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：
10444134
负责人：
Sunwen Chou
金额：
$ 13万
依托单位：
PORTLAND VA RESEARCH FOUNDATION, INC.
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：
2015-08-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444134
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 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 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 has completed Phase 3 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 objective of this research is to determine the genetic mechanisms of CMV drug resistance in order to improve clinical diagnosis and the development of new antivirals. 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) study 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.

项目摘要毒性和耐药性限制了抗病毒疗法对巨细胞病毒的疗效（CMV）免疫抑制宿主的疾病，例如癌症和移植受者。当前的治疗包括DNA聚合酶抑制剂Ganciclovir，Foscarnet和Cidofovir。末端酶抑制剂Letermovir最近被批准用于预防，UL97 激酶抑制剂Maribavir已完成3期试验作为替代疗法。在临床上练习，CMV耐药性无法通过直接的表型测试来诊断分离株，而取决于检测到的病毒突变的准确相关性和相关的抗性表型。这项研究的目的是确定 CMV耐药性的遗传机制，以改善临床诊断和新抗病毒药的发展。许多抗性突变和多态性 CMV UL97激酶，UL54 DNA聚合酶和UL56/UL89/UL51末端酶基因具有已经并且继续进行表型，并具有诊断重要的新电阻基因座在每个项目期间被确定。重组的技术进步表型和整个基因组深度测序正在促进这项研究。在即将到来的项目期，新的重点领域包括突变的表征在已知抗病毒靶标之外的基因暴露后选择在药物暴露后选择，并分析基线病毒应变变异对药物敏感性的影响。具体目的是（1）研究在体外或中发生的CMV突变的进化和表型体内暴露于抗病毒化合物和组合中；（2）评估表型通过病毒全基因组深度测序鉴定的遗传变化的意义在已知的抗病毒靶基因之外，（3）确定基线的影响通过表征替代病毒的药物敏感性表型的病毒应变克隆和宿主细胞。