Comparative Characterization of Dengue Virus Serotype 2 Isolates from a South Pacific Epidemic Sweep

Abstract

The four serotypes of dengue virus (DENV-1, DENV-2, DENV-3 and DENV-4) cause a wide spectrum of clinical disease, ranging from febrile illnesses to life-threatening hemorrhagic fever. Worldwide incidence has increased alarmingly to where DENV is now the most common mosquito-borne viral disease in the world. However, understanding the mechanisms by which DENV causes disease remains elusive, due both to the complexity of vector-host transmission and the lack of effective in vitro and animal models with which to test mechanisms of pathogenesis. Our previous work, in which we carried out phylogenetic analysis of an epidemic sweep of DENV-2 among South Pacific islands that occurred in the early 1970s, suggests that strain variation might have a significant impact on epidemic severity. Specifically, DENV-2 isolates from an outbreak on the island of Tonga – whose epidemiology was notable for being distinctly attenuated compared with outbreaks on all other affected islands – were found to have three unique amino acid substitutions in the prM, NS2A and NS4A gene regions that distinguished them from all other DENV-2 isolates. Therefore, based on the hypothesis that changes in the DENV genome can lead to variations in disease severity and epidemic potential between different DENV strains, this study explores the relationship between genetic changes in DENV-2 epidemic strains and their phenotypic effects using in vitro models. Phenotypic differences between DENV-2 isolates from the entire South Pacific sweep were measured on the basis of viral productivity (i.e., viral titer and replication rate or rate of virus production per cell) in both human and mosquito cells. In addition, the specific mutations characterizing the Tonga synapomorphies suggested additional measurements to examine the proportion of infectious virions and possibly the viral effects on host-immune responses.