Page 58 - TBE_Book_V2_2019

Chapter 2b: The molecular and antigenic structure of TBEV

endosomes (see above and Figure 2,3), the E antibodies have been mapped to individual
protein is the major target and inducer of domains in E or were shown to be more
neutralizing antibodies, and all experimental complex and to comprise residues from
data obtained with TBEV are consistent with adjacent domains, from both monomers in the
this notion. Potently neutralizing and protective dimer or even adjacent dimers in the
antibodies were induced by E solubilized from herringbone arrangement of E at the viral
61
purified TBEV, confirming the primary role of surface (quaternary epitopes) [reviewed in
such antibodies in the induction of a protective references 99-101 ].
88
immunity. While soluble forms of E and even
the isolated DIII were capable of inducing Mechanisms of virus neutralization
neutralizing antibodies, 61,89 particulate or
aggregated forms (E rosettes) had a much The most apparent mechanism of virus
higher specific immunogenicity and would neutralization by E-specific antibodies is the
61
therefore be preferred vaccine antigens. blocking of cell attachment, as shown for
different flaviviruses. 102 In addition, the
Epitopes of TBEV protein E inhibition of post-entry processes by antibodies
bound to the internalized virus is likely to
More precise mapping of epitopes in E and their contribute to virus neutralization. 102 This holds
involvement in virus neutralization became especially true for membrane fusion, which
possible with the preparation of TBEV-specific requires substantial relocations of protein
monoclonal antibodies (mAbs). 90-92 By the domains (see above) that may be impeded by
application of these mAbs for immunochemical bound antibodies. Insights into such activities
analyses and the selection of mAb-resistant were provided by in vitro analyses of TBEV
82
virus mutants topological and functional models fusion inhibition by E-specific mAbs.
of epitopes could be defined and epitopes Depending on the location of the bound
involved in virus neutralization were structurally antibody, early and late stages of the fusion
characterized. 37,58,91-96 The elucidation of the process were impaired, by either blocking the
crystal structure of the E dimer then allowed initial interaction with the target membrane or
the precise localization of antibody binding sites by interfering with the required relocation of
(Figure 4). It became apparent that neutralizing DIII and the formation of the post-fusion E
antibodies can be induced by each of the three trimer (see above).A special case are antibodies
domains, consistent with a plethora of publica- directed to the fusion loop at the tip of DII
tions on the antigenic structure of other (Figure 1A) which – because of the high
flaviviruses [reviewed in references 97-99 ]. conservation of this structural element - are
highly cross-reactive with E proteins from all
The complexity of the antigenic structure flaviviruses. They react strongly with soluble
56
cannot be understood completely on the basis forms of E and inhibit in vitro liposomal fusion,
82
of the isolated E protein. Studies with different but they have virtually no neutralizing activity
soluble and particulate forms of E revealed a against TBEV. An explanation of this phe-
strong influence of its quaternary structure and nomenon is the fact that FL-specific antibodies
58
specific display at the surface of virions. The are unable to react with intact mature TBE
TBEV data are fully consistent with those virions (‘cryptic epitopes’) and therefore
56
obtained by high-resolution structural analyses cannot reach the endosomal compartment
of antibody-E complexes of other flaviviruses where fusion takes place. The cryptic nature of
[reviewed in references 99,100 ]. Taken together, it the FL may however differ among flaviviruses,
can be concluded that TBEV, like all other depending on their stability and breathing
flaviviruses, displays a continuum of antigenic behavior (see above). As a consequence,
sites at its surface with the potential of inducing broadly flavivirus cross-reactive antibodies may
neutralizing antibodies. Epitopes of such display neutralizing activity against certain
53