Morphological Diversity and Dynamics of Dengue Virus Affecting Antigenicity

Abstract

The four serotypes of the mature dengue virus can display different morphologies, including the compact spherical, the bumpy spherical and the non-spherical clubshape morphologies. In addition, the maturation process of dengue virus is inefficient and therefore some partially immature dengue virus particles have been observed and they are infectious. All these viral particles have different antigenicity profiles and thus may affect the type of the elicited antibodies during an immune response. Understanding the molecular determinants and environmental conditions (e.g., temperature) in inducing morphological changes in the virus and how potent antibodies interact with these particles is important for designing effective therapeutics or vaccines. Several techniques, including cryoEM, site-directed mutagenesis, hydrogen-deuterium exchange mass spectrometry, time-resolve fluorescence resonance energy transfer, and molecular dynamic simulation, have been performed to investigate the structural changes. This review describes all known morphological variants of DENV discovered thus far, their surface protein dynamics and the key residues or interactions that play important roles in the structural changes.

Impact of structural dynamics on biological functions of flaviviruses

“…These and other experiments suggest that members of the dengue virus serocomplex are especially prone to breathing and the exposure of internal protein surfaces [ 13 , 14 ]. Such a conclusion would also be consistent with the observation that dengue viruses (at least certain strains) are less thermostable than other flaviviruses [ 49 , 58 , 65 , 66 , 67 ] and readily change morphology when exposed to increased temperature [ 68 , 69 ]. The biological consequences of this property are incompletely understood, but it certainly can influence virus neutralization.…”

“…High‐resolution cryo‐EM structures of flavivirus particles at different stages of virus maturation as well as X‐ray structures of individual proteins and protein complexes have provided unprecedented structural insights into the molecular biology of these viruses [ 11 , 69 , 84 ]. This holds especially true for the mechanisms of viral entry, including receptor interactions [ 12 , 21 ] as well as the molecular acrobatics of E required for viral membrane fusion [ 16 , 31 ], its triggering by acidic pH in the endosome and how premature fusion during exocytosis is prevented by specific oligomeric interactions in immature particles [ 37 , 39 , 85 ].…”

The Japanese Encephalitis Antigenic Complex Viruses: From Structure to Immunity

“…However, in the broader context of the structural architecture of flaviviruses that is pertinent for pathogenesis, common features are shared while finer details may differ between type-specific viruses or strains. The morphology of the mature DENV virions spans a broad range: the particles include those with a ‘smooth’ (diameter of ~500 Å) appearance or a rough, ‘bumpy’ appearance (somewhat variable sizes with reported diameters between 360–550 Å), depending on the host infected or types of cells used for virus production, and a non-spherical structure referred to as the club-shaped particles [ 110 , 111 , 112 ]. Dengue virions change to the ‘bumpy’ morphology above 33 °C, and, therefore, at the physiological body temperature of the human host (37 °C), this form is expected to dominate, whereas in the mosquito vector (28 °C), Aedes spp.…”

Hidden symmetry of the flavivirus protein shell and pH-controlled reconstruction of the viral surface

“…In the absence of the C protein, heterodimers in vitro can self-assemble into subviral particles (SVPs) [14][15][16] but most of them are smaller in size than the virions assembled in vivo and consist only of 60 heterodimers. While SVPs consisting of 180 heterodimers are also assembled, they differ in structure from the surface of native flaviviruses.…”