Antiviral Drug Resistance in Human Cytomegalovirus

人类巨细胞病毒的抗病毒耐药性

• 批准号: 6510499
• 负责人: Sunwen Chou
• 金额: $ 26.43万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6510499
• 关键词: antiviral agents; benzimidazoles; cidofovir; cytomegalovirus; drug resistance; foscarnet; ganciclovir; gene mutation; microorganism population study; molecular cloning; riboside; tissue /cell culture; transfection; virus genetics

DESCRIPTION (provided by applicant): Drug resistance limits the efficacy of long-term antiviral therapy for cytomegalovirus (CMV) disease in severely immunosuppressed hosts. Although the advent of combination antiretroviral therapy has reduced the frequency of invasive CMV disease, it continues as a problem in those failing anti-HIV therapy and in transplant recipients who develop primary CMV infection. In the past few years we have developed a reasonable understanding of the common mutations in the CMV UL97 phosphotransferase and UL54 DNA polymerase genes that confer resistance to the current systemic anti-CMV drugs ganciclovir, foscarnet and cidofovir. This information is already widely used for genotypic diagnosis of CMV resistance. Some gaps in our knowledge remain. There are probably additional resistance mutations in lesser-known regions of UL97 and UL54, or in other viral genes involved in DNA replication. Yet other mutations seen in isolates from treated subjects probably confer little or no resistance. Specific resistance mutations seem to confer varying degrees of resistance to the same drugs when assessed in different viral genetic backgrounds. The effect of mutations on CMV replication ("fitness") has not been systematically investigated. A new class of anti-CMV benzimidazole riboside drugs offers potential therapeutic advantages in potency, oral bioavailability and different mechanisms of antiviral action from previous drugs. Exploring CMV strains resistant to these drugs will be important not only for therapeutic monitoring but for future drug development as well. Accordingly, the specific aims for the upcoming period are (1) to study additional viral mutations that appear to confer resistance and cross-resistance to current anti-CMV drugs, by transfer of the mutations to reference CMV strains, (2) investigate the phenotypic effects of single and multiple mutations on different viral genetic backgrounds, and (3) determine the genetic basis of CMV resistance to GW1263W94, a benzimidazole riboside drug now undergoing development for clinical use.

描述（由申请人提供）：耐药性限制了 重症巨细胞病毒病的长期抗病毒治疗 免疫抑制宿主。尽管联合抗逆转录病毒药物的出现 治疗已经降低了侵袭性CMV疾病的频率，它继续作为一种 在那些抗艾滋病毒治疗失败的人和移植接受者中， 发生原发性CMV感染。在过去的几年里，我们开发了一个 对CMV UL97中常见突变的合理理解 磷酸转移酶和UL54 DNA聚合酶基因，赋予耐药性， 目前系统性抗CMV药物有更昔洛韦、膦甲酸和西多福韦。这 信息已经广泛用于CMV抗性的基因型诊断。 我们的知识中仍然存在一些空白。可能还有其他阻力 在UL97和UL54或其他病毒基因中不太为人所知的区域中的突变 参与DNA复制。然而，在治疗的分离株中观察到的其他突变 受试者可能很少或没有抵抗力。特异性耐药突变 似乎赋予不同程度的耐药性相同的药物时，评估， 不同的病毒遗传背景突变对CMV复制的影响 （“适应性”）没有得到系统的研究。一类新的抗CMV药物 苯并咪唑核苷类药物提供了潜在的治疗优势， 效力，口服生物利用度和不同的抗病毒作用机制， 以前的药物探索对这些药物耐药的CMV菌株将是 不仅对治疗监测而且对未来药物开发都很重要 也因此，下一阶段的具体目标是：（1） 研究额外的病毒突变，似乎赋予耐药性， 对目前抗CMV药物的交叉耐药性，通过将突变转移到 参考CMV菌株，（2）研究单个和 不同病毒遗传背景上的多个突变，和（3）确定 CMV对苯并咪唑核苷类药物GW1263W94抗性遗传基础 目前正在开发用于临床用途。