Project 1: Impact of sustained ZIKV viremia in pregnancy

项目1 -项目摘要/摘要

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 In our published and unpublished studies, we have found that maternal infec- tion with ZIKV in the first but not the third trimester results in inflammation tissue damage in the visual system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.