Caister Academic Press

Frontiers in Dengue Virus Research

"a valuable point of reference" (Microbiology Today) "up-to-date and cutting-edge ... an important reference" (Expert Review of Vaccines)
Publisher: Caister Academic Press
Edited by: Kathryn A. Hanley1 and Scott C. Weaver2
1Department of Biology, New Mexico State University, Las Cruces, New Mexico, USA and 2Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
Pages: viii + 304
Publication date: January 2010
ISBN: 978-1-904455-50-9
Price: GB £219 or US $319Buy book
Publication date: January 2010
ISBN: 978-1-912530-90-8
Price: US $319Buy ebook

Dengue virus (DENV), a mosquito-borne flavivirus, is the causative agent of dengue fever, currently one of the most significant emerging disease challenges to global public health. Although dengue is an old disease, recent decades have seen an unprecedented increase in the geographic range, incidence, and severity of infection. The virus infects 100 million people annually and is endemic in many tropical and sub-tropical regions in the world. At present, neither a licensed vaccine nor anti-viral drugs are available to control dengue disease, prompting a plethora of research initiatives aimed at understanding the molecular and cellular virology, genomics, and evolution of this important virus.

This book brings together a panel of expert dengue virologists to produce a timely review of the rapidly expanding dengue research literature. In addition authors identify the most pressing questions that remain to be answered, thus providing a stimulus for future research. Topics include: evolutionary history, epidemiology, translation and processing of the viral polyprotein, viral replication, the role of the viral untranslated regions, pathogenesis, host response to DENV, development of animal models, DENV-mosquito interactions, dynamics of dengue virus transmission, emergence of DENV from its ancestral, sylvatic cycle, vaccines, novel anti-dengue drugs, and passive immunotherapy. Essential reading for every dengue virologist and highly recommended for all flavivirus and arbovirus virologists.


"an up-to-date and cutting-edge anthology from the leading experts in the dengue field. The chapters are balanced by contributions from established investigators who have dedicated their careers to DENV research with those from newcomers who have recently made significant contributions the study of DENV. ... the book addresses a range of important topics in DENV research. The authors identify many important questions that remain to be answered. The book will be considered as an important reference to DENV and other flavivirus researchers at the graduate level and beyond." from Expert Review of Vaccines (February 2010)

"a reference for scientists studying arboviruses and infections. Chapters are well written with very little overlap. It would be a good investment for laboratories interested in arboviral diseases" from Doodys (2010)

"well-organized and informative, yet highly accessible ... a thorough and up-to-date account ... a valuable point of reference" from Microbiology Today

Table of contents
1 . Dengue Virus - Past, Present and Future
Timothy P. Endy, Scott C. Weaver, and Kathryn A. Hanley
Dengue is an old disease caused by the mosquito-borne dengue viruses (DENV-1-4). In the last century, dengue has escalated in geographic distribution and disease severity to become now the most common arboviral infection of humans in the subtropical and subtropical regions of the world. In this chapter the authors discuss the historical aspects of dengue virus transmission and factors contributing to its evolution as one of the most important public health problems of this century.
2 . Translation and Processing of the Dengue Virus Polyprotein
R. Padmanabhan and Alex Y. Strongin
Positive strand RNA viruses, including flaviviruses, generally utilize the translational machinery of the host to synthesize viral proteins either in a cap-dependent or cap-independent manner to produce polyprotein precursors which are then processed into mature proteins. Polyprotein processing is accomplished by the concerted action of host and viral proteases. While some viruses, such as the hepatitis C virus code for more than one protease to perform distinct functions, flaviviruses code for a novel two-component serine protease which participates in early and late stages of the viral life cycle. This chapter summarizes the state of knowledge of polyprotein processing by the viral protease since its discovery approximately 20 years ago.
3 . The Dengue Virus Replication Complex
Sven Miller, Ines Romero-Brey, and Ralf Bartenschlager
Replication of all positive-stranded RNA viruses investigated so far occurs in close association with virus-induced intracellular membrane structures. Dengue virus (DENV), as a member of the family Flaviviridae, also induces such extensive rearrangements of intracellular membranes, called replication complex (RC). These RCs seem to contain viral proteins, viral RNA and host cell factors. However, the biogenesis of the RC and the three-dimensional organisation is to the most part unclear. In this chapter we summerize the current state of research as regards 1) the individual steps involved in DENV replication, 2) the viral and host cell proteins involved in DENV replication, 3) the intracellular sites of DENV replication, 4) the architecture of the DENV RCs and 5) the host cell nucleus and DENV replication. Finally, we present a hypothetical model of the biogenesis of the DENV replication complex.
4 . Role of the Dengue Virus 5' and 3' Untranslated Regions in Viral Replication
Andrea Gamarnik
As for all plus-stranded RNA viruses, dengue virus (DENV) genomic RNA is infectious. Transfection of full length DENV RNA genome into a susceptible cell triggers a complete cycle of viral replication. Construction of cDNA clones together with reverse genetics has proven to be a valuable tool to uncover genetic determinants of viral replication and to understand the function of the viral untranslated regions (UTRs). Translation initiation and initiation of RNA synthesis occur at the 5' and 3' terminal regions of the genome, respectively, and rely on complex RNA-RNA and RNA- protein interactions. The DENV 5'UTR contains two defined RNA structures, Stem-Loop A and Stem-Loop B, which have distinct functions during the process of viral RNA synthesis. The viral 3'UTR contains three domains with conserved sequences and structures. In these domains, there are RNA elements that are essential for the replication process and other elements that act as enhancers of the process. The 5' and 3' terminal regions of the viral RNA also carry inverted complementary sequences that mediate long-range RNA-RNA interactions and genome cyclization. It has been demonstrated for dengue and other flaviviruses that the circular conformation of the genome is a crucial determinant for viral replication. In the last few years, a great deal has been learned about the mechanisms by which the viral UTRs function during DENV replication. In this chapter, I discuss the current understanding of the function of different RNA structures of the DENV UTRs and provide some working models of how genome cyclization enables DENV RNA synthesis.
5 . Host and Virus Determinants of Susceptibility and Dengue Disease Severity
Maria G. Guzman, Beatriz Sierra, Gustavo Kouri, Jeremy Farrar, and Cameron Simmons
The pathogenesis of dengue infection is complicated and, despite intensive research, not well understood. Here, we review the burden of disease and the host (age, ethnicity, co-morbidities, immune and genetic factors) and viral (epidemiological and genetic factors) determinants for disease severity. This review is informed both by current knowledge of the topics and our specific experiences accumulated from Cuba and Vietnam.
6 . Animal Models of Dengue Virus Infection and Disease: Applications, Insights, and Frontiers
Scott J. Balsitis and Eva Harris
Many important questions in dengue pathogenesis are difficult to address without appropriate animal models of infection and disease. However, animal models of dengue virus (DENV) infection have been hampered by the fact that no non-human species naturally exhibits disease similar to human dengue fever or dengue shock syndrome following natural or experimental infection. Recently, though, many aspects of human DENV infection and disease have been reproduced in mice by manipulating the host and/or the virus to facilitate susceptibility to infection, and judicious use of these mouse models in combination with non-human primate models of DENV infection has resulted in substantial progress. This chapter briefly reviews the animal models for DENV infection currently available, and surveys the contributions each has made to four key areas in dengue research: pathogenesis, immunity and immunopathogenesis, therapeutic drug development, and vaccine development.
7 . Modulation of the Antiviral Response by Dengue Virus
Jorge L. Muñoz-Jordán and Irene Bosch
Dengue virus (DENV) produces a wide range of human illness, ranging from asymptomatic infections to hemorrhagic and potentially fatal disease. Severe disease is associated with high viremia, immune enhancement of sequential infections, and exacerbated inflammatory response. DENV is sensed in mammalian cells by endosomal and cytoplasmic receptors and stimulates the type-1 interferon (IFNα/ β) response. Secreted IFNα/ β stimulates JAK/STAT signaling, which results in the activation of IFNα/ β- stimulated genes that lead the infected cells toward the establishment of an antiviral response. Genomic technology has enabled the identification of a remarkable list of genes induced in human host cells in response to DENV infection. The results define antiviral and pro-inflammatory responses mainly composed of IFNα/ β- induced genes, which likely participate in the regulation of the immune response and vascular leakage during acute illness. DENV counteracts the IFNα/ β response of the host. The evidence indicates that non-structural proteins of DENV weaken IFNα/ β signaling, causing reduced activation of IFNα/ β-induced genes. The increased virus uptake, weakened host cell defense, and unrestrained inflammatory response likely predispose patients to develop severe illness. The unveiling of these virus-host interactions leads to a better understanding of dengue pathogenesis, and to innovative diagnostic and therapeutic approaches.
8 . Dengue Virus-mosquito Interactions
Eng-Eong Ooi and Duane J. Gubler
Dengue/dengue hemorrhagic fever is the most important vector-borne viral disease globally, with over half of the world's population living at risk of infection. While vaccines for other flaviviruses such as yellow fever, Japanese encephalitis and tick-borne encephalitis have been developed, dengue vaccine development is complicated by the need to incorporate all four virus serotypes into a single formulation. The only way to prevent dengue transmission presently is to reduce the vector population. This chapter focuses on the latest information on mosquito-dengue virus interaction, with the overall goal of identifying areas of research where improved understanding would likely contribute to our ability to predict and prevent cyclical epidemics.
9 . Evolutionary Dynamics of Dengue Virus
Shannon N. Bennett
This chapter addresses the following topics with respect to the evolutionary dynamics of dengue viruses in humans. Beginning with an introduction to evolutionary thinking and terminology, particularly with relevance to RNA viruses, the macroevolutionary divergence from dengue progenitors into the 4 serotypes is discussed. The microevolutionary dynamics within dengue serotypes and the forces of evolution-mutation, migration, recombination, selection and drift-that drive them are outlined. Finally, I summarize frontiers in understanding the evolutionary ecology of dengue, epitomized by the study of phylodynamics, in which interactions amongst host, vector and virus population sizes, their dynamic distributions, immune landscapes and evolutionary dynamics are modeled.
10 . Temporal and Spatial Dynamics of Dengue Virus Transmission
Derek Cummings
The geographical range in which dengue virus (DENV) is transmitted expanded rapidly in the latter decades of the 20th century. Within locations where dengue (DEN) is endemic, incidence varies widely from year to year, often exhibiting multi-annual cycles. At sub-national and even sub-community spatial scales, incidence varies from place to place within seasons. In this chapter, I describe the variability in DEN incidence that has been observed at multiple spatial and temporal scales and some of the mechanisms that are thought to drive this variability. The chapter is divided into three parts: statics, emergence and dynamics. In the first part of this chapter, I consider geographical patterns of DEN that have remained fairly static for decades. I describe the spatial distribution of DEN globally and mechanisms that dictate the presence or absence of endemic DEN over long time scales. In the second, emergence, I describe epidemics in which DEN has recently emerged or re-emerged, and I consider mechanisms that dictate the speed and success with which this occurs. In the third part, dynamics, I describe mechanisms that are thought to drive temporal variation in incidence within endemic settings. A key focus is on mechanisms of cycles in DEN incidence and, extending this to include space, on mechanisms that create spatial-temporal patterns in incidence, including synchrony of incidence between regions and traveling waves in incidence. Finally, I end with a discussion of the utility of determining the mechanisms that drive spatial-temporal dynamics of DEN, specifically, the improvements in public health that might be created by an understanding of these mechanisms.
11 . Dengue Virus Emergence from its Sylvatic Cycle
Nikos Vasilakis, Kathryn A. Hanley, and Scott C. Weaver
Dengue viruses (DENV) are members of the genus Flavivirus in the family Flaviviridae and include four antigenically distinct serotypes (DENV-1-4). In the last half-century, DENV have emerged as the most important arboviral pathogens in tropical and subtropical regions throughout the world, putting a third of the human population worldwide at risk of infection. The transmission of DENV includes a sylvatic, enzootic cycle, most likely between non-human primates and arboreal Aedes mosquitoes, and an urban, endemic/epidemic cycle (henceforth referred to as endemic) between peridomestic Aedes mosquitoes and human reservoir hosts. Phylogenetic analyses suggest that the four currently circulating urban DENV serotypes emerged independently from ancestral sylvatic progenitors in the forests of Southeast Asia after the establishment of urban populations large enough to support continuous inter-human transmission. In this chapter we examine the sylvatic origins of DENV, including ecology, adaptation for urban transmission, and molecular epidemiology, as well as the forces that have shaped the molecular evolution of extant sylvatic DENV strains. The potential for sylvatic DENV to re-emerge into the human transmission cycle in the face of immunity to current urban strains or vaccine candidates currently under development is also discussed. The lines of information addressed in this chapter will provide an overview of how sylvatic DENV population dynamics and transmission influence pathogenesis and how study of sylvatic DENV will improve our ability to understand and predict DENV emergence.
12 . Prospects and Challenges for Dengue Virus Vaccine Development
Stephen S. Whitehead and Anna P. Durbin
A safe and effective vaccine for the control of dengue virus disease is urgently needed and long overdue. Because each of the four dengue virus serotypes can cause the full spectrum of dengue disease, vaccination must protect against each serotype. An unprecedented number of vaccine candidates are in development and under clinical evaluation, with live attenuated vaccines being the most advanced. Considerable effort is also being made in the development of inactivated, subunit protein, virus vectored, and DNA vaccine candidates. The need to elicit protective immunity without predisposing for antibody-mediated enhanced disease, the need for rapid and tetravalent protection, and the need for an economical vaccine have presented challenges in the development pathway. Nevertheless, innovative research and development continues to provide solutions to these obstacles.
13 . Novel Therapeutic Approaches for Dengue Disease
Mayuri, Elisa La Bauve and Richard J. Kuhn
Dengue has emerged as the most common mosquito-borne viral disease of humans in the past three decades. There are no available vaccines or antivirals against DENV. Currently, vector control is the only method for prevention of the disease. Development of a successful vaccine would require for it to be effective against all four DENV serotypes, economical, and provide long-term protection. Antivirals directed against one or more stages of the virus life cycle are likely to form an important part of dengue disease therapeutics. The strategies that have been used in the past towards development of an effective antiviral against dengue, as well as those being employed currently are discussed in light of information from structural biology, computational biology and molecular virology, highlighting the potential opportunities and obstacles to their use.
14 . Progress in Passive Immunotherapy
Ana P. Goncalvez, Robert H. Purcell, and Ching-Juh Lai
Dengue is currently endemic in more than one hundred countries around the world. It causes approximately 50-100 million infections annually, including 250,000-500,000 cases of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). According to the World Health Organization (WHO), two fifths of the world population is at risk of dengue virus (DENV) infection. It has been suggested that globalization and climate change have had a significant impact on the emergence of DENV in new areas. No vaccine or therapy against DENV is currently approved for use in humans, and alternative strategies to control DENV infection are urgently needed, particularly because the design of such strategies may also inform efforts in vaccine design. This chapter outlines the prophylaxis/therapeutic potential of monoclonal antibodies (MAbs) against DENV and highlights the challenges to implementation of this strategy, including antibody-dependent enhancement (ADE), genetic variability of DENV strains, potential for selection of MAb escape variants, and financial cost. Moreover, we describe recent immunologic and structural studies that have provided a new understanding of antibody-mediated neutralization mechanisms and protection against DENV and other flavivirus infections. These insights are having an important impact on the development of vaccines and antibody-based therapies.

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(EAN: 9781904455509 9781912530908 Subjects: [virology] [microbiology] [medical microbiology] )