Emerging Antiviral Resistance in Congenital Cytomegalovirus Infection

描述（由申请人提供）：先天性巨细胞病毒感染中出现的抗病毒耐药性在美国，巨细胞病毒（CMV）是先天性感染的主要原因，每年导致超过6，000名婴儿出现永久性后遗症。更昔洛韦治疗6周后，对患有中枢神经系统症状的受影响婴儿的听力和神经发育结果的潜在益处已得到证实。随后的研究正在评估6周与6个月的口服缬更昔洛韦，以确定是否更长时间的抗病毒治疗将进一步改善结果。我们的初步研究表明，先天性感染的婴儿群体在治疗期间可能处于发展抗病毒药物耐药性的高风险中。我们对先天性CMV疾病婴儿抗病毒耐药性的研究旨在解决这一弱势人群最佳治疗管理医学知识的关键空白。我们假设先天性感染的婴儿有发生抗病毒耐药性的显著风险，这种耐药性会使受影响婴儿的听力和神经发育结果恶化。一个应用研究策略将被用来测试这一假设，努力促进我们的知识，如何最有效地改善长期的结果。在超过100名接受长期抗病毒治疗的先天性CMV感染婴儿的对照研究人群中，将使用常规和下一代DNA测序技术来证明耐药CMV菌株的多数和少数亚群的出现。下一代测序将进一步应用于研究有和没有选择性抗病毒压力的CMV感染的混合病毒群体动态。含有新型UL 97和UL 54序列变体的工程病毒的重组表型分析将探索以前未被识别的耐药突变。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，并直接适用于我们的研究人群之外。这些研究的候选主要研究者是伯明翰亚拉巴马大学儿科传染病部的初级教员，具有培训背景和研究环境，为实现研究目标提供了良好的支持。短期培训目标载于一个多方面的职业发展计划，该计划将教学和实践培训相结合，以确保候选人在实施这些研究期间成为成熟的研究人员。在授予期间的职业发展最终将旨在为候选人提供有竞争力的R 01申请，以符合其成为独立调查员的长期职业目标。 相关性：巨细胞病毒（CMV）是美国最常见的先天性感染，通常导致听力损失和/或神经发育迟缓形式的永久性残疾。抗病毒治疗可改善临床结局，但抗病毒药物耐药的临床意义尚不清楚。该项目调查了有症状的先天性CMV感染婴儿中抗病毒耐药性的出现，探讨了耐药性对临床结局的影响，并使用新技术推进CMV耐药性分析领域。

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.