Antiviral Drug Resistance in Human Cytomegalovirus

描述(申请人提供)：毒性和耐药性限制了巨细胞病毒(CMV)疾病在严重免疫抑制的宿主中的长期抗病毒治疗的有效性，包括那些抗HIV治疗失败的宿主和发生原发CMV感染的移植接受者。这笔赠款的长期目标是确定临床使用中对CMV药物产生抗药性的病毒突变的特征。我们现在对CMV UL97激酶和UL54 DNA聚合酶基因的突变有了合理的了解，这些突变导致了对特许药物(更昔洛韦、磷甲酸钠和环多福韦)的耐药性，但仍在继续发现许多新的突变。可用的信息被广泛用于CMV耐药性的基因分型诊断和替代疗法的选择。一种有前景的实验性CMV UL97激酶抑制剂药物maribavir在早期临床试验中似乎具有高效力、口服生物利用度和低毒性，目前正在进行移植人群的第三阶段试验。目前正在研究maribavir耐药的遗传机制，已经在UL97、UL27和其他地方发现了突变。UL97外的maribavir耐药突变尚不清楚，但可能弥补了UL97激酶的关闭。进一步的分析应该阐明UL97在病毒复制中的作用和作为抗病毒药物的靶点。下一阶段的具体目标是：(1)确定在临床标本中观察到的单个和多个CMV突变对耐药性和病毒生长的影响；(2)确定maribavir耐药性的基因和表型特征；以及(3)确定病毒适应UL97抑制的遗传机制。实验重点包括继续改进重组表型技术，验证包括对maribavir耐药在内的其他耐药突变，评估交叉耐药，识别UL97外的适应性突变，以及确定与UL97和细胞激酶的相互作用。公共卫生相关性：巨细胞病毒病是免疫抑制宿主长期存在的管理问题。确定对现有和新的抗病毒药物产生耐药性的病毒突变的特征，解决了临床上重要的问题，如耐药性的基因诊断、交叉耐药和替代疗法的选择。为了应对耐药性和毒性，需要具有不同作用机制的新药。详细了解耐药性的遗传机制将有助于设计合适的新药结构和抗病毒靶点。

DESCRIPTION (provided by applicant): Toxicity and drug resistance limit the efficacy of long term antiviral therapy for cytomegalovirus (CMV) disease in severely immunosuppressed hosts, including those failing anti-HIV therapy and in transplant recipients who develop primary CMV infection. The long-term objective of this grant is to characterize the viral mutations that confer resistance to CMV drugs in clinical use. We now have a reasonable understanding of the mutations in the CMV UL97 kinase and UL54 DNA polymerase genes that confer resistance to the licensed drugs (ganciclovir, foscarnet and cidofovir), yet many new mutations continue to be identified. Available information is widely used for genotypic diagnosis of CMV resistance and selection of alternate therapies. A promising experimental CMV UL97 kinase inhibitor drug maribavir appears to have high potency, oral bioavailability and low toxicity in early clinical trials, and is currently undergoing Phase III trials in transplant populations. Genetic mechanisms of maribavir resistance are being studied, with mutations already identified in UL97, UL27 and elsewhere. Maribavir resistance mutations outside of UL97 are unexplained, but probably compensate for shutoff of the UL97 kinase. Further analysis should clarify the role of UL97 in viral replication and as an antiviral drug target. The specific aims for the upcoming period are (1) determine the effects on drug resistance and viral growth of single and multiple CMV mutations observed in clinical specimens, (2) genotypic and phenotypic characterization of maribavir resistance, and (3) define the genetic mechanisms of viral adaptation to UL97 inhibition. Experimental priorities include continued improvements in recombinant phenotyping technology, validation of additional resistance mutations including those for maribavir, assessment of cross-resistance, identifying adaptive mutations outside UL97 and determining the interaction with UL97 and cellular kinases. PUBLIC HEALTH RELEVANCE: CMV disease is a longstanding management problem in immunosuppressed hosts. Characterizing the viral mutations that confer resistance to existing and new antiviral drugs addresses clinically important issues, such as genotypic diagnosis of resistance, cross-resistance and the selection of alternate therapy. To deal with drug resistance and toxicity, new drugs are needed that have different mechanisms of action. Detailed understanding of the genetic mechanisms of resistance will improve the design of suitable new drug structures and antiviral targets.