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Hlaing Myat Thu Thesis VIRUS DIVERSITY AND THE EMERGENCE OF DENGUE Hlaing Myat Thu M.B.,B.S, M.Med.Sc. Centre for Molecular Biotechnology, School of Life Sciences, Queensland University of Technology, Brisbane, Australia. A thesis submitted for the degree of Doctor of Philosophy of the Queensland University of Technology, 2004 DEDICATION To my parents, my husband Win Maw and my daughter Thawdar (Mee Mee). ABSTRACT The aims of this study were to investigate the role of the diversity of dengue virus populations in changing patterns of virus transmission and disease. Prior to the commencement of this study, dengue 2 virus (DENV-2) had been associated most frequently with severe disease, so the study commenced with this serotype. Because it was not possible to quantitate diversity in the entire 11 kb of the viral genome, the study focussed on the envelope (E) gene, because the E protein is the major protein on the surface of the virion and thus might be under strong selective pressure from the host immune system and from the requirement to engage specific receptors on host cells. This study was the first direct quantification of the diversity of dengue virus populations in individual hosts. The nucleotide sequences of more than 70 per cent of the E genes in each virus population differed from the consensus nucleotide sequence for the population. In the course of quantitating genetic diversity in DENV-2 virus populations in patients and in mosquitoes, recombinant DENV-2 and both parental virus populations were detected in a single mosquito. This was the first such report. In 2001, just after the commencement of this study, Myanmar had the largest outbreak of dengue on record. Unlike previous outbreaks, 95 per cent of dengue viruses isolated from patients were of a single serotype, DENV-1. Despite the large number of cases of dengue, the proportion of patients with severe dengue was low. In the light of these observations, the direction of this study changed to focus on DENV- 1. Phylogenetic analysis of the E genes of DENV-1 collected before and after the 2001 dengue outbreak suggested that some time before 1998, an early lineage of DENV-1 had become extinct and had been replaced by two new lineages. There was no evidence that these changes were due to selection or to recombination within the E protein genes of the old clade of viruses and the newly introduced viruses. A more detailed analysis was undertaken, of the entire genome of 11 human DENV-1 isolates and of 4 from mosquitoes recovered in Yangon between 1971 and 2002, to determine whether the extinction of the pre-1998 lineage of DENV-1 (clade A) and the appearance of the two new lineages (clades B and C) could have been due to selective pressures acting on genes other than E. Evidence of only weak selection was found in the NS5 gene (at amino acids 127,135 and 669) but the resultant amino acid changes did not distinguish all recent viruses from viruses belonging to the extinct clade. The phylogenetic relationships between individual genes from these viruses and between the open reading frames were similar. No evidence was found of recombination that might have given rise to two new clades of virus with enhanced fitness. Collectively, these data suggested that the extinction of clade A viruses and their replacement by the two new clades, between 1998 and 2000 was a stochastic event in an inter-epidemic period when rates of virus transmission were low. This was the first report of such an extinction of a lineage of DENV-1 and its replacement by new lineages. At about the same time as the 2001 outbreak of DENV-1 infection in Myanmar, an outbreak of DENV-1 began in the Pacific. A comparison of the nucleotide sequences of the E genes of viruses from the Pacific with those of viruses from throughout south-east Asia suggested that the outbreak in the Pacific was due to the introduction of multiple genotypes of DENV-1 from Asia and that some of these DENV-1 could have originated in Myanmar. The principal observations from this study are: - (a) Dengue virus populations in individual hosts are extremely heterogenous and may contain a significant proportion of non-infectious genomes. (b) Intra-serotypic recombination between dengue viruses may be far more common than the literature suggests but it may not be detected because of the almost universal use of consensus nucleotide sequences. (c) Significant changes in dengue virus genotypes that occur at single localities may be due to genetic bottlenecks rather than to selection or to recombination. (d) Dengue viruses can be transported more than 10,000 km to cause outbreaks in non-endemic areas. Key words: Dengue viruses, diversity, recombination, selection, genetic bottleneck LIST OF PUBLICATIONS The following references are to publications and manuscripts prepared in conjunction with this thesis. Craig, S., Thu, H.M., Lowry, K., Wang, X.F., Holmes, E.C., and Aaskov, J (2003). Diverse dengue type 2 virus populations contain recombinant and both parental viruses in a single mosquito host. Journal of Virology, 77, 4463-4467. (Joint first author) Thu, H.M., Lowry, K., Myint, T.T., Shwe, T.N., Han, A.M., Khin, K.K., Thant, K.Z., Thein, S. and Aaskov, J.G (2004). Myanmar dengue outbreak associated with displacement of serotypes 2, 3 and 4 by dengue 1. Emerging Infectious Diseases 10, 593-597. A-Nuegoonpipat, A., Berlioz-Arthaud, A., Chow, V., Endy, T., Lowry, K., Mai, L.Q., Ninh, T.U., Pyke, A., Reid, M., Reynes, J.M., Su Yun, S-.T., Thu, H.M., Wong, S-S, Holmes, E.C and Aaskov, J.G (2004). Sustained transmission of dengue virus type 1 in the Pacific due to repeated introduction of different Asian strains. Virology 329, 505-512. Thu, H.M., Lowry, K., Jiang, L., Hlaing, T., Holmes, E.C. and Aaskov, J.G (2004). Lineage extinction and replacement in dengue type 1 virus populations due to stochastic events rather than to natural selection. Virology (accepted for publication). TABLE OF CONTENTS PAGE TITLE PAGE 1 CERTIFICATE RECOMMENDING ACCEPTANCE 2 DEDICATION 3 ABSTRACT AND KEYWORDS 4 LIST OF PUBLICATIONS AND MANUSCRIPTS 7 TABLE OF CONTENTS 8 DECLARATION 9 ACKNOWLEDGEMENTS 10 CHAPTER 1. INTRODUCTION 1.1 A DESCRIPTION OF THE SCIENTIFIC PROBLEM INVESTIGATED 11 1.2 THE OVERALL OBJECTIVES OF THE STUDY 13 1.3 THE SPECIFIC AIMS OF THE STUDY 13 1.4 AN ACCOUNT OF SCIENTIFIC PROGRESS LINKING PAPERS 13 CHAPTER 2. LITERATURE REVIEW 18 CHAPTER 3. DIVERSE DENGUE TYPE 2 VIRUS POPULATIONS CONTAIN 59 RECOMBINANT AND BOTH PARENTAL VIRUSES IN A SINGLE MOSQUITO HOST CHAPTER 4. MYANMAR DENGUE OUTBREAK ASSOCIATED WITH DISPLACEMENT OF SEROTYPES 2,3 AND 4 BY DENGUE 1 66 CHAPTER 5. LINEAGE EXTINCTION AND REPLACEMENT IN DENGUE TYPE 1 VIRUS POPULATIONS DUE TO STOCHASTIC EVENTS RATHER THAN TO NATURAL SELECTION 73 CHAPTER 6. SUSTAINED TRANSMISSION OF DENGUE VIRUS TYPE 1 IN THE PACIFIC DUE TO REPEATED INTRODUCTION OF DIFFERENT ASIAN STRAINS 91 CHAPTER 7. GENERAL DISCUSSION 112 DECLARATION The work presented in this thesis has not been submitted previously for a degree at this or any other university to the best of my knowledge and belief, this thesis contains no material previously published or written by another person except where due reference is made. Signed ..................................... Hlaing Myat Thu Date ........................................ ACKNOWLEDGEMENTS I would like to express my sincere gratitude to my supervisors Dr John Aaskov and Dr Soe Thein for their invaluable advice and encouragement. My thanks to the World Health Organization and the Wellcome Trust for allowing me to undertake this project and providing the scholarship and research funding. I would also like to thank Dr Edward C. Holmes, from the Department of Zoology, University of Oxford, Oxford, U.K. for helping me with analysis of my data. My sincere thanks to the academic and administrative staff of the School of Life Sciences, Queensland University of Technology for all their help and support. To my friends and colleagues from the Arbovirology group (past and present), CMB and CRC, all your help and support have made my hardships away from home bearable. My sincere thanks to Dr Kyaw Moe, deputy director and head of the Virology Research Division and all the staff of the Virology Research Division and the Medical Entomology Research division, Department of Medical Research, Yangon, Myanmar for their support and help during sample collections. Finally, to my parents, my husband Win Maw and my daughter Mee Mee, for their love and continuous encouragement throughout my PhD. CHAPTER 1 INTRODUCTION 1.1 A DESCRIPTION OF THE SCIENTIFIC PROBLEM INVESTIGATED Dengue fever / Dengue haemorrhagic fever (DF/DHF) is caused by a flavivirus, of the same name from the family Flaviviridae. DHF can progress from a mild, non-specific, viral disease to irreversible shock and death within a few hours and is the major cause of hospitalization and death in children in Southeast Asian countries (Gubler, 1997; Gubler and Meltzer, 1999). The case fatality rate can be as high as 44% (Rigau-Perez et al., 1998). In the last few decades, both the incidence of dengue and the areas affected have increased dramatically (Monath, 1994). Currently, more than 100 countries have endemic dengue (Gubler, 1998). The global burden of DHF is estimated to be 750,000 disability adjusted life years (DALYs) per year per million population (Meltzer et al., 1998).The burden of DHF in Myanmar was estimated to be 83.8 DALYs per year per million population (Naing, 2000). There are four antigenically distinct dengue virus serotypes (DENV 1, 2, 3 and 4) and multiple genotypes have been identified in each virus serotype (Holmes, 1998, Lanciotti et al., 1994, Lanciotti et al., 1997, Lewis et al., 1993 and Rico-Hesse, 1990).
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