JVI Accepts, published online ahead of print on 24 June 2009

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J. Virol. doi:10.1128/JVI.00660-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Impact of Quaternary Organization on the Antigenic Structure of the Tick-Borne Encephalitis Virus Envelope Glycoprotein E

Stefan Kiermayr, Karin Stiasny, and Franz X. Heinz^*

Institute of Virology, Medical University of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria

^* To whom correspondence should be addressed. Email: franz.x.heinz{at}meduniwien.ac.at.

The envelope protein E of flaviviruses mediates both receptor-binding and membrane fusion. At the virion surface, 180 copies of E are tightly packed and organized in a herringbone-like icosahedral structure whereas, in non-infectious subviral particles, 60 copies are arranged in a T=1 icosahedral symmetry. In both cases, the basic building block is an E dimer which exposes the binding sites for neutralizing antibodies at its surface. It was the objective of our study to assess the dependence of the antigenic structure of E on its quaternary arrangement, i.e. as part of virions, recombinant subviral particles (RSPs) or soluble dimers. For this purpose, we used a panel of 11 E protein-specific neutralizing monoclonal antibodies – mapped to distinct epitopes in each of the three E protein domains – and studied their reactivity with the different soluble and particulate forms of tick-borne encephalitis (TBE) virus E protein under non-denaturing immuno-assay conditions. Significant differences in the reactivities with these forms were observed that could be related to (i) limited access of certain epitopes at the virion surface, (ii) limited occupancy of epitopes in virions due to steric hindrance between antibodies, (iii) differences in the avidity to soluble forms as compared to the virion, presumably related to the flexibility of E at its domain junctions, and (iv) modulations of the external E protein surface through interactions with its ‘stem-anchor’ structure. We have thus identified several important factors that influence the antigenicity of the flavivirus E protein and have an impact on the interaction with neutralizing antibodies.