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Dengue virus type 1 clade replacement in recurring homotypic outbreaks.

ABSTRACT: BACKGROUND: Recurring dengue outbreaks occur in cyclical pattern in most endemic countries. The recurrences of dengue virus (DENV) infection predispose the population to increased risk of contracting the severe forms of dengue. Understanding the DENV evolutionary mechanism underlying the recurring dengue outbreaks has important implications for epidemic prediction and disease control. RESULTS: We used a set of viral envelope (E) gene to reconstruct the phylogeny of DENV-1 isolated between the periods of 1987-2011 in Malaysia. Phylogenetic analysis of DENV-1 E gene revealed that genotype I virus clade replacements were associated with the cyclical pattern of major DENV-1 outbreaks in Malaysia. A total of 9 non-conservative amino acid substitutions in the DENV-1 E gene consensus were identified; 4 in domain I, 3 in domain II and 2 in domain III. Selection pressure analyses did not reveal any positively selected codon site within the full length E gene sequences (1485 nt, 495 codons). A total of 183 (mean dN/dS = 0.0413) negatively selected sites were found within the Malaysian isolates; neither positive nor negative selection was noted for the remaining 312 codons. All the viruses were cross-neutralized by the respective patient sera suggesting no strong support for immunological advantage of any of the amino acid substitutions. CONCLUSION: DENV-1 clade replacement is associated with recurrences of major DENV-1 outbreaks in Malaysia. Our findings are consistent with those of other studies that the DENV-1 clade replacement is a stochastic event independent of positive selection.

SUBMITTER: Teoh BT

PROVIDER: S-EPMC3850903 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Dengue virus type 1 clade replacement in recurring homotypic outbreaks.

Teoh Boon-Teong BT Sam Sing-Sin SS Tan Kim-Kee KK Johari Jefree J Shu Meng-Hooi MH Danlami Mohammed Bashar MB Abd-Jamil Juraina J MatRahim NorAziyah N Mahadi Nor Muhammad NM AbuBakar Sazaly S

BMC evolutionary biology 20130928

<h4>Background</h4>Recurring dengue outbreaks occur in cyclical pattern in most endemic countries. The recurrences of dengue virus (DENV) infection predispose the population to increased risk of contracting the severe forms of dengue. Understanding the DENV evolutionary mechanism underlying the recurring dengue outbreaks has important implications for epidemic prediction and disease control.<h4>Results</h4>We used a set of viral envelope (E) gene to reconstruct the phylogeny of DENV-1 isolated b ...[more]

PMID: 24073945

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Project description:Four antigenically distinct serotypes (1-4) of dengue viruses (DENVs) cause dengue disease. Antibodies to any one DENV serotype have the potential to predispose an individual to more severe disease upon infection with a different DENV serotype. A dengue vaccine must elicit homotypic neutralizing antibodies to all four DENV serotypes to avoid the risk of such antibody-dependent enhancement in the vaccine recipient. This is a formidable challenge as evident from the lack of protective efficacy against DENV-2 by a tetravalent live attenuated dengue vaccine that has completed phase III trials recently. These trial data underscore the need to explore non-replicating subunit vaccine alternatives. Recently, using the methylotrophic yeast Pichia pastoris, we showed that DENV-2 and DENV-3 envelope (E) glycoproteins, expressed in absence of prM, implicated in causing severe dengue disease, self-assemble into virus-like particles (VLPs), which elicit predominantly virus-neutralizing antibodies and confer significant protection against lethal DENV challenge in an animal model. The current study extends this work to a third DENV serotype.We cloned and expressed DENV-1 E antigen in P. pastoris, and purified it to near homogeneity. Recombinant DENV-1 E underwent post-translational processing, namely, signal peptide cleavage and glycosylation. Purified DENV-1 E self-assembled into stable VLPs, based on electron microscopy and dynamic light scattering analysis. Epitope mapping with monoclonal antibodies revealed that the VLPs retained the overall antigenic integrity of the virion particles despite the absence of prM. Subtle changes accompanied the efficient display of E domain III (EDIII), which contains type-specific neutralizing epitopes. These VLPs were immunogenic, eliciting predominantly homotypic EDIII-directed DENV-1-specific neutralizing antibodies.This work demonstrates the inherent potential of P. pastoris-expressed DENV-1 E glycoprotein to self-assemble into VLPs eliciting predominantly homotypic neutralizing antibodies. This work justifies an investigation of the last remaining serotype, namely, DENV-4, to assess if it also shares the desirable vaccine potential manifested by the remaining three DENV serotypes. Such efforts could make it possible to envisage the development of a tetravalent dengue vaccine based on VLPs of P. pastoris-expressed E glycoproteins of the four DENV serotypes.

Project description:BackgroundDengue fever is a febrile disease caused by dengue virus (DENV), which affects people throughout the tropical and subtropical regions of the world, including Indonesia. East Kalimantan (Borneo) province suffered a dramatic increase in dengue cases in 2015 and 2016, making it the province with the second highest incidence of dengue in Indonesia. Despite this, dengue in East Kalimantan is understudied; leaving transmission dynamics of the disease in the area are mostly unknown. In this study, we investigate the factors contributing to the outbreaks in East Kalimantan.MethodsProspective clinical and molecular virology study was conducted in two main cities in the province, namely Samarinda and Balikpapan, in 2015-2016. Patients' clinical, hematological, and demographic data were recorded. Dengue detection and confirmation was performed using NS1-antigen and IgG/IgM antibody detection. RT-PCR was conducted to determine the serotypes of the virus. Phylogenetic analysis was performed based on envelope gene sequences.ResultsThree hundred patients with suspected dengue were recruited. Among these, 132 (44%) were diagnosed with dengue by NS1 antigen and/or nucleic acid detection. The majority of the infections (60%) were primary, with dengue hemorrhagic fever (DHF) the predominant manifestation (71.9%). Serotyping detected all four DENV serotypes in 112 (37.3%) cases, with the majority of patients (58.9%) infected by DENV-3. Phylogenetic analysis based on envelope gene sequences revealed the genotypes of the viruses as DENV-1 Genotype I, DENV-2 Cosmopolitan, and DENV-3 Genotype I. Most virus strains were closely-related to strains from cities in Indonesia.ConclusionsOur observations indicate that multiple introductions of endemic DENV from surrounding cities in Indonesia, coupled with relatively low herd immunity, were likely responsible for the outbreak of the dominant viruses. The study provides information on the clinical spectrum of the disease, together with serology, viral genetics, and demographic data, which will be useful for better understanding of dengue disease in Borneo.

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Dengue virus type 1 clade replacement in recurring homotypic outbreaks.

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Dengue virus type 1 clade replacement in recurring homotypic outbreaks.

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