Evolutionary relationships of endemic/epidemic and sylvatic dengue viruses

Abstract

Endemic/epidemic dengue viruses (DEN) that are transmitted among humans by the mosquito vectors Aedes aegypti and Aedes albopictus are hypothesized to have evolved from sylvatic DEN strains that are transmitted among nonhuman primates in West Africa and Malaysia by other Aedes mosquitoes. We tested this hypothesis with phylogenetic studies using envelope protein gene sequences of both endemic/epidemic and sylvatic strains. The basal position of sylvatic lineages of DEN-1, -2, and -4 suggested that the endemic/epidemic lineages of these three DEN serotypes evolved independently from sylvatic progenitors. Time estimates for evolution of the endemic/epidemic forms ranged from 100 to 1,500 years ago, and the evolution of endemic/epidemic forms represents relatively recent events in the history of DEN evolution. Analysis of envelope protein amino acid changes predicted to have accompanied endemic/epidemic emergence suggested a role for domain III in adaptation to new mosquito and/or human hosts.

FIG. 1

Phylogenetic tree derived from E protein gene nucleotide sequences of sylvatic and representative endemic/epidemic DEN strains using maximum parsimony (PAUP, version 3.0) and drawn using branch lengths derived by neighbor joining using the Kimura two-parameter formula (PHYLIP, version 3.5p). The scale shows a genetic distance of 0.1, or 10% nucleotide sequence divergence. Homologous sequences from Japanese encephalitis, Kunjin, and West Nile viruses (a sister group to DEN [20]) were used as the outgroup to root the DEN tree. Numbers indicate bootstrap (8) values for monophyletic groups to the right. Branches labeled “E” indicate periods of evolution predicted to represent emergence of endemic/epidemic DEN and used to generate Table 3; branches labeled “S” represent continued sylvatic evolution during the same time period. Node A defines the clade used for the regression analysis of the DEN evolutionary rate.

FIG. 2

Three-dimensional model of the DEN E protein, based on the crystal structure of the soluble portion of the E protein of central European tick-borne encephalitis virus as determined by Rey et al. (30). Circles represent amino acids predicted to have changed during the period of evolution representing emergence of endemic/epidemic DEN-4 from a sylvatic ancestor (Fig. 1 and Table 3). (A) View of the E protein homodimer from above the virion; (B) side view of the E protein homodimer.