Mechanism of Enhanced Immature Dengue Virus Attachment to Endosomal Membrane Induced by prM Antibody.

Summary Dengue virus (DENV) particles are released from cells in different maturation states. Fully immature DENV (immDENV) is generally non-infectious, but can become infectious when complexed with anti-precursor membrane (prM) protein antibodies. It is unknown how anti-prM antibody-coated particles can undergo membrane fusion since the prM caps the envelope (E) protein fusion loop. Here, we determined cryoelectron microscopy (cryo-EM) maps of the immDENV:anti-prM complex at different pH values, mimicking the extracellular (pH 8.0) or endosomal (pH 5.0) environments. At pH 5.0, there are two structural classes with fewer antibodies bound than at pH 8.0. These classes may represent different maturation states. Molecular simulations, together with the measured high-affinity pr:antibody interaction (versus the weak pr:E interaction) and also the low pH cryo-EM structures, suggest how antibody:pr complex can dislodge from the E protein at low pH. This exposes the E protein fusion loop enhancing virus interaction with endosomes. Graphical Abstract Highlights • ImmDENV3 complexed with anti-prM antibody structures at neutral and acidic pH • Two structural classes at acidic pH represent DENV maturation intermediates • Structures show how the antibody helps overcome barrier for immature virus to fuse • MD simulates maturation structural transitions and antibody assisted removal of pr Wirawan et al. present structures of immature dengue virus complexed with anti-prM Fabs at pH 8.0 and pH 5.0. The two structural classes at pH 5.0 showed different maturation stages. These structures also suggest the mechanism on how antibodies stimulate immature dengue virus attachment to liposomes. [ABSTRACT FROM AUTHOR]