Hemagglutinin-targeting Artificial MicroRNAs Expressed by Adenovirus Protect Mice From Different Clades of H5N1 Infection.
Hemagglutinin-targeting Artificial MicroRNAs Expressed by Adenovirus Protect Mice From Different Clades of H5N1 Infection.
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DOI：
10.1038/mtna.2016.25
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发表时间：
2016-04-19
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流感病毒（IV）是一种持续进化的病毒，在人类中广泛传播，并导致大量的发病率和死亡率。人类再次感染禽流感病毒H5 N1对IV控制构成额外挑战。人工microRNA（amiRNA）介导的RNA干扰因其特异性强、作用迅速而成为一种强有力的抗病毒方法。在这里，我们设计了几个amiRNA靶向H5 N1的血凝素基因，致病性的主要决定因素。通过用黑猩猩腺病毒血清型68（AdC 68）呈递功能性amiRNA来增强表达和递送效率。一种amiRNA HA-1405在体外显著限制H5 N1复制，并抑制96.7%的进化枝2.3.2复制。AdC 68缀合的HA-1405处理显著降低Madin-Darby犬肾细胞中H5 N1噬斑形成的不同分支。此外，在癌症研究所（ICR）小鼠中，用rAd（HA-1405）预防性给药显著减轻临床症状，并降低针对H5 N1的四个进化枝的肺病毒RNA拷贝约3至40倍。我们的结果进一步表明，rAd（HA-1405）赋予70%和40%的立即保护对致命的进化枝2.3.2和进化枝2.3.4 H5 N1攻击，分别。总之，这些数据提供的信息表明，由AdC 68递送的HA靶向amiRNA可以作为高致病性禽流感病毒预防的潜在试剂。
Influenza virus (IV) is a continuously evolving virus that widely spreads in humans and contributes to substantial morbidity and mortality. Re-emergence of human infection with avian influenza virus H5N1 poses extra challenge to IV control. Artificial microRNA (amiRNA)-mediated RNA interference has become a powerful antiviral approach due to its high specificity and rapid effect. Here, we designed several amiRNAs targeting the hemagglutinin gene of H5N1, a major determinant of pathogenicity. Expression and delivery efficiency were enhanced by presenting functional amiRNA with chimpanzee adenovirus serotype 68 (AdC68). One amiRNA, HA-1405, significantly limited H5N1 replication in vitro and inhibited 96.7% of clade 2.3.2 replication. AdC68-conjugated HA-1405 treatment remarkably decreased different clades of H5N1 plaque formation in Madin–Darby canine kidney cells. Moreover, prophylactic administration with rAd(HA-1405) markedly alleviated clinical symptoms and reduced ~3- to 40-folds of lung viral RNA copies against four clades of H5N1 in Institute of Cancer Research (ICR) mice. Our results further showed that rAd(HA-1405) conferred 70 and 40% immediate protection against lethal clade 2.3.2 and clade 2.3.4 H5N1 challenge, respectively. In conclusion, these data provided information that HA-targeting amiRNA delivered by AdC68 could be pursued as a potential agent for highly pathogenic avian influenza viruses prevention.
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DOI：
10.1016/s1386-6532(03)00122-7
发表时间：
2004-03
期刊：
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
影响因子：
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作者：
Ward CL;Dempsey MH;Ring CJ;Kempson RE;Zhang L;Gor D;Snowden BW;Tisdale M
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DOI：
10.1038/mtna.2014.59
发表时间：
2014-11-04
期刊：
Molecular therapy. Nucleic acids
影响因子：
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Subbarao, K;Klimov, A;Cox, N
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