Analysis of Dengue Virus Genetic Diversity during Human and Mosquito Infection Reveals Genetic Constraints.
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.
Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
October M
OM
Sessions
Computational and Systems Biology, Genome Institute of Singapore, Singapore.
Andreas
A
Wilm
Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
Uma Sangumathi
US
Kamaraj
Computational and Systems Biology, Genome Institute of Singapore, Singapore.
Milly M
MM
Choy
Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
Angelia
A
Chow
Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
Yuwen
Y
Chong
Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
Xin Mei
XM
Ong
Computational and Systems Biology, Genome Institute of Singapore, Singapore.
Niranjan
N
Nagarajan
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.
Alex R
AR
Cook
Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
Eng Eong
EE
Ooi
D000818:Animals; D017124:Conserved Sequence; D009033:Culicidae / Q000821:virology*; D003715:Dengue / Q000821:virology*; D003716:Dengue Virus / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D011446:Prospective Studies; D012367:RNA, Viral / Q000235:genetics
D012367:RNA, Viral