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，发生率为美国所有活产婴儿的0.5% -1.0%。据估计，25%至40%的儿童听力损失是由宫内巨细胞病毒感染引起的。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%的儿童发展为SNHL。近一半患有巨细胞病毒相关SNHL的儿童在出生时听力正常，在语言发育的关键阶段出现听力缺陷。CCMV相关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。多种病毒株感染时有发生，但最近的数据显示，宿主内巨细胞病毒株的变异性等于RNA病毒的变异性。由于患有CCMV的儿童多年来携带大量病毒，我们假设多样性可能是由高水平的病毒复制产生的，而高水平的病毒多样性会导致这种感染的不良后果。本建议的目的是确定先天性巨细胞病毒感染儿童的大量明确人群中所有脱落区室巨细胞病毒株的多样性。我们还将研究改变病毒复制的因素的影响；免疫反应和抗病毒治疗，对病毒种群随时间的变化。通过确定CCMV感染中病毒多样性的总体意义，并进一步确定选择压力如何影响多样性和随后的后遗症，我们将能够确定SNHL的相关因素，并设计更好的抗病毒药物来改善CCMV婴儿的长期预后。

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.