A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface
Adamberage R de Alwis, Eva Harris, Shee‐Mei Lok, James E. Crowe, Scott A. Smith, G. Fibriansah, Aravinda de Silva, Jiaqi Wang, Thiam‐Seng Ng, Joanne L. Tan, V.A. Kostyuchenko, Kristie D Ibarra
Abstract
Dengue virus (DENV), which consists of four serotypes (DENV1-4), infects over 400million 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 6Å 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.Subject Categories Microbiology, Virology & Host Pathogen Interaction; Immunology