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

William Messer, Ruklanthi De Alwis, Boyd L. Yount, Scott R. Royal, Jeremy P. Huynh, Scott A. Smith, James E. Crowe, Benjamin J. Doranz, Kristen M. Kahle, Jennifer M. Pfaff, Laura J. White, Carlos A. Sariol, Aravinda M. De Silva, Ralph S. Baric

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1939-1944
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number5
DOIs
StatePublished - Feb 4 2014

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Viral Envelope Proteins
Dengue Virus
Dengue
Immunity
Severe Dengue
Neutralizing Antibodies
Dengue Vaccines
Glycoproteins
Vaccines
Viruses
AIDS Vaccines
Protein Domains
Serogroup
Influenza Vaccines
Infection
Macaca mulatta
Coinfection
Innate Immunity
Hepacivirus
Primates

Keywords

  • Infectious clone
  • Neutralizing antibody

ASJC Scopus subject areas

  • General

Cite this

Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity. / Messer, William; De Alwis, Ruklanthi; Yount, Boyd L.; Royal, Scott R.; Huynh, Jeremy P.; Smith, Scott A.; Crowe, James E.; Doranz, Benjamin J.; Kahle, Kristen M.; Pfaff, Jennifer M.; White, Laura J.; Sariol, Carlos A.; De Silva, Aravinda M.; Baric, Ralph S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 5, 04.02.2014, p. 1939-1944.

Research output: Contribution to journalArticle

Messer, W, 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 2014, 'Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 5, pp. 1939-1944. https://doi.org/10.1073/pnas.1317350111
Messer, William ; De Alwis, Ruklanthi ; Yount, Boyd L. ; Royal, Scott R. ; Huynh, Jeremy P. ; Smith, Scott A. ; Crowe, James E. ; Doranz, Benjamin J. ; Kahle, Kristen M. ; Pfaff, Jennifer M. ; White, Laura J. ; Sariol, Carlos A. ; De Silva, Aravinda M. ; Baric, Ralph S. / Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 5. pp. 1939-1944.
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