Abstract
BackgroundThe 4 dengue serotypes (DENV) are mosquito-borne pathogens that are associated with severe hemorrhagic disease. DENV particles have a lipid bilayer envelope that anchors two membrane glycoproteins prM and E. Two E-protein monomers form head-to-tail homodimers and three E-dimers align to form “rafts” that cover the viral surface. Some human antibodies that strongly neutralize DENV bind to quaternary structure epitopes displayed on E protein dimers or higher order structures forming the infectious virus. Expression of prM and E in cell culture leads to the formation of DENV virus-like particles (VLPs) which are smaller than wildtype virus particles and replication defective due to the absence of a viral genome. There is no data available that describes the antigenic landscape on the surface of flavivirus VLPs in comparison to the better studied infectious virion.MethodsA large panel of well characterized antibodies that recognize epitope of ranging complexity were used in biochemical analytics to obtain a comparative antigenic surface view of VLPs in respect to virus particles. DENV patient serum depletions were performed the show the potential of VLPs in serological diagnostics.ResultsVLPs were confirmed to be heterogeneous in size morphology and maturation state. Yet, we show that many highly conformational and quaternary structure-dependent antibody epitopes found on virus particles are efficiently displayed on DENV1–4 VLP surfaces as well. Additionally, DENV VLPs can efficiently be used as antigens to deplete DENV patient sera from serotype specific antibody populations.ConclusionsThis study aids in further understanding epitopic landscape of DENV VLPs and presents a comparative antigenic surface view of VLPs in respect to virus particles. We propose the use VLPs as a safe and practical alternative to infectious virus as a vaccine and diagnostic antigen.
Highlights
The 4 dengue serotypes (DENV) are mosquito-borne pathogens that are associated with severe hemorrhagic disease
When flavivirus prM and E proteins are co-expressed in cells, these proteins assemble into virus-like particles (VLPs) that are secreted from cells
In this study we describe in detail the properties of epitopes present on Dengue viruses (DENV) VLPs of all 4 serotypes using a large panel of well-defined human mAbs and immune sera from dengue patients
Summary
The 4 dengue serotypes (DENV) are mosquito-borne pathogens that are associated with severe hemorrhagic disease. Some human antibodies that strongly neutralize DENV bind to quaternary structure epitopes displayed on E protein dimers or higher order structures forming the infectious virus. Even though TBEV VLPs are heterogeneous in size, investigators analyzed a uniform population of particles that were smaller than virions and concluded that VLPs contain 30 E-homodimers assembled in a T = 1 icosahedral lattice [12]. It is unclear if quaternary structure antibody epitopes, especially those containing residues from different adjacent E homo-dimers, are displayed on VLPs and the larger infectious virions [12]
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