Assessment of development of resistance to neuraminidase inhibitors in A (H5N1) influenza viruses using a ferret model

神经氨酸酶（NA）抑制剂被认为是预防和治疗包括A（H5N1）病毒在内的流感病毒感染的最有效的抗流感药物。这些药物对甲型流感的所有亚型都有效，使它们成为在生产适当疫苗之前大流行的最初几个月使用的理想药物。因此，包括澳大利亚在内的世界上许多国家都储备了这些药物（主要是达菲），作为其大流行准备计划的一部分。然而，令人关切的是，最近越来越多的报告表明，流行性流感对这些药物产生的耐药性高于预期水平。最近从一名越南女孩身上分离出的H5N1病毒突出表明，这些病毒也可以对达菲产生抗药性。在澳大利亚，达菲将是对付流感大流行最初一波的关键武器，因此，至关重要的是，更多地了解H5N1病毒产生耐药性的倾向，并可能使这些药物在临床上不那么有效。该项目的目的是确定当雪貂实验性感染HPA（H5N1）病毒，然后用达菲等NA抑制剂药物治疗时可能出现的耐药性水平、模式和类型。如果在达菲的药物压力下分离出耐药病毒，则将测试这些菌株对其他NA抑制剂药物Relenza（扎那米韦）或peramivir（第三种目前未经许可的NA抑制剂）的敏感性。来自该交叉抗性工作的结果将允许在大流行病毒获得特定NA突变的情况下实施关于施用替代NA抑制剂的策略，所述特定NA突变可例如导致达菲抗性。为了确定对NA抑制剂具有耐药性的A（H5N1）病毒对人类的相对风险，将对所有分离出的耐药性毒株进行研究，以确定病毒的传染性或传播性。NA抑制剂耐药菌株表现出不同程度的传播性和适应性，因此，对于本研究产生的任何菌株进行分类将是有益的，以便在出现特定耐药菌株时更好地了解公共卫生影响。

The neuraminidase (NA) inhibitors are considered the most effective anti-influenza drugs available for both prevention and treatment of influenza virus infection including A(H5N1) viruses. The drugs are effective against all subtypes of influenza A, making them ideal for use in the early months of a pandemic prior to an appropriate vaccine being produced. As a result many countries around the world, including Australia, have stockpiled these drugs (mainly Tamiflu) as part of their pandemic preparedness plans. However, of concern is the increasing number of recent reports of a higher than expected level of resistance in epidemic influenza being generated against these drugs. A recent isolation of an H5N1 virus from a Vietnamese girl highlights that these viruses can also be resistant to Tamiflu. Within Australia, Tamiflu will be a critical weapon against the initial wave of an influenza pandemic, therefore it is vital that more is known about the propensity of the H5N1 virus to generate resistance, and possibly make these drugs clinically less effective. The aim of the project is to determine the levels, mode and type of resistance that may occur when ferrets are experimentally infected with HP A(H5N1) virus and then treated with NA inhibitors drugs such as Tamiflu. In the event of resistant viruses being isolated following drug pressure from Tamiflu, the strains will then be tested for their sensitivity to the other NA inhibitor drugs Relenza (zanamivir) or the peramivir (a third currently unlicensed NA inhibitor). The results from this cross resistance work will allow strategies to be put into place regarding the administration of an alternative NA inhibitor in the event of a pandemic virus acquiring particular NA mutations which may for example result in Tamiflu resistance. To determine the relative human risk of a NA inhibitor resistant A(H5N1) virus, studies to determine how infectious or transmissible the viruses are would be performed on all resistant strains isolated. NA inhibitor resistant strains demonstrate varying degrees of transmissibility and fitness, therefore it would be beneficial to classify this for any strains generated from this study so as to be in a better position to understand the public health implications if a particular resistant strain was to arise.