Constraints on the evolution of influenza oseltamivir resistance

描述（由申请人提供）：该提案概述了杰西D两年的过渡补助金。Bloom博士一旦布鲁姆博士开始在一家研究机构担任助理教授一职，这笔赠款将被激活，并将用于资助他最初几年的工作。布鲁姆博士目前是加州理工学院大卫巴尔的摩博士实验室的博士后学者。布鲁姆博士的研究考察了病毒进化的分子限制。这一具体建议涉及H1N1流感病毒通过His 274->Tyr（H274 Y）突变为神经氨酸酶蛋白质而产生的奥司他韦（达菲）耐药性的演变。这种耐药性突变长期以来被认为不太可能传播，因为它减弱了季节性H1N1病毒，但最近它在世界范围内传播。Bloom博士的初步研究表明，H274 Y的这种全球传播是由二次“允许”突变实现的，这些突变挽救了H274 Y在神经氨酸酶蛋白表面表达中引起的缺陷。这项研究将详细研究H274 Y引起的生物物理缺陷，以及它在组织培养和动物模型中影响病毒生长的机制。为了帮助识别可能使H274 Y进化传播的其他可能的允许突变，该研究将开发和测试计算预测方法。最后，这些计算和实验工具将用于预测H274 Y赋予猪源2009年H1N1流感大流行株广泛的奥司他韦耐药性的潜力。因此，拟议中的工作将是朝着预测病毒演变目标迈出的实质性一步。这一目标的进展将对流感等医学上重要的病毒具有公共卫生价值。 公共卫生相关性：病毒性疾病，如流感是如此的问题，因为它们迅速进化，以逃避免疫和抗病毒药物。该提案研究了病毒逃逸的一个具体例子，即H1N1流感中奥司他韦（达菲）耐药性的演变。我们的目标是在分子水平上理解这种逃逸，并利用由此产生的洞察力来预测未来潜在的奥司他韦耐药途径。

DESCRIPTION (provided by applicant): This proposal outlines a two-year transitional grant for Jesse D. Bloom, Ph.D. The grant would be activated once Dr. Bloom begins an assistant professor position at a research institution, and would be used to fund the initial years of his work. Dr. Bloom is currently a postdoctoral scholar in the laboratory of Dr. David Baltimore at the California Institute of Technology. Dr. Bloom's research examines molecular constraints on viral evolution. This specific proposal deals with the evolution of oseltamivir (Tamiflu) resistance in H1N1 influenza viruses via the His274->Tyr (H274Y) mutation to the neuraminidase protein. This resistance mutation had long been thought unlikely to spread since it attenuated seasonal H1N1 viruses, but it recently spread worldwide. Dr. Bloom's preliminary research has shown that this global spread of H274Y was enabled by secondary "permissive" mutations that rescued a defect that H274Y caused in the surface expression of neuraminidase protein. The proposed research will examine in detail the biophysical defect caused by H274Y, and the mechanism by which it affects viral growth in tissue culture and animal models. In order to aid in the identification of other possible permissive mutations that might enable the evolutionary spread of H274Y, the research will develop and test computational prediction methods. Finally, these computational and experimental tools will be used towards forecasting the potential for H274Y to confer widespread oseltamivir resistance on the swine-origin 2009 pandemic H1N1 influenza strain. The proposed work will therefore represent a substantial step towards the goal of predicting virus evolution. Progress towards this goal will be of public health value in regards to medically important viruses such as influenza. Public Health Relevance: Viral diseases such as influenza are so problematic because they rapidly evolve to escape immunity and antiviral drugs. This proposal examines a specific example of viral escape, the evolution of oseltamivir (Tamiflu) resistance in H1N1 influenza. The goal is to understand this escape at a molecular level, and use the resulting insight to anticipate potential future routes of oseltamivir resistance.