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Chapter 2b: The molecular and antigenic structure of TBEV

provided us with deep insights into antigenic Perspectives and future research
structure and details of antibody interactions
with these viruses. In contrast, relatively little is The era of flavivirus structural biology was
known about the fine specificities of antibodies initiated by the X-ray structure determination of
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in polyclonal responses as well as their the TBEV E protein dimer and has now led to
individual variation after TBEV infections and unprecedented insights into the organization
vaccinations. The issue was addressed by and molecular changes of flavivirus particles in
Jarmer et al. 112 who deconstructed human anti- different phases of the viral life cycle. 114-116
body responses after TBEV infection and Although a high resolution particle structure of
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vaccination using immunoassays with recombin- TBEV is now available in its mature form, the
ant proteins consisting of individual domains structure of immature particles has not yet
and domain combinations of E. Extensive varia- been determined and will be a topic of future
tion was not only observed with respect to the research. The same also holds true for
extent of antibody formation but also with investigations in the complex area of viral
respect to the fine specificities of antibodies receptors. Recent data obtained with other
produced in the course of immune responses, flaviviruses suggest that populations of
suggesting that patterns of immunodominance heterogeneous, partially mature but infectious
are strongly influenced by individual-specific virus particles may be produced in different
factors. Importantly, most of the neutralizing hosts and tissues involved in the viral life cycles.
activity could be depleted from sera by the Such heterogeneity in combination with the
dimeric E protein, indicating that complex phenomenon of virus breathing is a mechanism
quaternary epitopes, depending on the that modulates the viral surface and thus
herringbone-like arrangement of E dimers at increases potential interaction sites with cellular
the viral surface (Figure 1G), play only a minor attachment factors. 34,36,117 Particle hetero-
role in the neutralizing antibody response, both geneity also promotes the exposure of the viral
after infection and vaccination. membrane as a prerequisite for using apoptotic
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mimicry in virus entry, a mechanism that has
In humans, it is currently unknown, to what yet to be investigated for TBEV. Populations of
extent the fine specificities of antibody heterogeneous particles may not only be
responses can be modulated by pre-existing
essential for virus replication in quite distantly
antibodies (against homologous or heterolo-
related invertebrate and vertebrate hosts, but
gous flavivirus antigens) when present at the also modulate antibody responses and epitope
time of infection or vaccination. A mouse recognition. 109,110,118 These are new exciting
immunization study with the recombinant TBEV aspects of flavivirus structure that provide a
E protein dimer and passively administered
fertile ground for interesting and important
monoclonal antibodies, however, revealed that investigations in the future, aiming at a more
such influences may be substantial. 113 Mecha- profound understanding of the complex biology
nistically, the differences observed in antibody of TBEV as a human pathogen.
responses were related to shielding of epitopes
in E by the co-administered mAb and to mAb-
induced dissociation of the E dimer, resulting in Acknowledgments: Research performed by the
the exposure of antigenic surfaces that would authors was supported by the Austrian Science
be cryptic in the native protein. It remains to be Fund FWF.
seen, whether human antibody responses may
be modulated by similar mechanisms and
whether the resulting changes in antibody fine
specificity and composition can affect virus Contact: franz.x.heinz@meduniwien.ac.at
neutralization.

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