MBE：科学家发现流感病毒产生抗药性的原因

生物谷

    过去几年来，流感病毒对抗病毒药物金刚烷胺的抗药性从２％增加到了９０％。美国科学家研究发现，这一现象背后的原因可能与人们原先认为的不同，通过谨慎用药预防抗药性的策略并不总是有效。

    传统观点认为，病原体抗药性增强是滥用药物所致，例如大量使用金刚烷胺会对病毒形成进化压力，使对药物敏感的毒株灭亡，具有抗药性的毒株获得生存优势，从而扩散开来，导致抗药性愈演愈烈。

    根据这种理论，在大量使用金刚烷胺的国家，病毒对这种药的抗药性会比较普遍，而在很少使用金刚烷胺的国家，针对该药的抗药性应很罕见。但美国疾病控制和预防中心的科学家发现情况并非如此，不管是在每年开出１５０万剂金刚烷胺处方的美国，还是在很少使用金刚烷胺的日本和新西兰，病毒对该药的抗药性普遍存在。

    为了弄清楚这种现象，美国国家卫生研究院的科学家对来自世界多个地区的流感病毒样本的基因组进行分析。结果发现，他们研究的所有金刚烷胺抗药性事例都是由同一个基因变异导致，这种变异使病毒得以逃过人体免疫系统的侦测。

    假如抗药性是滥用药物所致，人们应该从不同抗药毒株中发现多种导致抗药性的基因变异，而不是只有一种。科学家认为，这个特定的基因变异与药物无关，它诞生的初衷是为了对付人体免疫系统，针对金刚烷胺的抗药性只是一个“副产品”。有关论文发表在《分子生物学与进化》杂志上。（引自新华网）

原始出处:

MBE Advance Access published online on May 23, 2007
Molecular Biology and Evolution, doi:10.1093/molbev/msm103

The Genesis and Spread of Reassortant Human Influenza A/H3N2 Viruses Conferring Adamantane Resistance

Lone Simonsen*, Cécile Viboud ${dagger}$ , Bryan T. Grenfell ${dagger}$ , $§$ , Jonathan Dushoff ${dagger}$ ,¶, Lance Jennings ${ddagger}$ , Marita Smit ${ddagger}$ , Catherine Macken**, Mami Hata ${dagger}$ ${dagger}$ , Julia Gog $§$ $§$ , Mark A Miller ${dagger}$ and Edward C. Holmes ${dagger}$ , $§$

* National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20818, USA
${dagger}$ Fogarty International Center, National Institutes of Health, Bethesda, MD 20892, USA
$§$ Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, University Park, PA 16802, USA
¶ Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08544, USA
${ddagger}$ Canterbury Health Laboratories, Christchurch, New Zealand
** Los Alamos National Laboratory, Los Alamos, NM 87545, USA
${dagger}$ ${dagger}$ Department of Microbiology, Aichi Prefectural Institute of Public Health, Nagoya 462-8576, Japan
$§$ $§$ Department of Zoology, University of Cambridge, Downing Street, Cambridge, CB2 3EJ, UK

Address for Correspondence: Dr. Edward C. Holmes, Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, University Park, PA 16802, USA. Tel: 814 863 4689 Fax: 814 865 9131 Email: ech15@psu.edu

Received for publication March 29, 2007. Accepted for publication May 15, 2007.

A dramatic rise in the frequency of resistance to adamantane drugs by influenza A (H3N2) viruses has occurred in recent years – from $~$ 2% 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 two 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.