Constraints on the evolution of influenza oseltamivir resistance

描述(由申请人提供)：这项提案概述了杰西·D·布鲁姆博士的两年过渡性拨款。一旦布鲁姆博士开始在研究机构担任助理教授职位，这笔拨款将被激活，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制约因素。这项具体的提案涉及H1N1流感病毒中通过神经氨酸酶蛋白His274-&gt；Tyr(H274Y)突变的奥司他韦(达菲)耐药性的进化。长期以来，人们一直认为这种抗药性突变不太可能传播，因为它削弱了季节性H1N1病毒，但最近它在全球范围内传播。布卢姆博士的初步研究表明，H274Y的这种全球传播是由次级“许可”突变实现的，这些突变修复了H274Y导致的神经氨酸酶蛋白表面表达的缺陷。这项拟议的研究将详细检查H274Y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。为了帮助识别可能导致H274Y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H274Y对2009年猪源大流行H1N1流感毒株产生广泛的奥司他韦耐药性的可能性。因此，拟议的工作将是朝着预测病毒进化目标迈出的实质性一步。在流感等具有重要医学意义的病毒方面，实现这一目标的进展将具有公共卫生价值。 公共卫生相关性：流感等病毒疾病之所以问题重重，是因为它们会迅速进化以逃避免疫和抗病毒药物。这项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可能出现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.