James Crowe
Faculty Member
Last active: 3/31/2019

Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity.

Messer WB, de Alwis R, Yount BL, Royal SR, Huynh JP, Smith SA, Crowe JE, Doranz BJ, Kahle KM, Pfaff JM, White LJ, Sariol CA, de Silva AM, Baric RS
Proc Natl Acad Sci U S A. 2014 111 (5): 1939-44

PMID: 24385585 · PMCID: PMC3918811 · DOI:10.1073/pnas.1317350111

The four dengue virus (DENV) serotypes, DENV-1, -2, -3, and -4, are endemic throughout tropical and subtropical regions of the world, with an estimated 390 million acute infections annually. Infection confers long-term protective immunity against the infecting serotype, but secondary infection with a different serotype carries a greater risk of potentially fatal severe dengue disease, including dengue hemorrhagic fever and dengue shock syndrome. The single most effective measure to control this threat to global health is a tetravalent DENV vaccine. To date, attempts to develop a protective vaccine have progressed slowly, partly because the targets of type-specific human neutralizing antibodies (NAbs), which are critical for long-term protection, remain poorly defined, impeding our understanding of natural immunity and hindering effective vaccine development. Here, we show that the envelope glycoprotein domain I/II hinge of DENV-3 and DENV-4 is the primary target of the long-term type-specific NAb response in humans. Transplantation of a DENV-4 hinge into a recombinant DENV-3 virus showed that the hinge determines the serotype-specific neutralizing potency of primary human and nonhuman primate DENV immune sera and that the hinge region both induces NAbs and is targeted by protective NAbs in rhesus macaques. These results suggest that the success of live dengue vaccines may depend on their ability to stimulate NAbs that target the envelope glycoprotein domain I/II hinge region. More broadly, this study shows that complex conformational antibody epitopes can be transplanted between live viruses, opening up similar possibilities for improving the breadth and specificity of vaccines for influenza, HIV, hepatitis C virus, and other clinically important viral pathogens.

MeSH Terms (22)

Amino Acid Sequence Animals Antibodies, Neutralizing Antibodies, Viral Dengue Dengue Virus HEK293 Cells Humans Immunity K562 Cells Macaca mulatta Molecular Sequence Data Neutralization Tests Protein Multimerization Protein Structure, Tertiary Recombinant Proteins Serotyping Species Specificity Structure-Activity Relationship Time Factors Viral Envelope Proteins Viremia

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