Invasion and maintenance of dengue virus type 2 and type 4 in the Americas

Abstract

Dengue virus type 4 (DENV-4) was first reported in the Americas in 1981, where it caused epidemics of dengue fever throughout the region. In the same year, the region's first epidemic of dengue hemorrhagic fever was reported, caused by an Asian strain of dengue virus type 2 (DENV-2) that was distinct from the American subtype circulating previously. Despite the importance of these epidemics, little is known about the rates or determinants of viral spread among island and mainland populations or their directions of movement. We employed a Bayesian coalescent approach to investigate the transmission histories of DENV-2 and DENV-4 since their introduction in 1981 and a parsimony method to assess patterns of strain migration. For both viruses there was an initial invasion phase characterized by an exponential increase in the number of DENV lineages, after which levels of genetic diversity remained constant despite reported fluctuations in DENV-2 and DENV-4 activity. Strikingly, viral lineage numbers increased far more rapidly for DENV-4 than DENV-2, indicative of a more rapid rate of exponential population growth in DENV-4 or a higher rate of geographic dispersal, allowing this virus to move more effectively among localities. We propose that these contrasting dynamics may reflect underlying differences in patterns of host immunity. Despite continued gene flow along particular transmission routes, the overall extent of viral traffic was less than expected under panmixis. Hence, DENV in the Americas has a clear geographic structure that maintains viral diversity between outbreaks.

FIG. 1.

ML trees of (a) DENV-2 subtype III and (b) DENV-4 subtype II from the Americas. Bootstrap support values above 90% are indicated, and all horizontal branch lengths are drawn to scale. In both cases an Asian outgroup sequence is included to root the trees. The names of American isolates include reference to country of origin and year of isolation. Abbreviations used for country names are given in Table S2 in the supplemental material.

FIG. 2.

Genealogies and corresponding Bayesian skyline plots showing the transmission histories of (a) DENV-2 subtype III and (b) DENV-4 subtype II, drawn on the same time scale. The y axes of the skyline plots represent relative genetic diversity, which is equal to the product of effective population size and generation length in the absence of population structure (see Materials and Methods). For both viruses the maximum a posteriori tree is presented on the same time scale as the skyline plot, with tip times corresponding to sampling times. The thick black lines are the median estimates, and the areas between the 95% CIs are shaded gray. Isolates on the trees are identified by their country of origin; mainland countries are labeled in red and islands in blue, and the tips of the phylogenies correspond to their sampling times. Abbreviations used for country names are given in Table S2 in the supplemental material. The numbers of countries reporting DENV-2 and DENV-4 activity in each year are summarized in the histograms shown. In the case of DENV-2, this represents the activities of both subtype III and V, which are not distinguished in epidemiological reports.