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PLoS Negl Trop Dis. 2015 Sep 1;9(9):e0004044. doi: 10.1371/journal.pntd.0004044. eCollection 2015.

Analysis of Dengue Virus Genetic Diversity during Human and Mosquito Infection Reveals Genetic Constraints.

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Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
Computational and Systems Biology, Genome Institute of Singapore, Singapore.
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Yale-NUS College, National University of Singapore, Singapore; Program in Health Services and Systems Research, Duke-NUS Graduate Medical School, Singapore.


Dengue viruses (DENV) cause debilitating and potentially life-threatening acute disease throughout the tropical world. While drug development efforts are underway, there are concerns that resistant strains will emerge rapidly. Indeed, antiviral drugs that target even conserved regions in other RNA viruses lose efficacy over time as the virus mutates. Here, we sought to determine if there are regions in the DENV genome that are not only evolutionarily conserved but genetically constrained in their ability to mutate and could hence serve as better antiviral targets. High-throughput sequencing of DENV-1 genome directly from twelve, paired dengue patients' sera and then passaging these sera into the two primary mosquito vectors showed consistent and distinct sequence changes during infection. In particular, two residues in the NS5 protein coding sequence appear to be specifically acquired during infection in Ae. aegypti but not Ae. albopictus. Importantly, we identified a region within the NS3 protein coding sequence that is refractory to mutation during human and mosquito infection. Collectively, these findings provide fresh insights into antiviral targets and could serve as an approach to defining evolutionarily constrained regions for therapeutic targeting in other RNA viruses.

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