Emerging Antiviral Resistance in Congenital Cytomegalovirus Infection

在美国，巨细胞病毒（CMV）是先天性感染的主要原因，每年导致6000多名婴儿永久性后遗症。更昔洛韦治疗6周后，对有中枢神经系统症状的患儿的听力和神经发育结果有潜在益处。随后的研究正在评估口服缬更昔洛韦6周与6个月的对比，以确定更长时间的抗病毒治疗是否会进一步改善预后。我们的初步研究表明，先天性感染的婴儿群体在接受治疗时可能有很高的抗病毒药物耐药性风险。我们提出的对先天性巨细胞病毒疾病婴儿抗病毒药物耐药性的研究旨在解决这一弱势群体在最佳治疗管理方面的医学知识的关键空白。我们假设，先天性感染的婴儿有很大的风险产生抗病毒药物耐药性，这种耐药性会使受影响婴儿的听力和神经发育结果恶化。我们将采用应用研究策略来检验这一假设，以帮助我们了解如何最有效地改善长期结果。在一项超过100名接受长期抗病毒治疗的先天性巨细胞病毒感染婴儿的对照研究中，将利用传统和下一代DNA测序技术来证明耐药巨细胞病毒菌株的大多数和少数亚群的出现。下一代测序技术将进一步应用于研究有和无选择性抗病毒压力时巨细胞病毒感染的混合病毒种群动态。含有新型UL97和UL54序列变异的工程病毒的重组表型分析将探索以前未被识别的抗性突变。确认新的耐药突变是推进CMV抗病毒耐药知识领域的一个重要方面，并且直接适用于我们的研究人群之外。这些研究的候选首席研究员是阿拉巴马大学伯明翰分校儿科传染病科的一名初级教员，具有良好的培训背景和研究环境，为研究目标的实现提供了良好的支持。短期培训目标是在多方面的职业发展计划中制定的，该计划将教学和实践培训相结合，以确保候选人在这些研究的实施过程中成熟为一名研究人员。在奖励期间的职业发展最终将旨在为候选人准备有竞争力的R01提交，以保持其成为独立研究者的长期职业目标。

DESCRIPTION (provided by applicant): Emerging Antiviral Resistance in Congenital Cytomegalovirus Infection In the United States, cytomegalovirus (CMV) is the leading cause of congenital infection and leads to permanent sequelae in over 6,000 infants per year. Potential benefits for hearing and neurodevelopmental outcomes have been demonstrated in affected infants with central nervous system symptoms after a 6-week course of ganciclovir. Subsequent studies are evaluating 6 weeks versus 6 months of oral valganciclovir to determine if a longer duration of antiviral therapy will further improve outcomes. Our preliminary studies indicate that the population of congenitally infected infants could be at high risk for developing antiviral resistance while on therapy. Our proposed investigation into the emergence of antiviral resistance in infants with congenital CMV disease seeks to address a critical gap in medical knowledge of optimal therapeutic management in this vulnerable population. We hypothesize that congenitally infected infants are at significant risk for developing antiviral resistance and that such resistance will worsen the hearing and neurodevelopmental outcomes of affected infants. An applied research strategy will be employed to test this hypothesis in an effort to contribute to our knowledge of how to most effectively improve long-term outcomes. In a controlled study population of over 100 infants with congenital CMV infection who are exposed to prolonged antiviral therapy, both conventional and next-generation DNA sequencing techniques will be utilized to demonstrate the emergence of majority and minority subpopulations of drug-resistant CMV strains. Next- generation sequencing will be further applied to investigate the mixed virus population dynamics of CMV infections with and without selective antiviral pressure. Recombinant phenotyping of engineered viruses containing novel UL97 and UL54 sequence variants will explore previously unrecognized resistance mutations. Confirmation of new resistance mutations is an important aspect of advancing the field of knowledge of CMV antiviral resistance and is directly applicable beyond our study population. The candidate Principal Investigator for these studies is a junior faculty member in the Division of Pediatric Infectious Diseases at the University of Alabama at Birmingham, with a training background and research environment that provides excellent support for the accomplishment of the study aims. Short-term training objectives are laid out in a multifaceted career development plan that integrates a combination of didactic and hands-on training that will ensure that the candidate matures as a researcher during the implementation of these studies. Career development over the course of the award period ultimately will aim to prepare the candidate for a competitive R01 submission in keeping with his long-term career goal of becoming an independent investigator. RELEVANCE: Cytomegalovirus (CMV) is the most common congenital infection in the United States, often leading to permanent disability in the form of hearing loss and/or neurodevelopmental delay. Antiviral therapy improves clinical outcomes, but the clinical significance of antiviral resistance is unknown in this population. This project investigates the emergence of antiviral resistance in infants with symptomatic congenital CMV infection, explores the impact of developing resistance on clinical outcomes, and uses new technologies to advance the field of CMV resistance analysis.