In this evaluate we present the state-of-the-art in this field, highlighting the need of deeper knowledge on neutralizing immune response for making decisions about future vaccine approval and the potential need for different vaccine composition for regional administration

In this evaluate we present the state-of-the-art in this field, highlighting the need of deeper knowledge on neutralizing immune response for making decisions about future vaccine approval and the potential need for different vaccine composition for regional administration. and serve as vectors leading to rapid worldwide spread of the disease. worldwide spread of the disease. The disease is usually caused by dengue viruses (DENV), which are members of the genus (family) causing asymptomatic, moderate (dengue with or without warning indicators), or severe disease (severe dengue), sometimes leading to death.1 The infection in humans starts when DENV reaches cells of the mononuclear phagocyte lineage by interaction with Rabbit Polyclonal to TGF beta Receptor II (phospho-Ser225/250) some of the proposed receptors (DC-SIGN, heparan sulfate, Hsp70, Hsp90, etc.) and the viral particle is usually internalized by receptor-mediated endocytosis. Subsequently, low pH-dependent membrane fusion and uncoating lead to viral RNA release, polyprotein translation and processing, viral RNA synthesis by the replicase complex, computer virus assembly and in the endoplasmic reticulum and Golgi, maturation in the Golgi, and release of progeny viruses.3 You will find no specific treatments available for dengue and the development of a vaccine has been limited by there factors: first the huge antigenic and genetic diversity of the computer virus, the lack of cross-protection immunity among DENV serotypes and eventually genotypes, and the host immune interactions that have been associated with disease severity.4 Several tetravalent vaccine candidates are currently under development. Though the vaccine studies have shown some promising end result, the overall studies are not encouraging and needs a lot of research. Because of the presence of enormous intra-serotype genetic diversity, the possibility of cross-protection after vaccination is usually questionable. Hence the vaccine composition should be based on circulating strains of DENV. A more intense DENV genotype surveillance must be conducted in those countries where vaccine candidates are planed. The results from such surveillance should be available in real-time for helping decision makers about potentially different vaccine composition for administration in the different regions, a novel challenge for vaccine developers attempting a worldwide coverage. DENV Genetic Diversity DENVs are enveloped single-stranded positive-sense RNA viruses (ssRNA+) whose genomes encode for any viral RNA-dependent RNA polymerase lacking proofreading activity5 that leads to very high substitution rates, rapid divergence, and the presence of at least four serotypes (DENV-1 to -4) with high intra-serotype genetic diversity.6 Differences in phylogeny-based estimations of DENV substitution rates depending of prior assumptions (strict or relaxed molecular clock, changes in the distribution of variable and invariable sites across the phylogeny, full-length genome or OSU-03012 gene-based analysis) have been OSU-03012 reported.7 The rates for DENV-1 range from 4.55 10?4 to 9.08 10?4 substitutions per site per year (subs/site/12 months); for DENV-2 the rates range from 6.07 10?4 to 9.84 10?4 subs/site/12 months; for DENV-3 the nucleotide substitution rates range from 9.01 10?4 to 10.40 10?4 subs/site/12 months, and estimations for DENV-4 range from 6.02 10?4 to 10.63 10?4 subs/site/12 months.6,8 Based on these rates and the coalescent theory, the more recent common ancestor (MRCA) of the 4 DENV serotypes could have existed more than 1000 y ago.9 DENV-4 was probably the first diverging serotype, followed by DENV-2 (around 350 y ago) and finally DENV-1 (125 y ago) and -3 (100 y ago).9 The 4 DENV serotypes were first defined by their antigenic properties OSU-03012 as members of the DENV serocomplex.10 However, the accumulation of genetic diversity during the last centuries has led to inter-serotype genetic distances even higher than those observed among different species within the genus.9 The spread of the DENV serotypes around the world has also OSU-03012 allowed the accumulation of intra-serotype genetic variation and the emergence of different monophyletic groups (genotypes) in the different geographic regions of the world (Fig.?1).11 Although genetic diversity has accumulated along the whole viral genome in which the structural and non-structural genes and untranslated regions (UTRs) are critical in one or more steps of the computer virus life cycle,5 the envelope gene has raised more attention because of the role of the envelope (E) protein in computer virus attachment and entry into the cell, as well as membrane fusion and conversation with the immune system.5 Open in a separate window Determine 1. Phylogenetic tree of the 4 DENV serotypes based on the complete (1479C1485?nt) envelope gene of 289 viral isolates worldwide. The intra-serotype genetic diversity has allowed the designation of genotypes within each DENV serotype.37-40 The Envelope Protein The E protein of DENV is a membrane-anchored glycoprotein of approximately 53?kDa that forms homodimers which are organized into rafts, each containing 3 parallel dimers in the mature computer virus.12 The arrangement of these rafts with the viral membrane (M) proteins and host-derived lipid membrane leads.