University of Massachusetts Medical School, Worcester, MA, USA.
Infect Genet Evol. 2011 Dec;11(8):2011-9. doi: 10.1016/j.meegid.2011.09.010. Epub 2011 Sep 23.
Dengue virus currently causes 50-100 million infections annually. Comprehensive knowledge about the evolution of Dengue in response to selection pressure is currently unavailable, but would greatly enhance vaccine design efforts. In the current study, we sequenced 187 new dengue virus serotype 3 (DENV-3) genotype III whole genomes isolated from Asia and the Americas. We analyzed them together with previously-sequenced isolates to gain a more detailed understanding of the evolutionary adaptations existing in this prevalent American serotype. In order to analyze the phylogenetic dynamics of DENV-3 during outbreak periods; we incorporated datasets of 48 and 11 sequences spanning two major outbreaks in Venezuela during 2001 and 2007-2008, respectively. Our phylogenetic analysis of newly sequenced viruses shows that subsets of genomes cluster primarily by geographic location, and secondarily by time of virus isolation. DENV-3 genotype III sequences from Asia are significantly divergent from those from the Americas due to their geographical separation and subsequent speciation. We measured amino acid variation for the E protein by calculating the Shannon entropy at each position between Asian and American genomes. We found a cluster of seven amino acid substitutions having high variability within E protein domain III, which has previously been implicated in serotype-specific neutralization escape mutants. No novel mutations were found in the E protein of sequences isolated during either Venezuelan outbreak. Shannon entropy analysis of the NS5 polymerase mature protein revealed that a G374E mutation, in a region that contributes to interferon resistance in other flaviviruses by interfering with JAK-STAT signaling was present in both the Asian and American sequences from the 2007-2008 Venezuelan outbreak, but was absent in the sequences from the 2001 Venezuelan outbreak. In addition to E, several NS5 amino acid changes were unique to the 2007-2008 epidemic in Venezuela and may give additional insight into the adaptive response of DENV-3 at the population level.
登革热病毒目前每年导致 5000 万至 1 亿例感染。目前还无法全面了解登革热病毒针对选择压力的进化情况，但这将极大地促进疫苗设计工作。在当前的研究中，我们对从亚洲和美洲分离的 187 株新的登革热病毒血清型 3（DENV-3）基因型 III 全基因组进行了测序。我们将它们与以前测序的分离株一起进行分析，以更详细地了解这种流行的美洲血清型中存在的进化适应。为了分析 DENV-3 在暴发期间的系统发育动态，我们将分别涵盖 2001 年和 2007-2008 年委内瑞拉两次重大暴发的 48 个和 11 个序列的数据集纳入其中。我们对新测序病毒的系统发育分析表明，基因组亚群主要按地理位置聚类，其次按病毒分离时间聚类。由于地理位置的分离和随后的物种形成，亚洲的 DENV-3 基因型 III 序列与美洲的序列有很大的差异。我们通过计算亚洲和美洲基因组之间每个位置的氨基酸变化来测量 E 蛋白的氨基酸变异。我们发现 E 蛋白结构域 III 内的七个氨基酸替换具有高变异性，这与先前报道的血清型特异性中和逃逸突变有关。在两次委内瑞拉暴发期间分离的序列中未发现 E 蛋白的新突变。NS5 聚合酶成熟蛋白的香农熵分析表明，在 2007-2008 年委内瑞拉暴发期间，一种 G374E 突变存在于亚洲和美洲序列中，该突变位于其他黄病毒中通过干扰 JAK-STAT 信号传导来抵抗干扰素的区域，而在 2001 年委内瑞拉暴发期间的序列中不存在。除 E 蛋白外，NS5 的几个氨基酸变化在 2007-2008 年委内瑞拉流行中是独特的，这可能使我们更深入地了解 DENV-3 在群体水平上的适应性反应。
