TRANSMISSION OF OSELTAMIVIR-RESISTANT INFLUENZA A H1N1 VIRUSES IN GUINEA PIGS

耐奥司他韦甲型 H1N1 流感病毒在豚鼠中的传播

• 批准号: 8274333
• 负责人: Nicole M. Bouvier
• 金额: $ 12.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274333
• 关键词: Antiviral Agents; Back; Blood Circulation; Case Study; Cavia; Data; Drug resistance; Enzymes; Equilibrium; Event; Evolution; Family suidae; Future; Gene Mutation; Genes; Genetic; Glean; Hemagglutinin; Histidine; Human; Human Virus; In Vitro; Individual; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Intention; Laboratories; Mammals; Marketing; Methods; Modeling; Mutate; Mutation; Neuraminidase; Oral; Oseltamivir; Persons; Pharmaceutical Preparations; Population; Prevalence; Prophylactic treatment; Proteins; Reassortant Viruses; Research; Resistance; Shoulder; Students; Techniques; Testing; Tyrosine; Viral; Viral Genes; Virus; Writing; anti-influenza drug; drug resistant virus; fitness; improved; in vivo; influenzavirus; insight; novel; pandemic disease; pandemic influenza; positional cloning; pressure; receptor; receptor binding; research study; resistance mutation; resistant strain; seasonal influenza; transmission process; viral resistance

DESCRIPTION (provided by applicant): Since the introduction of oseltamivir (Tamiflu(r)) to the market, oseltamivir-resistant influenza A/H1N1 and A/H3N2 viruses have occasionally been isolated from humans, usually from persons treated with the drug [41, 43, 66-69]. Previous in vitro and in vivo data suggested that drug-resistant viruses were less fit than sensitive strains, due to compromised enzymatic activity of the mutated neuraminidase (NA) [18, 48-50, 70, 71]. However, the sudden, exponential increase in the prevalence of oseltamivir resistance among seasonal A/H1N1 viruses - less than 1% resistant in 2007, 11% resistant in 2008, and near 100% resistant in 2009 [51, 52] - cannot be explained solely by selective pressure of oseltamivir use. These oseltamivir-resistant A/H1N1 viruses may have evolved a fitness advantage over sensitive strains, apart from drug resistance; specifically, resistant viruses may transmit more efficiently among mammalian hosts. Preliminary data from our laboratory supports this hypothesis. For seasonal A/H1N1 virus-es, the old paradigm - that, in acquiring oseltamivir resistance, viruses become less fit - may no longer hold true. The differential transmissibility of seasonal A/H1N1 viruses provides a timely and relevant case study to explore how drug-resistant influenza viruses evolve to overcome impaired mammalian transmissibility. The use of oseltamivir has dramatically increased during the current swine-origin A/H1N1 pandemic [72]; this has in turn increased the chances of selecting resistant viruses in novel A/H1N1-infected, oseltamivir-treated individuals. Indeed, in the seven months since the swine-origin A/H1N1 strain was first recovered from humans, more than 25 oseltamivir-resistant isolates have been detected worldwide, mainly (but not entirely) from oseltamivir-prophylaxed or -treated persons [54-56]. To date, all of these isolates have carried the same oseltamivir resistance mutation - a histidine-to-tyrosine change at residue 275 of the viral NA (NA-H275Y) - that is found in >99% of seasonal A/H1N1 viruses. Furthermore, seasonal A/H1N1 and A/H3N2 viruses have continued to co-circulate at low levels with swine-origin A/H1N1 viruses worldwide [56]; genetic reassortment among these strains could theoretically yield a novel human virus, with an oseltamivir-resistant N1 NA in combination with other seasonal and swine-origin genes. Using insights gleaned from our study of the differential transmissibility of oseltamivir-sensitive and -resistant seasonal A/H1N1 viruses, we propose to explore whether current oseltamivir-resistant swine-origin A/H1N1 isolates are less transmissible than sensitive strains, and, if so, how these viruses might evolve (like seasonal A/H1N1 viruses) to overcome any fitness deficiency that oseltamivir-resistance might confer. In 1973, E.D. Kilbourne wrote that the "student of influenza is constantly looking back over his shoulder and asking 'what happened?' in the hope that understanding of past events will alert him to the catastrophes of the future" [73]; in 2009, we find ourselves amidst the first influenza pandemic in forty years. It is our intention that, in understanding the recent evolution of oseltamivir-resistant seasonal A/H1N1 viruses, these experiments will not only be immediately applicable to the current A/H1N1 swine-origin influenza pandemic, but also might yield data that could inform our approach to antiviral prophylaxis and treatment in future pandemics. Project Narrative: In 2007, less than 1% of seasonal influenza A/H1N1 viruses were resistant to the oral anti-influenza drug oseltamivir (Tamiflu(r)); by 2009, nearly 100% had acquired a genetic mutation that rendered them drug resistant. We hypothesize that these viruses evolved in such a way that they became more transmissible among humans, and that it was more efficient transmission that allowed them to become so prevalent so quickly. The research we propose seeks to understand the genetic changes that occurred in seasonal A/H1N1 viruses to improve mammalian transmission, and in so doing, to assess the likelihood that oseltamivir-resistant swine-origin A/H1N1 viruses might evolve along a similar path to prevalence.

说明(由申请人提供)：自奥司他韦(达菲)推向市场以来，偶尔会从人体中分离到耐奥司他韦的甲型H1N1流感病毒和甲型H3N2型流感病毒，通常是从接受该药物治疗的人身上分离出来[41，43，66-69]。先前的体外和体内数据表明，由于突变的神经氨酸酶(NA)的酶活性降低，耐药病毒比敏感株更不适合[18，48-50，70，71]。然而，季节性甲型H1N1流感病毒中奥司他韦耐药性的突然指数上升--2007年耐药性不到1%，2008年耐药性11%，2009年几乎100%耐药性[51，52]--不能仅仅用奥司他韦的选择压力来解释。除了耐药性之外，这些耐奥司他韦的甲型H1N1病毒可能进化出了比敏感株更适合的优势；具体地说，耐药病毒可能在哺乳动物宿主中更有效地传播。我们实验室的初步数据支持这一假说。对于季节性甲型H1N1病毒，旧的范例--即在获得奥司他韦耐药性时，病毒变得不太适合--可能不再适用。季节性甲型H1N1流感病毒的不同传播性为探索抗药性流感病毒如何进化以克服哺乳动物传播性受损提供了一个及时和相关的案例研究。 在当前的猪源甲型H1N1流感大流行期间，奥司他韦的使用大幅增加[72]；这反过来又增加了在新型甲型H1N1感染患者和接受奥司他韦治疗的个人中选择耐药病毒的机会。事实上，自猪源甲型H1N1病毒首次从人类身上恢复以来的七个月里，全世界已经发现了25多个奥司他韦耐药菌株，主要(但不是全部)来自预防或治疗过奥司他韦的人[54-56]。到目前为止，所有这些分离株都携带相同的奥司他韦耐药突变--病毒NA(NA-H275Y)275位残基的组氨酸到酪氨酸的变化--99%的季节性A/H1N1病毒中存在这种突变。此外，季节性A/H1N1和A/H3N2型病毒继续在全球范围内与猪源A/H1N1病毒低水平共同传播[56]；这些毒株之间的基因重新组合理论上可能产生一种新的人类病毒，具有奥司他韦抗药性的N1 NA与其他季节性和猪源基因相结合。利用我们从对奥司他韦敏感和耐药的季节性甲型H1N1病毒的不同传播力研究中收集的见解，我们建议探索当前耐奥司他韦的猪源甲型H1N1病毒株是否比敏感株的传播性差，如果是这样，这些病毒可能如何进化(像季节性甲型H1N1病毒)，以克服对奥司他韦耐药可能带来的任何适应性缺陷。 1973年，E.D.基尔伯恩写道：“研究流感的学生经常回头看，问‘发生了什么？’希望对过去事件的理解能提醒他对未来的灾难”[73]；2009年，我们发现自己处于40年来的第一次流感大流行之中。我们的意图是，在了解耐奥司他韦季节性甲型H1N1病毒的最新演变过程中，这些实验不仅将立即适用于当前的甲型H1N1猪源性流感大流行，而且还可能产生数据，为我们在未来大流行中采取抗病毒预防和治疗方法提供参考。 项目简介：2007年，不到1%的季节性甲型H1N1流感病毒对口服抗流感药物奥司他韦(达菲)具有抗药性；到2009年，近100%的病毒获得了使其具有抗药性的基因突变。我们推测，这些病毒的进化方式使它们变得更容易在人类之间传播，而正是更有效的传播使它们如此迅速地流行起来。我们提出的研究旨在了解季节性甲型H1N1病毒中发生的基因变化，以改善哺乳动物的传播，并通过这样做，评估耐奥司他韦猪源甲型H1N1病毒可能沿着类似的流行路径进化的可能性。

项目成果

Animal Models for Influenza Virus Pathogenesis and Transmission.

• DOI: 10.3390/v20801530
• 发表时间: 2010
• 期刊: Viruses
• 作者: Bouvier NM;Lowen AC
• 通讯作者: Lowen AC

The science of security versus the security of science.

安全的科学与科学的安全。

• DOI: 10.1093/infdis/jis256
• 发表时间: 2012
• 期刊: The Journal of infectious diseases
• 作者: Bouvier,NicoleM

Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility.

• DOI: 10.1038/ncomms3854
• 发表时间: 2013
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Hai, Rong;Schmolke, Mirco;Leyva-Grado, Victor H.;Thangavel, Rajagowthamee R.;Margine, Irina;Jaffe, Eric L.;Krammer, Florian;Solorzano, Alicia;Garcia-Sastre, Adolfo;Palese, Peter;Bouvier, Nicole M.
• 通讯作者: Bouvier, Nicole M.

Environmental factors affecting the transmission of respiratory viruses.

• DOI: 10.1016/j.coviro.2011.12.003
• 发表时间: 2012-02
• 期刊: CURRENT OPINION IN VIROLOGY
• 影响因子: 5.9
• 作者: Pica, Natalie;Bouvier, Nicole M.
• 通讯作者: Bouvier, Nicole M.