Emerging Antiviral Resistance in Congenital Cytomegalovirus Infection

先天性巨细胞病毒感染中出现的抗病毒耐药性

• 批准号: 9315768
• 负责人: Scott H James
• 金额: $ 17.83万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315768
• 关键词: AIDS/HIV problem; Address; Affect; Alabama; Antiviral Agents; Antiviral Therapy; Antiviral resistance; Appearance; Applied Research; Award; Bacterial Artificial Chromosomes; Blinded; Characteristics; Childhood; Clinical; Communicable Diseases; Controlled Study; Cytomegalovirus; Cytomegalovirus Infections; DNA sequencing; Development; Development Plans; Disease; Drug resistance; Engineering; Enrollment; Ensure; Environment; Faculty; Future; Ganciclovir; Gene Amplification; Genes; Genotype; Goals; Growth; Hearing; Infant; Investigation; Knowledge; Mediating; Medical; Minority; Mutation; Neuraxis; Oral; Outcome; Outcomes Research; Phase; Phenotype; Point Mutation; Population; Population Dynamics; Principal Investigator; Randomized; Recombinants; Research; Research Personnel; Resistance; Resistance development; Resistance profile; Risk; Specimen; Symptoms; Techniques; Testing; Therapeutic; Training; Transplant Recipients; United States; Universities; Valganciclovir; Variant; Viral Load result; Virus; Vulnerable Populations; Whole Blood; career; career development; clinically significant; congenital cytomegalovirus; congenital infection; disability; hearing impairment; high risk; improved; improved outcome; member; new technology; next generation; next generation sequencing; novel; patient population; pressure; recombinant virus; resistance mutation; response; study population; therapy duration; virology

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.

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 6,000 多名婴儿出现永久性后遗症。在接受 6 周更昔洛韦疗程后，出现中枢神经系统症状的受影响婴儿已证明对听力和神经发育结果具有潜在益处。随后的研究正在评估 6 周与 6 个月的口服缬更昔洛韦，以确定较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，先天感染的婴儿群体在治疗期间可能面临产生抗病毒耐药性的高风险。我们提议对患有先天性 CMV 疾病的婴儿出现抗病毒耐药性进行调查，旨在弥补这一弱势群体最佳治疗管理的医学知识中的关键差距。我们假设先天性感染的婴儿存在产生抗病毒耐药性的重大风险，并且这种耐药性会恶化受影响婴儿的听力和神经发育结果。将采用应用研究策略来检验这一假设，以努力增进我们对如何最有效地改善长期结果的了解。在一项由 100 多名患有先天性 CMV 感染且长期接受抗病毒治疗的婴儿组成的对照研究中，将利用传统和下一代 DNA 测序技术来证明大多数和少数耐药 CMV 毒株亚群的出现。下一代测序将进一步应用于研究有或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 UL97 和 UL54 序列变体的工程病毒的重组表型分析将探索以前未识别的抗性突变。新耐药突变的确认是推进 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，其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作为一名成熟的研究人员。获奖期间的职业发展最终目标是让候选人为竞争性的 R01 提交做好准备，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，通常会导致听力损失和/或神经发育迟缓等永久性残疾。抗病毒治疗可改善临床结果，但抗病毒耐药性在该人群中的临床意义尚不清楚。该项目调查有症状的先天性 CMV 感染婴儿中抗病毒耐药性的出现，探讨耐药性对临床结果的影响，并利用新技术推进 CMV 耐药性分析领域。