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Dengue virus serotype 4, northeastern Peru, 2008.

ABSTRACT: In 2008, dengue virus serotype 4 (DENV-4) emerged in northeastern Peru, causing a large outbreak and displacing DENV-3, which had predominated for the previous 6 years. Phylogenetic analysis of 2008 and 2009 isolates support their inclusion into DENV-4 genotype II, forming a lineage distinct from strains that had previously circulated in the region.

SUBMITTER: Forshey BM

PROVIDER: S-EPMC2857240 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Dengue virus serotype 4, northeastern Peru, 2008.

Forshey Brett M BM Morrison Amy C AC Cruz Cristhopher C Rocha Claudio C Vilcarromero Stalin S Guevara Carolina C Camacho Daria E DE Alava Araceli A Madrid César C Beingolea Luis L Suarez Victor V Comach Guillermo G Kochel Tadeusz J TJ

Emerging infectious diseases 20091101 11

In 2008, dengue virus serotype 4 (DENV-4) emerged in northeastern Peru, causing a large outbreak and displacing DENV-3, which had predominated for the previous 6 years. Phylogenetic analysis of 2008 and 2009 isolates support their inclusion into DENV-4 genotype II, forming a lineage distinct from strains that had previously circulated in the region. ...[more]

PMID: 19891873

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Project description:BackgroundA majority infections caused by dengue virus (DENV) are asymptomatic, but a higher incidence of severe illness, such as dengue hemorrhagic fever, is associated with secondary infections, suggesting that pre-existing immunity plays a central role in dengue pathogenesis. Primary infections are typically associated with a largely serotype-specific antibody response, while secondary infections show a shift to a broadly cross-reactive antibody response.Methods/principal findingsWe hypothesized that the basis for the shift in serotype-specificity between primary and secondary infections can be found in a change in the antibody fine-specificity. To investigate the link between epitope- and serotype-specificity, we assembled the Dengue Virus Antibody Database, an online repository containing over 400 DENV-specific mAbs, each annotated with information on 1) its origin, including the immunogen, host immune history, and selection methods, 2) binding/neutralization data against all four DENV serotypes, and 3) epitope mapping at the domain or residue level to the DENV E protein. We combined epitope mapping and activity information to determine a residue-level index of epitope propensity and cross-reactivity and generated detailed composite epitope maps of primary and secondary antibody responses. We found differing patterns of epitope-specificity between primary and secondary infections, where secondary responses target a distinct subset of epitopes found in the primary response. We found that secondary infections were marked with an enhanced response to cross-reactive epitopes, such as the fusion-loop and E-dimer region, as well as increased cross-reactivity in what are typically more serotype-specific epitope regions, such as the domain I-II interface and domain III.Conclusions/significanceOur results support the theory that pre-existing cross-reactive memory B cells form the basis for the secondary antibody response, resulting in a broadening of the response in terms of cross-reactivity, and a focusing of the response to a subset of epitopes, including some, such as the fusion-loop region, that are implicated in poor neutralization and antibody-dependent enhancement of infection.

Project description:The DENV envelope (E) and pre-membrane (prM) glycoproteins are primary targets of serologic immunity after infection and vaccination. Of these, serotype-specific (TS) antibodies typically target E domains, while serotype cross-reactive (CR) antibodies typically the target prM protein and conserved E regions. To identify and quantify E-domain TS neutralizing antibody responses in polyclonal sera, we developed a panel of chimeric DENV4/2 viruses that incorporate DENV2 envelope domain I, II, and III (DENV4/2-EDI, EDII, EDIII) into the DENV4 E glycoprotein. Chimeric DENV4/2 viruses were recovered, replicated efficiently, and displayed similar maturation states as parental viruses. The recovery of viable DENV4/2-EDII recombinants required the inclusion of chimeric DENV4/2 prM that maintained critical interactions with chimeric E. To assess structural integrity and epitope display of chimeric viruses, we examined neutralization of mature virions by monoclonal antibodies (mAbs) and heterotypic polyclonal sera. The ED-chimeric virions preserved epitopes of TS and envelope-dimer-epitope CR mAbs and had similar sensitivity to CR polyclonal responses as parental strains. Primary sera from natural infection and human challenge target a region centered on EDIII and secondarily target EDII and EDI. Sera from natural infection had a unique neutralization pattern compared to sera from human challenge, which included greater frequency and higher titer of responses against DENV EDII. In summary, DENV4/2 E recombinant viruses delineate the subdomain targets of TS antibodies after vaccination and primary infection, which may provide new correlates of protection or identify epitopes of neutralizing monoclonal antibodies.IMPORTANCEThe four dengue virus (DENV) serotypes infect several hundred million people each year. Although primary infection is generally mild, subsequent infection by differing serotypes increases the risk for symptomatic disease ranging from fever to life-threatening shock. Despite the availability of licensed vaccines, a comprehensive understanding of antibodies that target the viral envelope protein and protect from infection remains incomplete. In this manuscript, we develop a panel of recombinant viruses that graft each envelope domain of DENV2 onto the DENV4 envelope glycoprotein, revealing protein interactions important for virus viability. Furthermore, we map neutralizing antibody responses after primary DENV2 natural infection and a human challenge model to distinct domains on the viral envelope protein. The panel of recombinant viruses provides a new tool for dissecting the E domain-specific targeting of protective antibody responses, informing future DENV vaccine design.

Dataset Information

Dengue virus serotype 4, northeastern Peru, 2008.

Publications

Dengue virus serotype 4, northeastern Peru, 2008.

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