Tao Jiang, Chenxiao Huang, Qianqian Ruan, Xiaorong Huang, Chumin Liang, Zhiqiang Chen, Xi Yu, Yihao Peng, Zheng Liu, Gong Cheng, Jianfeng Dai, Jiufeng Sun
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引用次数: 0
摘要
登革热病毒(DENV)在不断传播和进化过程中发生基因突变,使病毒更具适应性和毒性。DENV-1 基因型 I 支系已扩大并成为亚洲和太平洋地区的主要基因型,但其潜在机制尚不清楚。我们对包膜蛋白结构域 III 中的非同义突变及其对病毒致病和传播的生物学影响进行了综合分析评估。系统进化分析发现包膜蛋白第 III 结构域中存在三种非同义突变(V324I、V351L 和 V380I),它们出现于 20 世纪 70 年代至 90 年代,2000 年后在当代毒株中稳定遗传并扩展。我们根据流行性 DENV-1 株系(NIID02-20)的感染性克隆生成了反向突变病毒(I324V、L351V 和 I380V),结果表明,与反向突变病毒相比,当代流行性病毒(野生型,WT)在哺乳动物宿主(而非蚊子载体)中的感染力有所提高。WT 病毒与宿主细胞的结合亲和力更高,病毒的稳定性也更强。此外,WT 病毒的免疫原性更弱,对中和抗体的抵抗力更高,这表明病毒有免疫逃逸的趋势。这些数据表明,E蛋白的非同义突变(V324I、V351L和V380I)提高了DENV-1基因型I的感染性和免疫逃避能力,这可能会促进其在全球范围内的继续传播:我们提供的证据表明,登革热病毒(DENV)毒株之间的微小序列变异可导致适应性和毒力增强,从而影响病毒的生物学特性和抗病毒免疫反应。DENV-1在持续传播和进化过程中获得的基因突变将为设计新型黄病毒疫苗提供新的线索。
Envelope domain III E324, E351, and E380 mutations lever adaptive evolution of DENV-1 genotype I.
Dengue virus (DENV) gains genetic mutations during continuous transmission and evolution, making the virus more adaptive and virulent. The clade of DENV-1 genotype I has expanded and become the predominant genotype in Asia and the Pacific areas, but the underlying mechanisms are unclear. A combined analysis of nonsynonymous mutations in domain III of the envelope protein and their biological effects on virus pathogenesis and transmission was evaluated. Phylogenetic analyses found three nonsynonymous mutations (V324I, V351L, and V380I) in domain III of the envelope protein, which emerged in 1970s-1990s and stably inherited and expanded in contemporary strains after 2000. We generated reverse-mutated viruses (I324V, L351V, and I380V) based on an infectious clone of an epidemic DENV-1 strain (NIID02-20), and the results suggested that the infectivity of the contemporary epidemic virus (wild type, WT) has increased compared to the reverse mutant viruses in mammalian hosts but not mosquito vectors. The WT virus showed a higher binding affinity to host cells and increased virion stability. In addition, weaker immunogenicity and higher resistance to neutralizing antibodies of the WT virus indicated a trend of immune escape. The data suggested that nonsynonymous mutations of the E protein (V324I, V351L, and V380I) promote infectivity and immune evasion of DENV-1 genotype I, which may facilitate its onward transmission on a global scale.
Importance: We provide evidence that minor sequence variation among dengue virus (DENV) strains can result in increased adaptability and virulence, impacting both the biology of the virus and the antiviral immune response. The genetic mutations of DENV-1 gained during continuous transmission and evolution will offer new clues for the design of novel vaccines against flaviviruses.
期刊介绍:
Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.