Viral diversity in congenital cytomegalovirus infection

描述(由申请人提供)：先天性巨细胞病毒(CCMV)是最常见的先天性感染，发生在美国所有活产婴儿的0.5%-1.0%。据估计，所有儿童听力损失的25%至40%是由宫内CMV感染引起的。大多数先天性巨细胞病毒感染的婴儿(约90%)在出生时没有可检测到的临床异常(无症状感染)，其中约10%发展为SNHL。近一半患有CMV相关SNHL的儿童出生时听力正常，并在语言发育的关键阶段出现听力障碍。CCMV相关的SNHL的发病机制尚不清楚，目前还没有针对所有CCMV感染患者的既定治疗方法。会感染多种病毒株，但最近的数据显示，CMV株在宿主内的变异性与RNA病毒的变异性相同。由于患有CCMV的儿童多年来携带大量病毒，我们假设病毒的多样性可能是由高水平的病毒复制产生的，较高的病毒多样性会导致这种感染的不良后果。这项建议的目的是确定在大量明确定义的先天性巨细胞病毒感染儿童中，巨细胞病毒株在所有脱落间隔中的多样性。我们还将研究改变病毒复制的因素；免疫反应和抗病毒治疗，随着时间的推移对病毒种群变化的影响。通过确定病毒多样性在CCMV感染中的总体意义，并进一步定义选择性压力如何影响多样性和后续后遗症，我们将能够确定SNHL的相关性，并设计更好的抗病毒药物来改善CCMV婴儿的长期预后。 公共卫生相关性：先天性巨细胞病毒是新生儿中最先天性的感染，也是导致儿童听力损失的主要原因，但对该病毒如何致病知之甚少。该项目将确定多种巨细胞病毒株导致先天性感染的频率，并确定是否有更多的病毒株与听力损失有关。识别与巨细胞病毒相关的听力损失将有助于确定10%-15%的先天性巨细胞病毒婴儿的不良结局风险最高，并允许更有针对性地监测听力，并有机会在言语和语言发育的关键阶段采用更好的治疗方法进行干预。

DESCRIPTION (provided by applicant): Congenital CMV (CCMV) is the most common congenital infection occurring in 0.5% -1.0% of all live born infants in the U.S. It is estimated tat between 25% and 40% of all childhood hearing loss is caused by intrauterine CMV infection. Most infants (~90%) with congenital CMV infection have no detectable clinical abnormalities at birth (asymptomatic infection), and about 10% of these children develop SNHL. Nearly half of children with CMV-associated SNHL have normal hearing at birth and develop hearing deficits during critical stages of language development. The pathogenesis of CCMV-related SNHL is poorly understood and there is currently no established therapy for all patients with CCMV infection. Infection with multiple virus strains occurs but recent data has revealed that the variability of CMV strains within a host equals that of RNA viruses. As children with CCMV harbor large amounts of virus for many years, we hypothesize that diversity is likely generated by high levels of virus replication and higher viral diversity leads to adverse outcome in this infection. The purpose of this proposal is to define the diversity of CMV strains in all compartments of shedding in a large, well defined population of children with congenital CMV infection. We will also examine the effects of factors that alter viral replication; the immune response and antiviral therapy, on changes in viral populations over time. By determining the overall significance of viral diversity in CCMV infection, and further defining how selective pressures affect diversity and subsequent sequelae, we will then be able to define correlates of SNHL and design better anti-virals to improve long term outcomes in infants with CCMV. PUBLIC HEALTH RELEVANCE: Congenital CMV is the most congenital infection in newborns, and a leading cause of hearing loss in children, yet little is understood about how the virus causes disease. This project will define how frequent multiple strains of CMV cause congenital infection and determine if more viral strains are associated with hearing loss. Identifying a correlate for CMV related hearing loss will aid in identifying the 10-15% of infants with congenital CMV at highest risk for adverse outcome and allow for more focused monitoring of hearing and the opportunity to intervene with better therapies during critical stages of speech and language development.