Novel approach to the development of effective H5N1 influenza a virus vaccines: Use of M2 cytoplasmic tail mutants
Novel approach to the development of effective H5N1 influenza a virus vaccines: Use of M2 cytoplasmic tail mutants
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DOI：
10.1128/jvi.01899-07
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发表时间：
2008-03-01
影响因子：
5.4
通讯作者：
Kawaoka, Yoshihiro
中科院分区：
文献类型：
--
作者：
Watanabe, Tokiko;Watanabe, Shinji;Kawaoka, Yoshihiro
高致病性H5N1流感病毒在禽类中的暴发始于亚洲，此后已蔓延到其他大陆。对这些病毒在人类中大流行的可能性的担忧显然是有必要的，迫切需要开发有效的疫苗来预防它们。此前，我们和其他人证明了M2细胞质尾巴的缺失导致了A/WSN/33(HIN1)甲型流感病毒在体外的生长缺陷(K.Iwatsuki-Horimoto，T.Horimoto，T.Noda，M.Kiso，J.Maeda，S.Watanabe，Y.Muramoto，K.Fujii和Y.Kawaoka，J.Virol)。80：5233-5240,2006；M.F.McCown和A.Pekosz，J.Virol。79：3595-3605,2005；M.F.McCown和A.Pekosz，J.Virol。80：8178-8189,2006)。因此，我们测试了使用M2尾部突变体作为H5N1病毒减毒活疫苗的可行性。首先，我们构建了一系列高致病性H5N1(A/越南/1203/04[VN1203])M2细胞质尾部缺失突变体，并检测了它们在体内外的生长特性。我们发现，一个含有C末端11个氨基酸缺失的突变体(M2del11病毒)，生长得和野生型病毒一样好，但在小鼠身上的复制效率较低。然后我们构建了一个重组的VN1203M2del11病毒，它的血凝素(HA)基因被用一种无毒型HA(M2de111-HAavir病毒)的裂解位点的序列替换。这种M2del11-HAavir病毒保护小鼠免受致死剂量的同源(VN1203；分支1)和抗原性不同的异源(A/印度尼西亚/7/2005；分支2)H5N1病毒的攻击。我们的结果表明，M2胞质尾部突变体有可能作为H5N1流感病毒的减毒活疫苗。
Outbreaks of highly pathogenic H5N1 influenza viruses in avian species began in Asia and have since spread to other continents. Concern regarding the pandemic potential of these viruses in humans is clearly warranted, and there is an urgent need to develop effective vaccines against them. Previously, we and others demonstrated that deletions of the M2 cytoplasmic tail caused a growth defect in A/WSN/33 (HIN1) influenza A virus in vitro (K. Iwatsuki-Horimoto, T. Horimoto, T. Noda, M. Kiso, J. Maeda, S. Watanabe, Y. Muramoto, K. Fujii, and Y. Kawaoka, J. Virol. 80:5233-5240, 2006; M. F. McCown and A. Pekosz, J. Virol. 79:3595-3605, 2005; M. F. McCown and A. Pekosz, J. Virol. 80:8178-8189, 2006). We therefore tested the feasibility of using M2 tail mutants as live attenuated vaccines against H5N1 virus. First we generated a series of highly pathogenic H5N1 (A/Vietnam/1203/04 [VN1203]) M2 cytoplasmic tail deletion mutants and examined their growth properties in vitro and in vivo. We found that one mutant, which contains an 11-amino-acid deletion from the C terminus (M2del11 virus), grew as well as the wild-type virus but replicated in mice less efficiently. We then generated a recombinant VN1203M2del11 virus whose hemagglutinin (HA) gene was modified by replacing sequences at the cleavage site with those of an avirulent type of HA (M2de111-HAavir virus). This M2del11-HAavir virus protected mice against challenge with lethal doses of homologous (VN1203; clade 1) and antigenically distinct heterologous (A/Indonesia/7/2005; clade 2) H5N1 viruses. Our results suggest that M2 cytoplasmic tail mutants have potential as live attenuated vaccines against H5N1 influenza viruses.