TY - JOUR
T1 - Covalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope
AU - Rouvinski, Alexander
AU - Dejnirattisai, Wanwisa
AU - Guardado-Calvo, Pablo
AU - Vaney, Marie Christine
AU - Sharma, Arvind
AU - Duquerroy, Stéphane
AU - Supasa, Piyada
AU - Wongwiwat, Wiyada
AU - Haouz, Ahmed
AU - Barba-Spaeth, Giovanna
AU - Mongkolsapaya, Juthathip
AU - Rey, Félix A.
AU - Screaton, Gavin R.
N1 - Publisher Copyright:
© The Author(s) 2017.
PY - 2017/5/23
Y1 - 2017/5/23
N2 - A problem in the search for an efficient vaccine against dengue virus is the immunodominance of the fusion loop epitope (FLE), a segment of the envelope protein E that is buried at the interface of the E dimers coating mature viral particles. Anti-FLE antibodies are broadly cross-reactive but poorly neutralizing, displaying a strong infection enhancing potential. FLE exposure takes place via dynamic 'breathing' of E dimers at the virion surface. In contrast, antibodies targeting the E dimer epitope (EDE), readily exposed at the E dimer interface over the region of the conserved fusion loop, are very potent and broadly neutralizing. We here engineer E dimers locked by inter-subunit disulfide bonds, and show by X-ray crystallography and by binding to a panel of human antibodies that these engineered dimers do not expose the FLE, while retaining the EDE exposure. These locked dimers are strong immunogen candidates for a next-generation vaccine.
AB - A problem in the search for an efficient vaccine against dengue virus is the immunodominance of the fusion loop epitope (FLE), a segment of the envelope protein E that is buried at the interface of the E dimers coating mature viral particles. Anti-FLE antibodies are broadly cross-reactive but poorly neutralizing, displaying a strong infection enhancing potential. FLE exposure takes place via dynamic 'breathing' of E dimers at the virion surface. In contrast, antibodies targeting the E dimer epitope (EDE), readily exposed at the E dimer interface over the region of the conserved fusion loop, are very potent and broadly neutralizing. We here engineer E dimers locked by inter-subunit disulfide bonds, and show by X-ray crystallography and by binding to a panel of human antibodies that these engineered dimers do not expose the FLE, while retaining the EDE exposure. These locked dimers are strong immunogen candidates for a next-generation vaccine.
UR - http://www.scopus.com/inward/record.url?scp=85019563410&partnerID=8YFLogxK
U2 - 10.1038/ncomms15411
DO - 10.1038/ncomms15411
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C2 - 28534525
AN - SCOPUS:85019563410
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
M1 - 15411
ER -