Human Herpesvirus 6 in Lower Respiratory Tract Disease and Chromosomal Integration after Hematopoietic Cell Transplantation

 描述(由申请人提供)：本提案描述了一项为期五年的研究培训计划，该计划将使希尔博士能够实现他的长期目标，即成为一名独立的、面向临床的学术研究人员，专注于免疫受损宿主中的病毒感染。希尔博士的目标是通过增进对人类疱疹病毒6型(HHV-6)和其他病毒相关疾病的了解，改善造血细胞移植(HCT)的结果。他将利用这些知识开发诊断技术和治疗策略，以减少免疫受损宿主因病毒感染而引起的并发症。这项建议建立在他在传染病方面的临床培训和这一领域的临床研究方法的基础上。希尔博士提供了一个详细的计划，以提高他在高级流行病学、生物统计学、分子病毒学和进行前瞻性研究方面的知识。这项建议融合了一批杰出导师的专业知识，其中包括传染病、流行病学、实验室医学、病理学和统计学方面的专家，他们致力于确保该项目的成功和希尔博士作为独立临床研究人员的职业发展。这项建议的第一个目的是进行一项大型的回顾性研究，以确定HHV-6在HCT后下呼吸道疾病(LRTD)中的临床意义。希尔博士将用定量聚合酶链式反应检测存档的支气管肺泡灌洗液(BALF)中的HHV-6DNA。根据这些结果、对患者记录的回顾以及血液和肺组织的分子检测，他将描述HHV-6在患有LRTD的HCT接受者中的流行病学、危险因素和临床影响。他的第二个目标将采用前瞻性的收集和处理BALF和全血，分别使用逆转录聚合酶链式反应和RNA-seq研究病毒和宿主基因的表达。这些结果将进一步表征HHV-6的分子发病机制，告知HHV-6DNA检测的意义，并有助于患者风险分层。第三个目标将利用新的分子技术来识别和研究染色体整合HHV-6的大量HCT受者的追溯队列，这是一种影响1-2%总人口的鲜为人知的疾病。虽然普遍认为是良性的，但初步证据表明，染色体整合的HHV-6可能是病理性HHV-6重新激活的来源，并可能保证常规的HCT前筛查。通过实现这项建议中的目标，希尔博士将解决我们对HHV-6感染在接受HCT治疗的患者中的重要性以及我们利用临床特征和新的分子诊断方法预测疾病的能力方面的关键空白。鉴于现有有效但具有潜在毒性的药物可用于治疗HHV-6，更好地了解这种病毒将为制定诊断、预防和治疗策略提供基础。最终，这项提议将允许希尔博士建立一个更大的研究项目，以促进对免疫受损宿主中病毒感染的了解，并改善患者的预后。

 DESCRIPTION (provided by applicant): This proposal describes a five-year research training program that will allow Dr. Hill to achieve his long-term goal of becoming an independent clinically-oriented academic researcher, focusing on viral infections in immunocompromised hosts. Dr. Hill's goal is to improve hematopoietic cell transplantation (HCT) outcomes by advancing understanding of diseases associated with human herpesvirus 6 (HHV-6) and other viruses. He will apply this knowledge to develop diagnostic techniques and therapeutic strategies that mitigate complications due to viral infections in immunocompromised hosts. This proposal builds upon his clinical training in infectious diseases and methodology for clinical research in this field. Dr. Hill provides a detailed plan to improve his knowledge of advanced epidemiology, biostatistics, molecular virology, and conducting prospective studies. This proposal incorporates the expertise of an outstanding group of mentors, including experts in infectious diseases, epidemiology, laboratory medicine, pathology, and statistics, who are dedicated to ensuring the success of this project and the development of Dr. Hill's career as an independent clinical researcher. The first aim of this proposal involves a large retrospective study to determine the clinical significance of HHV- 6 in lower respiratory tract disease (LRTD) after HCT. Dr. Hill will test archived bronchoalveolar lavage fluid (BALF) for HHV-6 DNA with quantitative PCR. Based on these results, review of patient records, and molecular testing of blood and lung tissue, he will describe the epidemiology, risk factors, and clinical impact of HHV-6 in HCT recipients with LRTD. His second aim will employ prospective collection and processing of BALF and whole blood for viral and host gene expression studies using reverse transcription PCR and RNA- seq, respectively. These results will further characterize the molecular pathogenesis of HHV-6, inform the significance of HHV-6 DNA detection, and facilitate patient risk-stratification. The third aim will capitalize on novel molecular techniquesto identify and study a large retrospective cohort of HCT recipients with chromosomally integrated HHV-6, a poorly understood condition affecting 1-2% of the general population. While generally believed to be benign, preliminary evidence suggests that chromosomally integrated HHV-6 can be the source of pathologic HHV-6 reactivation and may warrant routine pre-HCT screening. Through accomplishing the aims in this proposal, Dr. Hill will address critical gaps in our knowledge of the importance of HHV-6 infection in HCT recipients and our ability to use clinical characteristics and novel molecular diagnostics to predict disease. Given that effective but potentially toxic medications are available to treat HHV-6, a better understanding of this virus will provide the basis to develop diagnostic, prevention, and treatment strategies. Ultimately, thi proposal will allow Dr. Hill to build a larger research program to advance understanding of viral infections in immunocompromised hosts and improve patient outcomes.