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Structure. 2019 Feb 5;27(2):253-267.e8. doi: 10.1016/j.str.2018.10.009. Epub 2018 Nov 21.

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

Author information

1
Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 169857, Singapore; Centre for BioImaging Sciences, National University of Singapore, Singapore 117557, Singapore.
2
Bioinformatics Institute, A(∗)STAR (Agency for Science, Technology and Research), Singapore 138671, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
3
Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
4
Bioinformatics Institute, A(∗)STAR (Agency for Science, Technology and Research), Singapore 138671, Singapore.
5
Centre for BioImaging Sciences, National University of Singapore, Singapore 117557, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
6
Department of Medicine, Division of Infectious Diseases, Vanderbilt University, Nashville, TN 37232, USA; The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
7
Bioinformatics Institute, A(∗)STAR (Agency for Science, Technology and Research), Singapore 138671, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
8
The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Departments of Pediatrics and Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: james.crowe@vanderbilt.edu.
9
Bioinformatics Institute, A(∗)STAR (Agency for Science, Technology and Research), Singapore 138671, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. Electronic address: peterjb@bii.a-star.edu.sg.
10
Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 169857, Singapore; Centre for BioImaging Sciences, National University of Singapore, Singapore 117557, Singapore. Electronic address: sheemei.lok@duke-nus.edu.sg.

Abstract

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.

KEYWORDS:

cryo-EM; dengue virus; enhancement of infection; human antibody; immature dengue virus; maturation

PMID:
30471923
PMCID:
PMC6365167
[Available on 2020-02-05]
DOI:
10.1016/j.str.2018.10.009

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