Nature Communications
Nature Communications
5 years ago

Covalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope

Covalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope
Arvind Sharma, Piyada Supasa, Gavin R. Screaton, Alexander Rouvinski, Ahmed Haouz, Wanwisa Dejnirattisai, Wiyada Wongwiwat, Giovanna Barba-Spaeth, Stéphane Duquerroy, Félix A. Rey, Marie-Christine Vaney, Pablo Guardado-Calvo, Juthathip Mongkolsapaya
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.

Publisher URL: http://www.nature.com/articles/ncomms15411

DOI: 10.1038/ncomms15411

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