巨细胞病毒原发传播和疾病的反应和病毒-宿主相互作用。要完成 这个项目建立在我们的恒河猴胎盘传播的新型非人灵长类(NHP)模型上 CMV(RhCMV)。具体地说，该计划将在RhCMV血清阴性的情况下使用这种新定义的NHP模型 孕妇研究胎盘病毒传播与胎儿疾病的免疫相关性(项目 1)和胎盘RhCMV传播的病毒决定因素(项目2)。一个行政核心和四个行政核心 科学核心提供整合方案活动所需的关键专业知识和资源，包括 行政基础设施和监督(行政核心)、国家惠普研究执行专门知识(核心) 1)、病毒生产和定量(核心2)、病毒全基因组测序和群体遗传学(核心 3)统计分析和数学建模(核心4)。我们的总体假设是母体 体液和细胞免疫对胎盘CMV传播和疾病提供部分保护，以及 病毒-宿主免疫相互作用决定胎盘传播和胎儿巨细胞病毒的出现 变种。我们的总体目标是：1)证明CMV特异性体液和/或细胞 反应赋予对先天性感染和胎儿疾病的保护效力；以及2)定义关键 胎盘CMV传播和随后胎儿的病毒学决定因素和病毒选择压力 疾病。我们希望该计划的工作将确定免疫反应和病毒学与宿主的相互作用 这将指导下一代先天性CMV疫苗的设计，并将完善NHP模型 为未来的CMV候选疫苗测试量身定做。

ABSTRACT – Immunologic and virologic determinants of congenital cytomegalovirus transmission and disease in rhesus monkeys. Congenital cytomegalovirus (CMV) is the leading infectious cause of birth defects and infant neurologic deficits, yet gaps in our knowledge of the protective maternal immune responses has impeded the development of a successful CMV vaccine to eliminate this cause of infant morbidity. The overarching goal of this Program is to end the stalemate in congenital CMV vaccine research by defining the key immune responses and viral-host interactions that dictate primary fetal CMV transmission and disease. To accomplish this, the Program builds on our novel nonhuman primate (NHP) model of placental transmission of rhesus CMV (RhCMV). Specifically, the Program will employ this newly defined NHP model in RhCMV-seronegative pregnant dams to investigate the immune correlates of placental virus transmission and fetal disease (Project 1) and the viral determinants of placental RhCMV transmission (Project 2). An Administrative Core and four scientific Cores provide critical expertise and resources required to integrate Program activities, including administrative infrastructure and oversight (Administrative Core), NHP study implementation expertise (Core 1), virus production and quantitation (Core 2), whole viral genome sequencing and population genetics (Core 3) and statistical analyses and mathematical modeling (Core 4). Our overall hypothesis is that maternal humoral and cellular immunity provides partial protection against placental CMV transmission and disease, and viral-host immune interactions determine the emergence of both placentally transmitted and fetal CMV variants. Our overall specific aims are: 1) Demonstrate whether CMV-specific humoral and/or cellular responses confer protective efficacy against congenital infection and fetal disease; and 2) Define the key virologic determinants and viral selection pressures of placental CMV transmission and subsequent fetal disease. We expect the work of this Program will identify immune responses and virologic-host interactions that will guide the design of the next generation of congenital CMV vaccines and will also refine the NHP model to tailor it for future CMV vaccine candidate testing.