Genetic diversity of the dengue virus population in dengue fever and dengue hemorrhagic fever patients

Background: The error-prone replication of dengue virus (DENV) in host results in the highly diverse viral population. Together with the host factor, intra-host diversity may influence the disease severity. Therefore, it is worth investigating whether there is a correlation between intra-host genetic diversity and disease severity.Objective: To investigate the genetic diversity in DENV for four serotypes of the dengue population from patients with dengue fever (DF) and dengue hemorrhagic fever (DHF) using next-generation sequencing (NGS) technology.Methods: Forty RNA samples categorized into eight groups by severity and serotypes were sequenced and analyzed for genetic variation. Analysis on the hot-cold genomic regions, selection pressure and correlation between genotype and disease severity were performed in this study.Results: Comparison between the NGS data of the DF and DHF specimens showed conservation between their major populations with the consensus sequences for DF and DHF sharing 99% similarity. However, the minor populations in DF and DHF were more diverse. Many genes in DF had an #NS/#S ratio higher than in DHF. Only NS4B of DENV1 DF has #NS/#S ratio higher than one. Hot regions of the DF were detected in NS3 of DENV1, DENV2 and Envelope of DENV3, whereas the hot regions of the DHF samples were detected in the small region in 3'UTR of DENV2 and DENV3. Conclusions: Various explorations of the variations of DF and DHF were performed in this study. However, we have not yet found any specific characteristics of intra-host diversity associated with disease severity.