Dengue 1 Diversity and Microevolution, French Polynesia 2001–2006: Connection with Epidemiology and Clinics

Abstract

BackgroundDengue fever (DF) is an emerging infectious disease in the tropics and subtropics. Determinants of DF epidemiology and factors involved in severe cases—dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS)—remain imperfectly characterized. Since 2000, serotype 1 (DENV-1) has predominated in the South Pacific. The aim of this study was (i) to determine the origin and (ii) to study the evolutionary relationships of DENV-1 viruses that have circulated in French Polynesia (FP) from the severe 2001 outbreak to the recent 2006 epidemic, and (iii) to analyse the viral intra-host genetic diversity according to clinical presentation.Methodology/Principal FindingsSequences of 181 envelope gene and 12 complete polyproteins of DENV-1 viruses obtained from human sera in FP during the 2001–2006 period were generated. Phylogenetic analysis showed that all DENV-1 FP strains belonged to genotype IV–“South Pacific” and derived from a single introduction event from South-East Asia followed by a 6-year in situ evolution. Although the ratio of nonsynonymous/synonymous substitutions per site indicated strong negative selection, a mutation in the envelope glycoprotein (S222T) appeared in 2002 and was subsequently fixed. It was noted that genetic diversification was very significant during the 2002–2005 period of endemic DENV-1 circulation. For nine DF sera and eight DHF/DSS sera, approximately 40 clones/serum of partial envelope gene were sequenced. Importantly, analysis revealed that the intra-host genetic diversity was significantly lower in severe cases than in classical DF.Conclusions/SignificanceFirst, this study showed that DENV-1 epidemiology in FP was different from that described in other South-Pacific islands, characterized by a long sustained viral circulation and the absence of new viral introduction over a 6-year period. Second, a significant part of DENV-1 evolution was observed during the endemic period characterized by the rapid fixation of S222T in the envelope protein that may reflect genetic drift or adaptation to the mosquito vector. Third, for the first time, it is suggested that clinical outcome may be correlated with intra-host genetic diversity.

Dengue-1 Virus Clade Replacement in Thailand Associated with Enhanced Mosquito Transmission

“…In contrast, elimination of deleterious mutations (purifying selection) strongly limits in situ evolution of lineages (23). Purifying selection is likely the dominant evolutionary force in DENV evolution (20), and nucleotide fixation events are due primarily to genetic drift (13,20,26). Although stochastic processes are undoubtedly important in DENV evolution, the present study indicates that more dramatic major clade replacement events may have an adaptive basis (43).…”

“…This lineage turnover is detected in phylogenetic analyses in two different, nonmutually exclusive forms: (i) continuous, ladderlike temporal structure within clades and (ii) more dramatic, major clade replacement events. Within a clade, the majority of sublineages present at a specific time point are not detected at later time points, resulting in a ladderlike tree topology (8,13,26). Occasionally, an entire clade that persisted for a number of years at a given location goes extinct as an entirely new clade takes over.…”

High-Resolution Analysis of Intrahost Genetic Diversity in Dengue Virus Serotype 1 Infection Identifies Mixed Infections

“…Several previous studies have confirmed that the population of DENV in humans and within individual Aedes mosquitoes contains measurable genetic variation (8,19,33,34). Levels of withinhost genetic diversity have been previously shown to vary among patients.…”

“…The basis for the genetic diversity in DENV is its error-prone RNA polymerase (10), such that mutations commonly occur during viral replication and on which a combination of genetic drift and negative and/or positive natural selection is able to act. This high rate of replication error results in DENV existing as a population of closely related variants within an individually infected host (33, 34), and this intrahost genetic diversity has been proposed to have implications for pathogenesis of DENV infection, variable disease outcomes, virus evolution, and host immunity (6).Several previous studies have confirmed that the population of DENV in humans and within individual Aedes mosquitoes contains measurable genetic variation (8,19,33,34). Levels of withinhost genetic diversity have been previously shown to vary among patients.…”

“…Lin et al (19) showed that DENV exhibits substantial sequence diversity in humans and to a lesser extent in mosquitoes, with the major variant transmitted in both humans and mosquitoes. Intriguingly, Descloux et al suggested that the level of intrahost genetic diversity was lower in patients suffering severe dengue disease, i.e., dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), than in those experiencing the milder dengue fever (DF), such that there is a direct link between viral genetic diversity and clinical outcome (8).…”