Clade replacements in dengue virus serotypes 1 and 3 are associated with changing serotype prevalence

Abstract

The evolution of dengue virus (DENV) is characterized by phylogenetic trees that have a strong temporal structure punctuated by dramatic changes in clade frequency. To determine the cause of these large-scale phylogenetic patterns, we examined the evolutionary history of DENV serotype 1 (DENV-1) and DENV-3 in Thailand, where gene sequence and epidemiological data are relatively abundant over a 30-year period. We found evidence for the turnover of viral clades in both serotypes, most notably in DENV-1, where a major clade replacement event took place in genotype I during the mid-1990s. Further, when this clade replacement event was placed in the context of changes in serotype prevalence in Thailand, a striking pattern emerged; an increase in DENV-1 clade diversity was associated with an increase in the abundance of this serotype and a concomitant decrease in DENV-4 prevalence, while clade replacement was associated with a decline in DENV-1 prevalence and a rise of DENV-4. We postulate that intraserotypic genetic diversification proceeds at times of relative serotype abundance and that replacement events can result from differential susceptibility to cross-reactive immune responses.

FIG. 1.

ML tree of 120 strains of DENV-1, including 92 newly sampled strains from Thailand. Thai strains sampled from regions other than Bangkok are denoted as follows: A, Ayuthaya; CN, Chai Nat; K, Kamphaeng Phet; NB, Nonthaburi; P, Pichit; PT, Pathum Thani; and S, Samut Prakan. Key clades are indicated. Bootstrap support values are shown for major nodes on the tree. The tree is midpoint rooted for purposes of clarity only, and all horizontal branch lengths are drawn to scale.

FIG. 2.

ML tree of 120 strains of DENV-3, including 66 newly sampled strains from Thailand. Thai strains sampled from regions other than Bangkok are denoted as follows: A, Ayuthaya; C, Chachoengsao; N, Nakhon Pathom; NB, Nonthaburi; KB, Kanchana Buri; PT, Pathum Thani; S, Samut Prakan; and SB, Suphan Buri. Key clades are indicated. Bootstrap support values are shown for major nodes on the tree. The tree is midpoint rooted for purposes of clarity only, and all horizontal branch lengths are drawn to scale.

FIG. 3.

Relative sampling frequency of each DENV serotype over 30 years as identified from patients admitted to the QSNICH in Bangkok, Thailand, from 1973 to 2002. The predominant dengue serotype varied through time: DENV-2, 1973 to 1986; DENV-3, 1987; DENV-2, 1988 to 1989; DENV-1, 1990 to 1992; DENV-4, 1993 to 1994; DENV-3, 1995 to 1999 (24); and DENV-1, 1999 to 2002 (A. Nisalak, unpublished observations). Note the inverse relationship between the prevalence of DENV-1 and that of DENV-4, while DENV-2 and DENV-3 cocirculated relatively constantly throughout the 30 years and only DENV-3 was associated with severe dengue epidemic years. Levels of genetic diversity and clade replacement in DENV-1 are described in the context of relative DENV-1 and DENV-4 prevalence (see Discussion).