A Nonhuman Primate Model of Infant CMV Infection

描述（由申请方提供）：人巨细胞病毒（HCMV）是全球最常见的先天性感染，也是新生儿严重出生缺陷的主要感染原因。HCMV长期以来被认为是对胎儿的感染性威胁，特别是在没有HCMV免疫力的妇女和怀孕期间有原发性HCMV感染的妇女中。孕妇的主要感染源是儿童亚临床HCMV感染。先天性或围产期感染的儿童比晚年感染HCMV的人传播病毒的时间更长，滴度更高。机制，为什么在产前或产后早期获得病毒的儿童脱落病毒的时间更长，滴度更高尚不清楚。考虑到与先天性HCMV感染相关的严重健康风险，打破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产生重要益处。这需要更好地了解病毒-宿主相互作用在非常年幼的儿童相比，成人。出于伦理原因，对新生儿的研究非常有限。因此，我们建议开发一个非人灵长类动物模型的婴儿HCMV感染的恒河猴巨细胞病毒（RhCMV）（目的1）经口感染的婴儿猕猴。已经开发了成年猕猴中HCMV发病机制的模型，其非常模拟人类中的HCMV感染。RhCMV感染婴儿模型的建立将为我们提供机会，以确定婴儿和成人之间的特异性免疫反应的差异，同时保持病毒接种物，剂量和传播途径恒定。潜在的假设是，HCMV感染患者的长期病毒学结果取决于最早的病毒-宿主相互作用。由于婴儿免疫系统不太成熟，因此整体HCMV反应不太可能控制病毒复制。HCMV特异性CD 4 +T细胞在控制病毒复制中起重要作用。因此，我们提出了一个假设，即婴儿CD 4 +T细胞的功能能力有限，如通过降低IFN-γ的产生来评估，结合婴儿中较高频率的调节性T细胞，干扰了有效的HCMV特异性CD 4 +T细胞的发育（目的2）。该假设将在目的1中建立的RhCMV感染的幼年猕猴模型中进行检验。拟议研究的结果对于了解婴儿对其他感染因子的免疫反应以及如何预防儿童的致病结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科抗病毒治疗和HCMV疫苗的有效性和安全性的独特资源。 公共卫生相关性：人巨细胞病毒（HCMV）是世界范围内最常见的先天性感染，是新生儿严重出生缺陷的主要感染原因。亚临床HCMV感染的儿童是孕妇HCMV感染的主要来源，因为HCMV感染的儿童比在生命后期获得HCMV的人更长时间和更高滴度地释放病毒。我们建议开发一种婴儿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发病机制中年龄相关差异的理解，长期目标是打破从亚临床感染儿童到孕妇再到胎儿的传播链。

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.