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Evidence for inter- and intra-genotypic variations in dengue serotype 4 viruses representing predominant and non-predominant genotypes co-circulating in Thailand from 1977 to 2001

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Abstract

In order to characterize viral genetic variation among predominant and non-predominant genotypes of Thai dengue serotype 4 viruses (DENV-4) and follow mutations that occur during virus evolution, we performed a comparative analysis of the complete genomic sequences of six DENV-4 isolates representing three genotypes (I, IIA, and III) co-circulating in Thailand over a 24-year period. The results revealed [1] remarkable genetic variation in the viral genome between predominant and non-predominant genotypes; [2] inter-genotype-specific amino acid and nucleotide mutations in most regions of the viral genome; [3] more amino acid and nucleotide substitutions in later as compared to earlier isolates for predominant genotype I strains; [4] a single nucleotide substitution at nucleotide position 77 of the 5-′NTR of two non-predominant genotype III strains that disrupted a small conserved 3′stem–loop (SL) in the cyclization sequence required for virus replication; [5] a high degree of conservation of PrM/M and NS2B proteins, and the 5′-NTR in predominant genotype I strains with no mutations observed over the 24-year period of observation; and [6] no molecular markers that appeared to correlate with disease severity. Several mutations identified in this study might have a significant impact on the persistence of virus in the population, including one in the 5′-NTR that disrupted a small, highly conserved 3′SL2 structure at the terminus of the cyclized 5′–3′ RNA sequences in two genotype III strains, and three amino acid (aa) charge change mutations in the E and NS5 proteins of genotype I strains. The conserved 3′-SL structure may be a target for antiviral drug development.

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Acknowledgements

We thank our field unit, Department of Virology, Armed Force Research Institute of Medical Sciences (AFRIMS) Bangkok, Thailand for sample characterization, sequencing, and storage; we thank the doctors and nurses of QSNICH/AFRIMS for sample collection and clinical grading. This research was supported by the Science and Engineering Apprentice Program (House support) sponsored by George Washington University/Walter Reed Army Institute of Research, and the US Military Infectious Disease Research Program at Fort Detrick, Maryland, USA.

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The opinions and assertions contained herein are the private views of the authors and are not to be construed as reflecting the official views of the U.S. Army or the Department of Defense.

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Authors and Affiliations

  1. Science and Engineering Apprentice Program at the Walter Reed Army Institute of Research, Silver Spring, MD, USA

    Richard Zhao

  2. Department of Virology, U.S. Army Medical Component-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand

    Piyawan Chinnawirotpisan & Chonticha Klungthong

  3. Division of Viral Diseases, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA

    Chunlin Zhang & Robert Putnak

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  1. Richard Zhao
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  2. Piyawan Chinnawirotpisan
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Correspondence to Robert Putnak.

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Zhao, R., Chinnawirotpisan, P., Klungthong, C. et al. Evidence for inter- and intra-genotypic variations in dengue serotype 4 viruses representing predominant and non-predominant genotypes co-circulating in Thailand from 1977 to 2001. Virus Genes 41, 5–13 (2010). https://doi.org/10.1007/s11262-010-0473-8

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