登革热病毒(DENV)在持续传播和进化过程中获得基因突变,使病毒更具适应性和毒性。DENV-1基因型I的进化枝已经扩展并成为亚洲和太平洋地区的主要基因型,但潜在的机制尚不清楚。对包膜蛋白结构域III中的非同义突变及其对病毒发病机理和传播的生物学作用进行了综合分析。系统发育分析发现了三个非同义突变(V324I,V351L,和V380I)在包膜蛋白的结构域III中,它出现在1970年代至1990年代,并在2000年后的当代品系中稳定遗传和扩展。我们产生了反向突变病毒(I324V,L351V,和I380V)基于流行的DENV-1株(NIID02-20)的感染性克隆,结果表明,当代流行病毒(野生型,WT)与哺乳动物宿主而不是蚊子载体中的反向突变病毒相比有所增加。WT病毒对宿主细胞表现出更高的结合亲和力和增加的病毒粒子稳定性。此外,较低的免疫原性和对WT病毒的中和抗体的较高抗性表明免疫逃逸的趋势。数据表明,E蛋白的非同义突变(V324I,V351L,和V380I)促进DENV-1基因型I的感染性和免疫逃避,这可能会促进其在全球范围内的传播。
目的:我们提供证据表明,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,影响病毒的生物学和抗病毒免疫反应。DENV-1在持续传播和进化过程中获得的基因突变将为设计抗黄病毒的新型疫苗提供新的线索。
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.
OBJECTIVE: 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.