Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-7354, USA.
Sci Transl Med. 2011 Dec 21;3(114):114ra128. doi: 10.1126/scitranslmed.3003084.
The rapid spread of dengue is a worldwide public health problem. In two clinical studies of dengue in Managua, Nicaragua, we observed an abrupt increase in disease severity across several epidemic seasons of dengue virus serotype 2 (DENV-2) transmission. Waning DENV-1 immunity appeared to increase the risk of severe disease in subsequent DENV-2 infections after a period of cross-protection. The increase in severity coincided with replacement of the Asian/American DENV-2 NI-1 clade with a new virus clade, NI-2B. In vitro analyses of viral isolates from the two clades and analysis of viremia in patient blood samples support the emergence of a fitter virus in later, relative to earlier, epidemic seasons. In addition, the NI-1 clade of viruses was more virulent specifically in children who were immune to DENV-1, whereas DENV-3 immunity was associated with more severe disease among NI-2B infections. Our data demonstrate that the complex interaction between viral genetics and population dynamics of serotype-specific immunity contributes to the risk of severe dengue disease. Furthermore, this work provides insights into viral evolution and the interaction between viral and immunological determinants of viral fitness and virulence.
登革热的迅速传播是一个全球性的公共卫生问题。在尼加拉瓜马那瓜的两项登革热临床研究中，我们观察到在几个登革热病毒血清型 2（DENV-2）传播的流行季节中，疾病严重程度突然增加。DENV-1 免疫力下降似乎增加了在交叉保护一段时间后随后的 DENV-2 感染中发生严重疾病的风险。严重程度的增加与亚洲/美洲 DENV-2 NI-1 分支被新的病毒分支 NI-2B 取代相吻合。来自两个分支的病毒分离株的体外分析以及对患者血液样本中病毒血症的分析支持在较晚的流行季节中出现了更适应的病毒。此外，NI-1 分支的病毒在对 DENV-1 具有免疫力的儿童中更具毒力，而 DENV-3 免疫力与 NI-2B 感染中更严重的疾病有关。我们的数据表明，病毒遗传学与特定血清型免疫的人群动态之间的复杂相互作用导致了严重登革热疾病的风险。此外，这项工作提供了对病毒进化以及病毒和免疫决定因素对病毒适应性和毒力的相互作用的深入了解。
