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Journal of Virology, October 2006, p. 9557-9568, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00080-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cryptic Properties of a Cluster of Dominant Flavivirus Cross-Reactive Antigenic Sites

Karin Stiasny, Stefan Kiermayr, Heidemarie Holzmann, and Franz X. Heinz*

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

Received 12 January 2006/ Accepted 5 July 2006

A number of flaviviruses are important human pathogens, including yellow fever, dengue, West Nile, Japanese encephalitis, and tick-borne encephalitis (TBE) viruses. Infection with or immunization against any of these viruses induces a subset of antibodies that are broadly flavivirus cross-reactive but do not exhibit significant cross-neutralization. Nevertheless, these antibodies can efficiently bind to the major envelope protein (E), which is the main target of neutralizing and protective antibodies because of its receptor-binding and membrane fusion functions. The structural basis for this phenomenon is still unclear. In our studies with TBE virus, we have provided evidence that such cross-reactive antibodies are specific for a cluster of epitopes that are partially occluded in the cage-like assembly of E proteins at the surfaces of infectious virions and involve—but are not restricted to—amino acids of the highly conserved internal fusion peptide loop. Virus disintegration leads to increased accessibility of these epitopes, allowing the cross-reactive antibodies to bind with strongly increased avidity. The cryptic properties of these sites in the context of infectious virions can thus provide an explanation for the observed lack of efficient neutralizing activity of broadly cross-reactive antibodies, despite their specificity for a functionally important structural element in the E protein.

* Corresponding author. Mailing address: Institute of Virology, Medical University of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria. Phone: 43-1-40490, ext. 79510. Fax: 43-1-40490, ext. 9795. E-mail: franz.x.heinz{at}meduniwien.ac.at.

Journal of Virology, October 2006, p. 9557-9568, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00080-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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Copyright © 2006 by the American Society for Microbiology. All rights reserved.