A potent anti‐dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface

EMBO Molecular Medicine

Guntur Fibriansah¹  Joanne L Tan¹  Scott A Smith⁵  Adamberage R de Alwis⁴  Thiam-Seng Ng¹  Victor A Kostyuchenko¹  Kristie D Ibarra²  Jiaqi Wang¹  Eva Harris²  Aravinda de Silva⁴  James E Crowe Jr³ 

[1] Program in Emerging Infectious Diseases, Duke–NUS Graduate Medical School, Singapore City, Singapore;Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, USA;The Vanderbilt Vaccine Center, Vanderbilt University, Nashville, TN, USA;Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC, USA;Department of Medicine, Vanderbilt University, Nashville, TN, USA

关键词: cryoEM;    dengue virus;    human antibody;    neutralization;    structure;   

DOI  :  10.1002/emmm.201303404

来源: Wiley

【 摘 要 】

Abstract

Dengue virus (DENV), which consists of four serotypes (DENV1-4), infects over 400 million people annually. Previous studies have indicated most human monoclonal antibodies (HMAbs) from dengue patients are cross-reactive and poorly neutralizing. Rare neutralizing HMAbs are usually serotype-specific and bind to quaternary structure-dependent epitopes. We determined the structure of DENV1 complexed with Fab fragments of a highly potent HMAb 1F4 to 6 Å resolution by cryo-EM. Although HMAb 1F4 appeared to bind to virus and not E proteins in ELISAs in the previous study, our structure showed that the epitope is located within an envelope (E) protein monomer, and not across neighboring E proteins. The Fab molecules bind to domain I (DI), and DI-DII hinge of the E protein. We also showed that HMAb 1F4 can neutralize DENV at different stages of viral entry in a cell type and receptor dependent manner. The structure reveals the mechanism by which this potent and specific antibody blocks viral infection.

Synopsis

Vaccine development against Dengue disease is complicated by the virus serotype priming to secondary infections. Structure of a potent human antibody 1F4 complexed with DENV serotype 1 highlights the hinge angle of the viral protein as critical for vaccine design.

• DI-DII hinge is a common epitope recognised by highly neutralising human antibodies.
• The conformation angle of the hinge is critical for 1F4 binding.
• 1F4 recognises E protein monomers on the virus surface but not recombinant E proteins due to the conserved hinge angle of endogenous viral E proteins.

【 授权许可】

CC BY   
© 2014 The Authors.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.