The following excerpt is from a recent review of the book Frontiers in Dengue Virus Research.

"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 Mark Schreiber et al (Novartis Institute for Tropical Diseases, Singapore) writing in the February 2010 issue of Expert Review of Vaccines read more ...

Frontiers in Dengue Virus Research

Labels: dengue, dengue virus, DENV

The spread of Aedes aegypti mosquitoes through the slave trade and later through the movement of ships and goods during the Second World War facilitated the global expansion of dengue virus. The first descriptions of dengue fever characterized the eighteenth-century pandemic of dengue infection as described in 1780 by Benjamin Rush during a large outbreak of dengue fever in Philadelphia, Pennsylvania, in the USA. Dengue was thought to have been introduced in the USA as a consequence of the rum and slave trade between Africa and Caribbean ports. Dengue outbreaks occurred throughout the USA, the Caribbean and South America during the nineteenth and early twentieth centuries. The second dengue pandemic was centred in the mining towns of northern Queensland, Australia, where boom towns and resulting Aedes aegypti population growth resulted in continuous dengue transmission from the 1870s until the First World War. Dengue outbreaks were also occurring in the Eastern Mediterranean and resulted in a large epidemic in Greece during 1928. During the Second World War, dengue strains were carried by ships and soldiers from South-East Asia to Japan, the Pacific Islands, Philippines and Hawaii. A new manifestation of severe dengue illness resulted, dengue haemorrhagic fever, first reported in the Philippines then later in Thailand during the 1950s.

The discovery of the role of Aedes aegypti in the transmission and spread of yellow fever and the subsequent isolation of the virus and creation of an effective yellow fever vaccine introduced the concept of mosquito control as an effective measure to disrupt yellow fever transmission. Subsequently the International Health Board and the Rockefeller Foundation instituted mosquito control strategies including the use of a larvicidal, Paris Green, throughout the USA and Central and South America. These techniques were soon applied to malaria control and during the years from 1924 to 1925, funding for malaria prevention through the strategy of mosquito control doubled. The success of this programme in Italy during the 1920s set the stage for the global use of mosquito control in the prevention of malaria. The Second World War prompted the creation of the Rockefeller Foundation Health Commission in 1942 to support national defence and in particular malaria control for U.S. forces. The need for lousicides to combat typhus ushered in a new insecticide developed by the Swiss firm, Geigy, called dichlorodiphenyl-trichloroethane (DDT). Led by Fred Soper, the Rockefeller team demonstrated the effectiveness of DDT as a lousicide and in disrupting typhus epidemics. DDT was soon used in aerial and ground spraying for Allied Forces during a malaria outbreak in Italy and was found to be a highly effective larvicide with a long environmental persistence. DDT subsequently became a key component of the World Health Organization's global malaria eradication campaign in 1955. This campaign resulted in the elimination of both the malaria mosquito vector and Aedes aegypti throughout South America and the virtual elimination of malaria, yellow fever and dengue throughout the Americas. A reassessment of this global strategy by the WHO and the growing concerns of the environmental effects of DDT led to the end of the use of DDT as a mosquito control larvicide in 1969. The cessation of DDT-based mosquito control programmes in the Americas and the social disruption that resulted from the Second World War allowed the spread of DENV in Asia, the reintroduction and resurgence of Aedes aegypti throughout the Americas and, consequently, resurgence of DENV, particularly South-East Asian strains, in the Americas.

The first two dengue pandemics were characterized by epidemics that produced severe outbreaks of fever, headache and myalgias, a clinical syndrome termed dengue fever. As waves of DENV-1 to -4 spread throughout the human population, especially in Asia, DENV adapted to be able to reach virus levels during a course of infection that allowed mosquitoes to become infected, thereby ensuring continued transmission of the virus. There is variation among vector species in their susceptibility to dengue and the potential selective effects of such variation on viral replication; however, high levels of co-circulation among serotypes also posed a challenge for the persistence of each serotype. Consider a DENV-2 strain entering a population that had a high degree of pre-existing antibody to an established DENV, such as DENV-1. Preexisting DENV-1 antibody, though not neutralizing, would under ordinary circumstances have provided significant heterotypic neutralization of DENV-2, potentially reducing viral levels in infected humans and thereby interrupting mosquito transmission. Thus, the presence of high levels of infection by multiple serotypes imposed significant selection for viruses that, via mutations in the E protein coat and changes in specific epitopes, were able to either fully escape the effects of heterotypic neutralization, or as is currently thought to be the case, to utilize these subneutralizing antibodies to enhance infection. This phenomenon of viral replicative enhancement due to subneutralizing heterotypic antibody is known as antibody-dependant enhancement (ADE). Since ADE results in higher viral loads, viruses with a particularly high tendency towards enhancement should have a selective advantage.

The ability of all DENV serotypes to utilize pre-existing heterotypic flavivirus antibody to enhance infection is a unique feature of DENV that is particularly common among South-East Asian strains. The tendency to be enhanced by heteroserotypic antibody distinguishes DENV from all other flaviviruses, and is the primary basis of DENV pathogenesis in severe dengue illness. During the third pandemic, this tendency of DENV to be enhanced in secondary dengue infection resulted in the clinical manifestation of a previously unrecognized sequelae of DENV infection - severe haemorrhagic disease and plasma leakage. First described as Philippine and Bangkok haemorrhagic fever during the 1950s, it is now recognized as dengue haemorrhagic fever (DHF).

from Endy et al. in Frontiers in Dengue Virus Research

Labels: Aedes aegypti, Dengue pandemics, dengue virus, Dichlorodiphenyl-trichloroethane, Haemorrhagic fever

The evolutionary path of dengue virus differs in several important aspects from its flavivirus cousins, though dengue retains many of the same clinical characteristics such as production of severe fever, myalgias, headache, hepatitis, encephalitis and haemorrhage. The phylogeny of the flaviviruses sheds little light on the origin of DENV because the closest relatives include mosquito-borne viruses that occur in several continents. However, as described by Vasilakis, more detailed phylogenetic studies of DENV suggest an Asian origin, where sylvatic cycles between non-human primates and Aedes mosquitoes arose. Unlike the other flaviviruses however, DENV evolved into four antigenically and phylogenetically distinct serotypes: DENV-1, DENV-2, DENV-3 and DENV-4. Subsequently, each of these four serotypes emerged independently into an endemic cycle of transmission between humans and Aedes albopictus. This endemic cycle is now both ecologically and evolutionarily separate from the sylvatic cycle. Thus, unlike other flaviviral pathogens, urban cycles of DENV can no longer be considered zoonotic.

It has been demonstrated that DENV evolves according to a molecular clock at a serotype- and genotype-specific rate, and that the transfer of DENV from a sylvatic cycle to sustained human transmission may have occurred on the order of 100 to 1500 years ago years ago, suggesting that the current global pandemic of all four serotypes of DENV appeared during the past century. The contemporary genetic diversity seen in all four dengue serotypes is related to population growth, urbanization, and mass transport of both virus and its mosquito vector. Using an analytical technique based on coalescent theory, it was demonstrated that DENV-2 and DENV-3 experienced two phases of exponential growth. In the first phase and for most of their history, the dengue viruses experienced a low rate of exponential growth. Thirty years ago, the rate of growth of DENV-2 and DENV-3 suddenly increased by a factor of between 15 and 20.

from Endy et al. in Frontiers in Dengue Virus Research

Labels: dengue, dengue virus, Sylvatic cycle

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.

Current research focuses on the prophylaxis/therapeutic potential of monoclonal antibodies (MAbs) against DENV and 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. Also important are the 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.

from Ana P. Goncalvez, Robert H. Purcell, and Ching-Juh Lai in Frontiers in Dengue Virus Research

Further reading: Dengue Virus

Labels: dengue, dengue fever, dengue virus

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.

from Mayuri, Elisa La Bauve and Richard J. Kuhn in Frontiers in Dengue Virus Research

Further reading: Dengue Virus

Labels: dengue, dengue fever, Dengue therapy, Dengue vaccine, dengue virus

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.

from Stephen S. Whitehead and Anna P. Durbin in Frontiers in Dengue Virus Research

Further reading: Dengue Virus

Labels: dengue, dengue fever, dengue virus, Dengue Virus Vaccine

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. Research 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.

from Eng-Eong Ooi and Duane J. Gubler in Frontiers in Dengue Virus Research

Further reading: Dengue Virus

Labels: dengue, dengue fever, dengue virus

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.

from Jorge L. Muñoz-Jordán and Irene Bosch in Frontiers in Dengue Virus Research

Further reading: Dengue Virus

Labels: dengue, dengue fever, dengue virus

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.

from Andrea Gamarnik in Frontiers in Dengue Virus Research

Further reading: Dengue Virus

Labels: dengue, dengue fever, dengue virus

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.

from Sven Miller, Ines Romero-Brey, and Ralf Bartenschlager in Frontiers in Dengue Virus Research

Further reading: Dengue Virus

Labels: dengue, dengue fever, dengue virus, Flaviviridae

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.

from R. Padmanabhan and Alex Y. Strongin in Frontiers in Dengue Virus Research

Further reading: Dengue Virus

Labels: dengue, dengue fever, dengue virus, flavivirus, Flaviviruses

Lentiviruses and Macrophages: Molecular and Cellular Interactions
Edited by: Moira Desport
Published: 2010 ISBN: 978-1-904455-60-8
In this timely book, top lentivirus and macrophage specialists comprehensively review cutting-edge topics in the molecular and cellular biology of the lentivirus-macrophage interaction. Topics include lentivirus tropism and disease, macrophage biology, macrophage in HIV-1 infection and disease progression, post-entry restrictions to lentiviral replication, HIV-2 tropism and disease, SHIV model of disease, the felid immunodeficiency viruses, EIAV, small ruminant lentiviruses, bovine lentiviruses, coinfections and superinfections.

Further reading: Lentiviruses and Macrophages: Molecular and Cellular Interactions

Labels: aids, books, dengue virus, hiv, lentivirus, lentiviruses, new book, virology books, virus books

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.

Further reading: Frontiers in Dengue Virus Research

Labels: dengue, dengue disease, dengue fever, dengue virus, DENV, flavivirus