Emerging Antiviral Resistance in Congenital Cytomegalovirus Infection

描述(申请人提供)：出现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6000多名婴儿出现永久性后遗症。在6周的更昔洛韦疗程后，有中枢神经系统症状的受影响婴儿已经证明对听力和神经发育结果有潜在的好处。随后的研究正在评估口服伐更昔洛韦的6周和6个月，以确定更长时间的抗病毒治疗是否会进一步改善结果。我们的初步研究表明，先天感染的婴儿在治疗期间可能处于产生抗病毒耐药性的高危状态。我们提出的关于先天性巨细胞病毒病婴儿出现抗病毒耐药性的调查旨在解决在这一脆弱人群中最佳治疗管理的医学知识方面的一个关键差距。我们假设，先天感染的婴儿有很大的风险产生抗病毒耐药性，这种耐药性将恶化受感染婴儿的听力和神经发育结果。将采用一种应用研究策略来检验这一假设，以努力帮助我们了解如何最有效地改善长期结果。在一项对100多名先天性巨细胞病毒感染婴儿进行长期抗病毒治疗的对照研究中，常规和下一代DNA测序技术将被用来证明大多数和少数耐药巨细胞病毒株亚群的出现。下一代测序将进一步应用于研究在有和没有选择性抗病毒压力的情况下CMV感染的混合病毒种群动力学。含有新的UL97和UL54序列变体的工程病毒的重组表型将探索以前未被识别的耐药性突变。确认新的耐药性突变是推进CMV抗病毒耐药性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。这些研究的候选人首席研究员是阿拉巴马大学伯明翰分校儿科传染病系的初级教员，他的培训背景和研究环境为实现研究目标提供了极好的支持。短期培训目标在多方面的职业发展计划中列出，该计划结合了授课培训和实践培训，将确保候选人在实施这些研究期间成熟为一名研究人员。在授权期内的职业发展最终将旨在为候选人准备一份竞争性的R01报告，以符合他成为一名独立调查员的长期职业目标。 相关：巨细胞病毒(CMV)是美国最常见的先天性感染，通常会导致永久性残疾，表现为听力损失和/或神经发育迟缓。抗病毒治疗改善了临床结果，但在这一人群中，抗病毒耐药性的临床意义尚不清楚。本项目研究婴儿先天性巨细胞病毒感染中出现的抗病毒耐药性，探索耐药性的形成对临床结局的影响，并利用新技术推动巨细胞病毒耐药性分析领域的发展。

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.