Structural insights into the neutralization mechanism of a higher primate antibody against dengue virus

The four serotypes of dengue virus (DENV‐1 to ‐4) cause the most important emerging viral disease. Protein E, the principal viral envelope glycoprotein, mediates fusion of the viral and endosomal membranes during virus entry and is the target of neutralizing antibodies. However, the epitopes of stro...

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Bibliographic Details
Published in:The EMBO journal 2012-02, Vol.31 (3), p.767-779
Main Authors: Cockburn, Joseph JB, Navarro Sanchez, M Erika, Goncalvez, Ana P, Zaitseva, Elena, Stura, Enrico A, Kikuti, Carlos M, Duquerroy, Stéphane, Dussart, Philippe, Chernomordik, Leonid V, Lai, Ching-Juh, Rey, Felix A
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antibodies, Viral
Antibodies, Viral - immunology
antibody
dengue
Dengue fever
Dengue Virus
Dengue Virus - immunology
Immunoglobulins
Life Sciences
Microbiology
Microbiology and Parasitology
Models, Molecular
Molecular Sequence Data
Neutralization Tests
Pan troglodytes
Pathology
Primates
Primates - immunology
Sequence Homology, Amino Acid
structure
Viral Proteins
Viral Proteins - chemistry
Virology
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Summary:The four serotypes of dengue virus (DENV‐1 to ‐4) cause the most important emerging viral disease. Protein E, the principal viral envelope glycoprotein, mediates fusion of the viral and endosomal membranes during virus entry and is the target of neutralizing antibodies. However, the epitopes of strongly neutralizing human antibodies have not been described despite their importance to vaccine development. The chimpanzee Mab 5H2 potently neutralizes DENV‐4 by binding to domain I of E. The crystal structure of Fab 5H2 bound to E from DENV‐4 shows that antibody binding prevents formation of the fusogenic hairpin conformation of E, which together with in‐vitro assays, demonstrates that 5H2 neutralizes by blocking membrane fusion in the endosome. Furthermore, we show that human sera from patients recovering from DENV‐4 infection contain antibodies that bind to the 5H2 epitope region on domain I. This study, thus, provides new information and tools for effective vaccine design to prevent dengue disease. The envelope (E) protein of Dengue virus is essential for virus entry, and various neutralizing antibodies have been identified that target this protein. Structural analysis of a chimpanzee antibody in complex with the E protein elucidates its mechanism of inhibition, providing a potential basis for vaccine design.
ISSN:0261-4189
1460-2075
DOI:10.1038/emboj.2011.439