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: 8085883
• 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/8085883
• 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.

描述（由申请人提供）：自从将Oseltamivir（Tamiflu（r））引入市场以来，偶尔会从人类中分离出对人类的抗oseltamivir抗性流感A/H1N1和A/H3N2病毒，通常是从使用药物治疗的人中分离出来的[41，43，66-66-69]。以前的体外和体内数据表明，由于突变神经氨酸酶（NA）的酶促活性受损，抗药性病毒的拟合度低于敏感菌株[18，48-50，70，71]。然而，季节性A/H1N1病毒中oseltamivir耐药性患病率的突然，指数增加 - 2007年的耐药性少于1％，2008年的耐药性为11％，在2009年的耐药性接近100％[51，52] - 不能完全通过Oseltamivir使用的选择性压力来解释。除了耐药性外，这些耐奥甲氨木耐药的A/H1N1病毒可能比敏感菌株具有适应性优势。具体而言，抗性病毒可能会在哺乳动物宿主之间更有效地传播。我们实验室的初步数据支持这一假设。对于季节性的A/H1N1病毒-ES，旧的范式 - 在获得oseltamivir抗性时，病毒变得不太适合 - 可能不再成立。季节性A/H1N1病毒的差异可传播性提供了及时和相关的案例研究，以探讨如何发展耐药的流感病毒以克服受损的哺乳动物可传播性。 在当前的猪 - 原始A/H1N1大流行期间，Oseltamivir的使用急剧增加[72]；这反过来又增加了在新型A/H1N1感染的，由Oseltamivir处理的个体中选择抗性病毒的机会。的确，自从首次从人类中回收猪源性A/H1N1菌株以来的七个月中，全世界已经发现了超过25种抗oseltamivir的分离株，主要是（但不是完全）从Oseltamivir-Prophylaxed或reateated的人那里[54-56]。迄今为止，所有这些分离株都携带了相同的oseltamivir抗性突变 - 病毒Na（Na-H275Y）残基275的组氨酸对酪氨酸变化 - 在季节性A/H1N1病毒中占99％。此外，季节性A/H1N1和A/H3N2病毒一直与全球猪 - 原始A/H1N1病毒在低水平上循环[56]；这些菌株之间的遗传重新分类从理论上讲可以产生一种新型的人类病毒，并具有抗oseltamivir耐药的N1 NA与其他季节性和猪源基因结合使用。使用从我们对奥斯塔木敏感敏感和耐药的季节性A/H1N1病毒的差异可传递性中收集的见解，我们建议探索当前的抗oseltamivir-oseltamivir a/h1n1隔离物是否能易于传播，而不是敏感的杂种，以及这些病毒的杂种（如果如此）的季节性（如果如此），那么季节性的适合度（例如奥塞达米维尔抵抗可能会赋予的不足。 1973年，E.D。基尔本写道：“流感的学生不断地回头看着他的肩膀，问'发生了什么事？'希望对过去的事件的理解会提醒他对未来的灾难” [73]；在2009年，我们发现自己是四十年来第一个流感大流行中。我们的意图是，在了解抗oseltamivir的季节性A/H1N1病毒的最新演变时，这些实验不仅将立即适用于当前的A/H1N1猪 - 原始流感流行病，而且还可以产生我们对未来Pandemics抗病毒预防和治疗方法的数据。 项目叙述：2007年，只有不到1％的季节性流感A/H1N1病毒对口服抗激素药物Oseltamivir（Tamiflu（r））具有抵抗力；到2009年，将近100％获得了一种遗传突变，使它们具有抗药性。我们假设这些病毒的发展方式使它们在人类中变得更加可传播，并且更有效的传播使它们变得如此普遍。我们提出的研究试图了解季节性A/H1N1病毒中发生的遗传变化，以改善哺乳动物的传播，以评估抗奥斯塔氨二维体抗猪 - 原始A/H1N1病毒的可能性可能会沿着类似的途径进化，从而进化。