权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Genetic Pathways of Human Cytomegalovirus Drug Resistance

人类巨细胞病毒耐药性的遗传途径

基本信息

批准号：
10455774
负责人：
Sunwen Chou
金额：
$ 31.5万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-13 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455774
关键词：
Alternative Therapies Antiviral Agents Antiviral Therapy Area Cells Cidofovir Cytomegalovirus Cytomegalovirus Infections DNA Polymerase Inhibitor DNA-Directed DNA Polymerase Data Development Diagnosis Diagnostic Disease Drug Exposure Drug resistance Evaluation Evolution Exposure to Foscarnet Future Ganciclovir Genes Genetic Genetic Polymorphism Genotype Human Immunocompromised Host In Vitro Laboratories Malignant Neoplasms Mission Morphologic artifacts Mutation Opportunistic Infections Oral Pathway interactions Pharmaceutical Preparations Phenotype Phosphotransferases Point Mutation Predisposition Prodrugs Prophylactic treatment Recombinants Research Resistance Resistance profile Specimen Structure Testing Therapeutic Toxic effect Transplant Recipients Tropism Valganciclovir Variant Viral active method anti-viral efficacy clinical Diagnosis clinical diagnostics clinical practice comparative cost deep sequencing design drug candidate experience fitness improved in vivo inhibitor/antagonist kinase inhibitor maribavir novel phase III trial receptor resistance gene resistance mechanism resistance mutation stem cells terminase viral DNA whole genome

项目摘要

Project Summary Toxicity and drug resistance limit the efficacy of antiviral therapy for cytomegalovirus (CMV) disease in immunosuppressed hosts such as cancer and transplant recipients. Current therapy includes DNA polymerase inhibitors ganciclovir, foscarnet and cidofovir. The terminase inhibitor letermovir was recently approved for prophylaxis, and the UL97 kinase inhibitor maribavir is in late stage trial as alternative therapy. In clinical practice, CMV drug resistance cannot be diagnosed by direct phenotypic testing of viral isolates, and instead is dependent on an accurate correlation of detected viral mutations and associated resistance phenotypes. The enduring objective of this research is to determine the genetic mechanisms of CMV drug resistance in order to improve clinical diagnosis and the development of alternate therapies. Many resistance mutations and polymorphisms in the CMV UL97 kinase, UL54 DNA polymerase and UL56/UL89/UL51 terminase genes have been and continue to be phenotyped, with diagnostically important new resistance loci being identified during each project period. Technical advances in recombinant phenotyping and whole genome deep sequencing are facilitating this research. In the upcoming project period, new focus areas include the characterization of mutations selected after drug exposure in genes outside of known antiviral targets, and analysis of the effects of baseline viral strain variation on drug susceptibility. Specific aims are (1) continued evaluation of the evolution and phenotypes of CMV mutations that develop after in vitro or in vivo exposure to antiviral compounds and combinations; (2) evaluate the phenotypic significance of genetic changes identified by viral whole genome deep sequencing that are outside of known antiviral target genes, and (3) determine the impact of baseline viral strain on drug susceptibility phenotypes by characterization of alternative viral clones and host cells.

项目概要毒性和耐药性限制了巨细胞病毒抗病毒治疗的疗效免疫抑制宿主（例如癌症和移植受者）中的巨细胞病毒（CMV）疾病。目前的疗法包括 DNA 聚合酶抑制剂更昔洛韦、膦甲酸和西多福韦。终止酶抑制剂莱特莫韦最近被批准用于预防，而 UL97 激酶抑制剂马瑞巴韦作为替代疗法正处于后期试验阶段。在临床实践中， CMV 耐药性不能通过病毒分离株的直接表型测试来诊断，相反，取决于检测到的病毒突变和相关的耐药表型。这项研究的持久目标是确定CMV耐药的遗传机制，以改善临床诊断和替代疗法的开发。许多耐药突变和 CMV UL97 激酶、UL54 DNA 聚合酶和 UL56/UL89/UL51 的多态性终止酶基因已经并将继续进行表型分析，具有诊断意义在每个项目期间都确定了重要的新抗性位点。技术的重组表型分析和全基因组深度测序的进展促进这项研究。在即将到来的项目期间，新的重点领域包括药物暴露后在已知基因之外选择的突变的特征抗病毒靶点，以及分析基线病毒株变异对药物的影响易感性。具体目标是（1）持续评估进化和表型体外或体内暴露于抗病毒化合物后发生的 CMV 突变和组合； (2)评估所鉴定的遗传变化的表型意义通过已知抗病毒靶基因之外的病毒全基因组深度测序， (3) 通过以下方法确定基线病毒株对药物敏感性表型的影响替代病毒克隆和宿主细胞的表征。