Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus
Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus
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DOI：
10.1073/pnas.212519699
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发表时间：
2002-10-15
影响因子：
11.1
通讯作者：
Basler, CF
中科院分区：
文献类型：
--
作者：
Tumpey, TM;García-Sastre, A;Basler, CF
1918年的流感大流行在全世界造成2000多万人死亡。因此，1918年或类似1918年流感病毒的重新出现的潜在影响，无论是通过自然手段还是生物恐怖主义的结果，都是一个重大问题。1918年病毒毒力的遗传决定因素尚未确定，也没有确定对重新出现的1918年或1918年样病毒有效的特定临床预防和/或治疗干预措施。根据已报道的核苷酸序列，我们重建了1918年病毒的血凝素（HA）、神经氨酸酶（NA）和基质（M）基因。在生物安全3级（农业）条件下，我们已经产生了携带1918 HA、NA或M片段的重组流感病毒。引人注目的是，同时具有1918 HA和1918 NA的重组病毒在小鼠中具有毒性。相比之下，具有来自最近的人类分离株的HA和NA的对照病毒在任何测试剂量下都不能杀死小鼠。重组病毒还在体外和体内测试了它们对美国食品和药物管理局批准的抗流感病毒药物的敏感性。具有1918 NA或1918 HA和1918 NA两者的重组病毒在组织培养物和小鼠中被NA抑制剂扎那米韦和奥司他韦有效抑制。具有1918 M片段的重组病毒在组织培养和体内均被M2离子通道抑制剂金刚烷胺和金刚乙胺有效抑制。这些数据表明，目前的抗病毒策略将有效遏制重新出现的1918年或1918年类似病毒的危险。
The 1918 influenza pandemic caused more than 20 million deaths worldwide. Thus, the potential impact of a re-emergent 1918 or 1918-like influenza virus, whether through natural means or as a result of bioterrorism, is of significant concern. The genetic determinants of the virulence of the 1918 virus have not been defined yet, nor have specific clinical prophylaxis and/or treatment interventions that would be effective against a re-emergent 1918 or 1918-like virus been identified. Based on the reported nucleotide sequences, we have reconstructed the hemagglutinin (HA), neuraminidase (NA), and matrix (M) genes of the 1918 virus. Under biosafety level 3 (agricultural) conditions, we have generated recombinant influenza viruses bearing the 1918 HA, NA, or M segments. Strikingly, recombinant viruses possessing both the 1918 HA and 1918 NA were virulent in mice. In contrast, a control virus with the HA and NA from a more recent human isolate was unable to kill mice at any dose tested. The recombinant viruses were also tested for their sensitivity to U.S. Food and Drug Administration-approved antiinfluenza virus drugs in vitro and in vivo. Recombinant viruses possessing the 1918 NA or both the 1918 HA and 1918 NA were inhibited effectively in both tissue culture and mice by the NA inhibitors, zanamivir and oseltamivir. A recombinant virus possessing the 1918 M segment was inhibited effectively both in tissue culture and in vivo by the M2 ion-channel inhibitors amantadine and rimantadine. These data suggest that current antiviral strategies would be effective in curbing the dangers of a re-emergent 1918 or 1918-like virus.