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甲型H5N1病毒在内的流感病毒感染最有效的抗流感药物。这些药物对所有甲型流感亚型都有效，因此在流感大流行的最初几个月，在生产出合适的疫苗之前，它们是使用的理想选择。因此，包括澳大利亚在内的世界上许多国家都储存了这些药物（主要是达菲），作为其大流行防范计划的一部分。然而，令人关切的是，最近越来越多的报告显示，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，这些病毒也可能对达菲具有耐药性。在澳大利亚，达菲将成为对抗流感大流行初期浪潮的关键武器，因此，对H5N1病毒产生耐药性的倾向有更多了解至关重要，这可能会降低这些药物的临床效果。该项目的目的是确定当雪貂实验性地感染HP A（H5N1）病毒，然后用达菲等NA抑制剂药物治疗时可能发生的耐药性的水平、模式和类型。如果在达菲的药物压力下分离出耐药病毒，那么将测试这些菌株对其他NA抑制剂药物Relenza（扎那米韦）或peramivir（第三种目前未获许可的NA抑制剂）的敏感性。交叉耐药工作的结果将有助于制定在大流行病毒获得特定NA突变（例如可能导致达菲耐药）的情况下使用替代NA抑制剂的策略。为确定NA抑制剂耐药a （H5N1）病毒对人类的相对风险，将对分离出的所有耐药毒株进行研究，以确定病毒的传染性或传染性。NA抑制剂耐药菌株表现出不同程度的传播性和适应性，因此对本研究产生的任何菌株进行分类是有益的，以便更好地了解如果出现特定耐药菌株对公共卫生的影响。

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.