The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance
The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance
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DOI：
10.1093/molbev/msm103
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发表时间：
2007-08-01
影响因子：
10.7
通讯作者：
Holmes, Edward C.
中科院分区：
文献类型：
--
作者：
Simonsen, Lone;Viboud, Cecile;Holmes, Edward C.
近年来，甲型H3N2型流感病毒对金刚烷胺类药物的耐药率急剧上升--在全球多个国家和地区从类似的2%上升到类似的90%--并与病毒基质M2蛋白中单一的S31N氨基酸替换有关。为了探索这些金刚烷胺耐药病毒的出现和传播，我们对最近采样的完整A/H3N2基因组序列进行了系统发育分析。引人注目的是，所有金刚烷胺抗性病毒都属于一个单一的谱系(“N谱系”)，其特征是整个病毒基因组中有17个氨基酸替换。此外，我们的分析表明，N系的起源是由于涉及两个不同的A/H3N2型流感病毒系的4+4片段重组事件。随后对血凝素HA1序列的研究表明，N血统在2005年期间在亚洲广泛传播，然后在日本和美国的北半球2005-2006年季节占据主导地位。鉴于金刚烷药物在许多国家很少使用，以及在美国使用了几十年，几乎没有耐药性，我们认为，金刚烷耐药性在全球范围内增加的频率更有可能归因于它与其他基因组位置的适合性增强突变的相互作用，而不是直接的药物选择压力。这意味着从长远来看，金刚烷对流感病毒的治疗和预防可能无用。更广泛地说，这些发现表明，药物选择压力并不是决定人类病原体耐药性进化和维持的唯一因素。
A dramatic rise in the frequency of resistance to adamantane drugs by influenza A (H3N2) viruses has occurred in recent years-from similar to 2% to similar to 90% in multiple countries worldwide-and associated with a single S31N amino acid replacement in the viral matrix M2 protein. To explore the emergence and spread of these adamantane resistant viruses we performed a phylogenetic analysis of recently sampled complete A/H3N2 genome sequences. Strikingly, all adamantane resistant viruses belonged to a single lineage (the "N-lineage") characterized by 17 amino acid replacements across the viral genome. Further, our analysis revealed that the genesis of the N-lineage was due to a 4+4 segment reassortment event involving 2 distinct lineages of influenza A/H3N2 virus. A subsequent study of hemagglutinin HA1 sequences suggested that the N-lineage was circulating widely in Asia during 2005, and then dominated the Northern hemisphere 2005-2006 season in Japan and the USA. Given the infrequent use of adamantane drugs in many Countries, as well as the decades of use in the US associated with little drug resistance, we propose that the globally increasing frequency of adamantane resistance is more likely attributable to its interaction with fitness enhancing mutations at other genomic sites rather than to direct drug selection pressure. This implies that adamantanes may not be useful for treatment and prophylaxis against influenza viruses in the long term. More generally, these findings illustrate that drug selection pressure is not the sole factor determining the evolution and maintenance of drug resistance in human pathogens.