Department of Chemical Engineering, Indian Institute of Science, Bengaluru, Karnataka, India.
Infectious Disease Research Foundation, Bengaluru, Karnataka, India.
PLoS Pathog. 2023 Apr 3;19(4):e1010862. doi: 10.1371/journal.ppat.1010862. eCollection 2023 Apr.
More than a hundred thousand dengue cases are diagnosed in India annually, and about half of the country's population carries dengue virus-specific antibodies. Dengue propagates and adapts to the selection pressures imposed by a multitude of factors that can lead to the emergence of new variants. Yet, there has been no systematic analysis of the evolution of the dengue virus in the country. Here, we present a comprehensive analysis of all DENV gene sequences collected between 1956 and 2018 from India. We examine the spatio-temporal dynamics of India-specific genotypes, their evolutionary relationship with global and local dengue virus strains, interserotype dynamics and their divergence from the vaccine strains. Our analysis highlights the co-circulation of all DENV serotypes in India with cyclical outbreaks every 3-4 years. Since 2000, genotype III of DENV-1, cosmopolitan genotype of DENV-2, genotype III of DENV-3 and genotype I of DENV-4 have been dominating across the country. Substitution rates are comparable across the serotypes, suggesting a lack of serotype-specific evolutionary divergence. Yet, the envelope (E) protein displays strong signatures of evolution under immune selection. Apart from drifting away from its ancestors and other contemporary serotypes in general, we find evidence for recurring interserotype drift towards each other, suggesting selection via cross-reactive antibody-dependent enhancement. We identify the emergence of the highly divergent DENV-4-Id lineage in South India, which has acquired half of all E gene mutations in the antigenic sites. Moreover, the DENV-4-Id is drifting towards DENV-1 and DENV-3 clades, suggesting the role of cross-reactive antibodies in its evolution. Due to the regional restriction of the Indian genotypes and immunity-driven virus evolution in the country, ~50% of all E gene differences with the current vaccines are focused on the antigenic sites. Our study shows how the dengue virus evolution in India is being shaped in complex ways.
印度每年诊断出超过 10 万例登革热病例，大约一半的人口携带登革热病毒特异性抗体。登革热在多种因素的选择压力下传播和适应，这些因素可能导致新变体的出现。然而，该国还没有对登革热病毒的进化进行系统分析。在这里，我们对 1956 年至 2018 年间从印度收集的所有 DENV 基因序列进行了全面分析。我们研究了印度特有基因型的时空动态、它们与全球和本地登革热病毒株的进化关系、血清型间动态以及它们与疫苗株的分化。我们的分析强调了所有 DENV 血清型在印度的循环传播，每隔 3-4 年就会出现周期性爆发。自 2000 年以来，DENV-1 的基因型 III、DENV-2 的世界性基因型、DENV-3 的基因型 III 和 DENV-4 的基因型 I 在全国范围内占主导地位。各血清型的替代率相当，表明缺乏血清型特异性进化分化。然而，包膜（E）蛋白在免疫选择下显示出强烈的进化特征。除了与祖先和其他当代血清型普遍漂移外，我们还发现了彼此之间经常发生的血清型间漂移的证据，这表明通过交叉反应性抗体依赖性增强作用进行了选择。我们在印度南部发现了高度分化的 DENV-4-Id 谱系的出现，该谱系获得了抗原位点中所有 E 基因突变的一半。此外，DENV-4-Id 正在向 DENV-1 和 DENV-3 进化枝漂移，表明交叉反应性抗体在其进化中的作用。由于印度基因型的区域限制和该国免疫驱动的病毒进化，与当前疫苗相比，约 50%的所有 E 基因差异都集中在抗原位点。我们的研究表明了印度登革热病毒进化是如何以复杂的方式进行的。
