Emergence of the Asian 1 Genotype of Dengue Virus Serotype 2 in Viet Nam: In Vivo Fitness Advantage and Lineage Replacement in South-East Asia

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Abstract
A better description of the extent and structure of genetic diversity in dengue virus (DENV) in endemic settings is central to its eventual control. To this end we determined the complete coding region sequence of 187 DENV-2 genomes and 68 E genes from viruses sampled from Vietnamese patients between 1995 and 2009. Strikingly, an episode of genotype replacement was observed, with Asian 1 lineage viruses entirely displacing the previously dominant Asian/American lineage viruses. This genotype replacement event also seems to have occurred within DENV-2 in Thailand and Cambodia, suggestive of a major difference in viral fitness. To determine the cause of this major evolutionary event we compared both the infectivity of the Asian 1 and Asian/American genotypes in mosquitoes and their viraemia levels in humans. Although there was little difference in infectivity in mosquitoes, we observed significantly higher plasma viraemia levels in paediatric patients infected with Asian 1 lineage viruses relative to Asian/American viruses, a phenotype that is predicted to result in a higher probability of human-to-mosquito transmission. These results provide a mechanistic basis to a marked change in the genetic structure of DENV-2 and more broadly underscore that an understanding of DENV evolutionary dynamics can inform the development of vaccines and anti-viral drugs. Dengue virus (DENV) is a mosquito transmitted RNA virus. One of the most characteristic patterns of DENV evolution is that viral lineages, including whole genotypes, are born and die-out on a regular basis. However, the precise cause of such lineage turnover is unclear. To address this issue we explored the genome-scale genetic diversity and evolution of dengue serotype 2 virus (DENV-2) in Viet Nam, a country with a high burden of dengue disease. We observed that DENV viruses assigned to the Asian 1 lineage were likely introduced into southern Viet Nam in the late 1990's (perhaps from Thailand) and subsequently displaced the resident Asian/American lineage serotype 2 viruses. A similar scenario seems to have occurred in Thailand and Cambodia, such that there appears to have been a region-wide proliferation of Asian 1 lineage viruses. Investigation of Vietnamese patients experiencing DENV-2 infection revealed that Asian 1 viruses also attain higher virus levels in the blood than viruses of the Asian/American lineage. This difference in virus titre is likely to have a profound impact on viral fitness by increasing the probability of mosquito transmission, and therein providing Asian 1 lineage viruses with a selective advantage.