A Nonhuman Primate Model of Infant CMV Infection

描述(申请人提供)：人类巨细胞病毒(HCMV)是世界上最常见的先天性感染，也是导致新生儿严重出生缺陷的主要感染原因。长期以来，巨细胞病毒一直被认为是对胎儿的一种传染性威胁，特别是在没有巨细胞病毒免疫力的妇女和在怀孕期间有原发巨细胞病毒感染的妇女中。孕妇的主要感染源是临床下感染巨细胞病毒的儿童。先天或围产期感染的儿童比晚年感染HCMV的儿童排出病毒的时间更长，滴度更高。机制(S)，为什么在产前或出生后早期感染病毒的儿童排出病毒的时间更长，滴度更高，这一点尚不清楚。考虑到与先天性巨细胞病毒感染相关的严重健康风险，切断从亚临床感染儿童到孕妇再到胎儿的传播链将对人类健康有重要好处。与成人相比，这需要更好地了解幼童体内的病毒与宿主的相互作用。出于伦理原因，对新生儿的研究非常有限。因此，我们建议建立一种非人类灵长类动物模型，通过口服感染猕猴巨细胞病毒(RhCMV)(目标1)。已建立了成年猕猴巨细胞病毒致病模型，该模型与人类巨细胞病毒感染十分相似。在保持病毒接种量、剂量和传播途径不变的情况下，建立婴儿RhCMV感染的婴儿模型将使我们有机会确定婴儿和成人对RhCMV感染的特异性免疫反应的差异。潜在的假设是，HCMV感染患者的长期病毒学结果取决于病毒与宿主最早的相互作用。由于婴儿的免疫系统不太成熟，整体的HCMV反应不太可能控制病毒复制。巨细胞病毒特异性的CD4+T细胞在控制病毒复制中起着重要作用。因此，我们提出假设，婴儿CD4+T细胞的功能能力有限，通过减少干扰素-g的产生来评估，再加上婴儿中较高频率的调节性T细胞，干扰了有效的HCMV特异性CD4+T细胞的发育(目标2)。这一假设将在AIM 1中建立的婴儿感染RhCMV的猕猴模型中得到验证。拟议的研究结果对于了解婴儿对其他感染源的免疫反应以及如何预防儿童的致病后果具有更广泛的重要性。因此，婴儿HCMV感染的非人灵长类动物模型将是测试儿童抗病毒治疗和HCMV疫苗有效性和安全性的独特资源。与公共卫生相关：人类巨细胞病毒(HCMV)是世界上最常见的先天性感染，也是导致新生儿严重出生缺陷的主要感染原因。儿童亚临床型HCMV感染是孕妇HCMV感染的主要来源，因为感染HCMV的儿童比晚年感染HCMV的儿童排出病毒的时间更长，滴度更高。我们建议建立婴儿HCMV感染的非人灵长类动物模型，以促进我们对婴儿和成人HCMV发病机制的年龄相关差异的理解，长期目标是切断从亚临床感染的儿童到孕妇到胎儿的传播链。

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is the most common congenital infection worldwide and the primary infectious cause of serious birth defects in newborns. HCMV has long been recognized as an infectious threat to the fetus, particularly in women without HCMV immunity and who have a primary HCMV infection during pregnancy. The major source of infection for pregnant women are children with subclincal HCMV infection. Children that become infected congenitally or perinatally shed virus for longer periods of time and at higher titers than people that acquire HCMV later in life. The mechanism(s), why children who acquire the virus early in prenatal or post-natal life shed the virus longer and in higher titers are not known. Considering the severe health risks associated with congenital HCMV infection, breaking the chain of transmission from subclinically infected children to pregnant women to fetuses would have important benefits for human health. This requires a better understanding of virus-host interactions in very young children as compared to adults. For ethical reasons, studies in newborns are very limited. Thus, we propose to develop a nonhuman primate model of infant HCMV infection by orally infecting infant macaques with rhesus CMV (RhCMV) (Aim 1). A model of HCMV pathogenesis in adult macaques has been developed and closely mimics HCMV infection in humans. The establishment of an infant model of RhCMV infection will provide us with the opportunity to define differences in specific immune responses to RhCMV infection between infants and adults while keeping the virus inoculum, the dose, and the route of transmission constant. The underlying assumption is that long-term virological outcome in HCMV infected patients depends on the earliest virus-host interactions. As the infant immune system is less mature, the overall HCMV response is less likely to control virus replication. HCMV-specific CD4+T cells have been implicated to play an essential role in the control of virus replication. Thus, we present the hypothesis that a limited functional capacity of infant CD4+T cells, as assessed by reduced IFN-g production, combined with higher frequencies of regulatory T cells in infants interfere with the development of effective HCMV-specific CD4+T cells (Aim 2). This hypothesis will be tested in the infant macaque model of RhCMV infection established in Aim 1. The results of the proposed studies should be of broader importance for understanding infant immune responses to other infectious agents and how to prevent a pathogenic outcome in children. Thus, a nonhuman primate model of infant HCMV infection would be a unique resource to test the efficacy and safety of pediatric antiviral therapies and HCMV vaccines. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus (HCMV) is the most common congenital infection worldwide and is the primary infectious cause of serious birth defects in newborns. Children with sublinical HCMV infection are the major source for HCMV infection in pregnant women because HCMV infected children shed virus for a longer time and at higher titers that people that acquire HCMV later in life. We propose to develop a nonhuman primate model of infant HCMV infection to advance our understanding of the age-related differences in HCMV pathogenesis in infants and adults with the longterm goal of breaking the chain of transmission from subclinically infected children to pregnant women to fetuses.