MOLECULAR EPIDEMIOLOGY OF PRIMARY CMV INFECTION

描述（由申请人提供）：Ravit Boger博士是约翰霍普金斯大学儿科传染病科的助理教授。近年来，她与她的导师海沃德博士和帕斯博士一起研究巨细胞病毒株变异。通过此次K08奖，她将进行转化研究，以确定健康成人原发性巨细胞病毒感染的分子流行病学，并获得分子流行病学和病毒学方面的专业知识，以及基因组测序、实时PCR和负责任的研究行为方面的高级技能。分子技术已经在人群中检测到许多巨细胞病毒株。传统上认为，人类原发性巨细胞病毒感染是由单一毒株引起的，分离出多个毒株被认为是再次感染的证据。虽然特定人群（移植受者、艾滋病患者、日托儿童等）可能随着时间的推移再次感染多种巨细胞病毒毒株，但此前没有研究确定健康受试者的初始巨细胞病毒感染是否涉及多种毒株。先前，我们从CMV诱导的胎儿死亡组织中鉴定出多种CMV菌株，但仅从CMV感染的活婴培养分离株中鉴定出一种菌株。目前尚不清楚这种差异是否具有临床意义，或者与直接从组织中测序而不是在培养中选择优先分离株后测序有关。本应用程序旨在描述一组参加随机双盲gB疫苗试验并在随访期间血清转化的健康妇女原发性巨细胞病毒感染期间的菌株异质性。Boger博士将分析从原始体液和培养分离物的系列样本中获得的高变巨细胞病毒基因，这些样本是在原发性巨细胞病毒感染期间和6-24个月后从这些个体获得的。她还将确定疫苗诱导的免疫是否会随着时间的推移影响病毒株的获得，以及特定基因型是否与各种体液中的病毒载量有关。这项研究将有助于了解毒株多样性在多大程度上可以作为再感染的证据，以及自然巨细胞病毒感染如何导致对该病毒的广泛免疫。这项工作与公共卫生有关，因为毒株变异可能导致某些感染的毒力增加，并且因为毒株变异现象可能影响旨在预防先天性巨细胞病毒感染的有效疫苗的开发。

DESCRIPTION (provided by applicant): Dr. Ravit Boger is an assistant professor, division of pediatric infectious diseases at Johns Hopkins. In recent years, she worked with her mentors Dr. Hayward and Dr. Pass on CMV strain variation. Through this K08 award, she will conduct translational research to determine the molecular epidemiology of primary CMV infection in healthy adults, and gain expertise in molecular epidemiology and virology, advanced skills in genome sequencing, real-time PCR, and the responsible conduct of research. Molecular techniques have detected numerous CMV strains in the population. Primary human CMV infection is traditionally believed to be caused by a single strain, and isolation of multiple strains has been considered proof of re-infection. While specific populations (transplant recipients, AIDS patients, children in day care, etc.) may over time be re-infected with multiple CMV strains, no previous studies have determined whether initial CMV infection in healthy subjects involves multiple strains. Previously, we identified multiple CMV strains from tissues of CMV-induced fetal demise, yet only a single strain was identified from cultured isolates of CMV-infected live infants. It is unclear whether this difference has clinical significance or is related to direct sequencing from tissue as opposed to sequencing after selection of preferential isolates in culture. This application aims to characterize strain heterogeneity during primary CMV infection in a cohort of healthy women who participated in a randomized double-blind gB vaccine trial and who seroconverted during follow up. Dr. Boger will analyze hypervariable CMV genes from serial samples of original body fluids and cultured isolates that have been obtained from these individuals during primary CMV infection and 6-24 months afterwards. She will also determine whether vaccine-induced immunity affects the acquisition of strains over time, and whether specific genotypes are associated with viral load in various body fluids. This study will help understand the extent to which strain diversity can be used as evidence of re-infection and how natural CMV infection leads to broad immunity to the virus. This work is relevant to public health since strain variation may be responsible for increased virulence of some infections and because the phenomenon of strain variation may impact on the development of effective vaccine aimed at prevention of congenital CMV infection.