Project 1: Impact of sustained ZIKV viremia in pregnancy

项目1-项目摘要/摘要 寨卡病毒(ZIKV)感染与出生谱增加有关 巴西的缺陷。孕妇的自然感染和恒河猴的实验感染 已经证明怀孕与长期的病毒血症有关，与感染 未怀孕的个体。在我们已发表和未发表的研究中，我们发现母体感染-- 妊娠早期而不是妊娠晚期使用ZIKV会导致视觉炎症组织损伤 系统(脉络膜、视网膜、视神经)，1例胎儿严重发育畸形 眼睛。此外，不分孕期感染，都有垂直传播给胎儿 是很常见的。因此，在ZIKV和MOS-1的地区，对胎儿的风险可能更大。 基多病媒比目前所认为的更流行。 严格检查母体病毒血症和胎儿生长发育情况，全面评估-- 新生儿感觉神经特征和病毒负荷的评估在人类临床上是不可能的 设置。非人灵长类动物提供了一个深入了解病理生理学的绝佳机会- ZIKV感染胎儿的CAL突起我们的总体假设是母体病毒血症的持续时间 提供明确的证据表明垂直传播与增加胎儿感染风险有关 因此，对胎儿神经发育的影响。为了将母体病毒血症与胎儿ZIKV感染联系起来，我们支持 提出两个具体目标。 具体目的1.确定母体ZIKV病毒血症对胎儿宫内发育的影响。 通过胎儿生长、垂直传播和组织损伤进行评估。 明确ZIKV宫内传播对出生缺陷发生率的影响。 我们将评估母体病毒血症和胎儿生长，并将母体病毒血症和母体 免疫反应随着对胎儿的影响，利用超声波监测胎儿发育。我们会 评估新生儿的畸形，并评估视觉、听觉和行为的功能缺陷 容量。病毒分布和组织病理学将在尸检时确定。最新进展 该模型对研究母体感染对新生儿感觉神经损伤的影响具有一定的价值。 在项目中为研究DENV与非人类灵长类动物的相互作用而向前迈进一步 2，并在项目3中用抗体治疗测试这些胎儿效应的治疗中断。

Project 1 - Project Summary/Abstract Infection with Zika virus (ZIKV) has been associated with an increased incidence of a spectrum of birth defects in Brazil. Natural infection in pregnant women, and experimental infection in rhesus macaques has demonstrated that pregnancy is associated with prolonged viremia, in comparison with infection of nonpregnant individuals. In our published and unpublished studies, we have found that maternal infec- tion with ZIKV in the first but not the third trimester results in inflammation tissue damage in the visual system (choroid, retina, optic nerve), and in one case, severe developmental malformations of the fetal eye. In addition, regardless of the gestational stage of infection, there vertical transmission to the fetus was common. Thus, there may be a more significant risk to the fetus in areas where ZIKV and the mos- quito vector is endemic than is currently appreciated. Rigorous examination of maternal viremia and fetal growth and development, and comprehensive eval- uation of neonatal sensorineural characteristics and viral burden will not be possible in human clinical settings. The nonhuman primate offers an outstanding opportunity to gain insight into pathophysiologi- cal processes in fetal infection with ZIKV. Our overall hypothesis is that duration of maternal viremia >28 provides unequivocal evidence of vertical transmission is associated with elevated fetal risk for infection and thus, fetal neurodevelopmental impact. To link maternal viremia and fetal ZIKV infection, we pro- pose two Specific Aims. Specific Aim 1. To determine the impact of maternal ZIKV viremia on fetal development in utero, as assessed by fetal growth, vertical transmission, and tissue damage. Specific Aim 2. To define the impact of in utero ZIKV transmission on the incidence of birth defects. We will assess maternal viremia and fetal growth, and associate maternal viremia and the maternal immune response with the impact on the fetus, using ultrasound to monitor fetal development. We will evaluate neonates for malformations of, and assess functional deficits in visual, auditory, and behavioral capacity. Viral distribution and tissue histopathology will be determined at necropsy. The development of this model to study impact of maternal infection on neonatal sensorineural injury will be a valuable step forward in building the nonhuman primate platform for studying interactions with DENV in Project 2, and testing therapeutic interruption of these fetal effects with antibody treatments in Project 3.