Division of Livestock Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, No. 678 Haping Road, Xiangfang District, Harbin 150069, PR China.
Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
Virology. 2018 May;518:87-94. doi: 10.1016/j.virol.2018.01.030. Epub 2018 Feb 20.
Previous studies have shown that the FMDV Asia1/YS/CHA/05 high-fidelity mutagen-resistant variants are attenuated (Zeng et al., 2014). Here, we introduced the same single or multiple-amino-acid substitutions responsible for increased 3D fidelity of type Asia1 FMDV into the type O FMDV O/YS/CHA/05 infectious clone. The rescued viruses O-DA and O-DAMM are lower replication fidelity mutants and showed an attenuated phenotype. These results demonstrated that the same amino acid substitution of 3D in different serotypes of FMDV strains had different effects on viral fidelity. In addition, nucleoside analogues were used to select high-fidelity mutagen-resistant type O FMDV variants. The rescued mutagen-resistant type O FMDV high-fidelity variants exhibited significantly attenuated fitness and a reduced virulence phenotype. These results have important implications for understanding the molecular mechanism of FMDV evolution and pathogenicity, especially in developing a safer modified live-attenuated vaccine against FMDV.
先前的研究表明，口蹄疫病毒 Asia1/YS/CHA/05 高保真度耐突变变体是减毒的（Zeng 等人，2014）。在这里，我们将导致类型 Asia1 口蹄疫病毒 3D 保真度增加的相同单个或多个氨基酸取代引入到类型 O 口蹄疫病毒 O/YS/CHA/05 感染性克隆中。拯救的病毒 O-DA 和 O-DAMM 是低复制保真度突变体，表现出减毒表型。这些结果表明，不同血清型口蹄疫病毒株的 3D 相同氨基酸取代对病毒保真度有不同的影响。此外，核苷类似物被用于选择高保真度耐突变的 O 型口蹄疫病毒变体。拯救的耐突变的 O 型口蹄疫病毒高保真度变体表现出显著降低的适应性和毒力降低的表型。这些结果对口蹄疫病毒进化和致病性的分子机制的理解具有重要意义，特别是在开发针对口蹄疫病毒的更安全的改良活疫苗方面。
