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Chapter 2a: Virology

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antibodies that neutralize the infectivity of molecules. The biological explanation for this
TBEV. However, the anti-idiotypic monoclonal is the double function of the genomic positive-
antibodies did not bind effectively to tick cells, strand RNA: it is used as a template both for
implying that different receptors are used by transcription of the negative strand and
vertebrate and invertebrate cells for the translation of the viral polyprotein, while the
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binding of TBEV. It remains unclear whether negative strand is only transcribed into the
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TBEV uses single or multiple receptors on new positive strands.
susceptible cells. Involvement of highly
The single viral polyprotein is cleaved by viral
conserved glycosaminoglycans, such as and cellular proteases into individual viral
heparan sulfate, during attachment and entry proteins. The surface structural proteins prM
of flaviviruses has been suggested, but it and E (and also NS1) are translocated into the
seems likely that other host-cell receptor(s)
lumen of the ER and their amino termini are
can also mediate entry of TBEV into the host liberated through proteolytic cleavage by host
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cells. Apparently, just the ability to use signalase. The newly synthesized RNA is
multiple receptors could be responsible for condensed by protein C into nucleocapsids on
the very wide host range of flaviviruses, which
the cytoplasmic site of ER. Viral envelope is
replicate in arthropods and in a broad range of
acquired by budding of the nucleocapsid into
vertebrates. 102
ER.
In addition, in the presence of sub-neutralizing TBEV replicates in the cytoplasm in close
levels of specific immunoglobulins, the association with virus-induced intracellular
attachment and uptake by cells expressing Fc
membrane structures, also called replication
receptors might be enhanced, and this is
compartments (Figure 6). These compart-
called antibody-dependent enhancement.
ments provide an optimal microenvironment
After binding to the receptor, virus is for viral RNA replication by limiting diffusion of
internalized into clathrin-coated vesicles by viral/host proteins and viral RNA, thereby
the process of endocytosis (see Chapter 2b for increasing the concentration of components
details). Acidification within the endosomal required for RNA synthesis, and by providing a
vesicle triggers conformational changes of the scaffold for anchoring the replication
E proteins leading to rearrangement of the complex. 103 These packets of vesicles have a
dimers to trimeric forms and subsequent diameter of about 80 nm and are formed as
fusion of the viral envelope with the invaginations of the endoplasmic reticulum
membrane of the vesicle (Figure 6). The viral within a highly-organized network of inter-
nucleocapsid is then released into the connected membranes (Figure 6). 103
cytoplasm and viral RNA is uncoated. The The immature non-infectious virions
exact mechanism of nucleocapsid uncoating
containing proteins prM and E in het-
remains unknown. The positive-sense viral
erodimeric association are transported to the
RNA is the translational template, also
Golgi complex, where the pr part of the prM
functioning as a template for negative-sense molecule is cleaved, and the E protein is
RNA synthesis and formation of the double- reorganized from trimers to form fusion-
stranded replicative intermediate.
competent homodimers. These mature virions
The ratio of the newly synthesized positive- pass through the host secretory pathway and
stranded RNA to negative-stranded RNA is at are finally released from the host cell by
least 10 or 100 to 1, indicating that some fusion of the transport vesicle membrane with
regulatory mechanism must exist to produce the plasma membrane (Figure 6). 102
higher numbers of positive-stranded RNA

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