in rabies - libdoc.who.int - World Health Organization

CHARACTERISTICS AND MOLECULAR BIOLOGY OF THE VIRUS
become functional templates for future transcription, the genome and antigenome
have to be coated with N proteins. This requires an exact coordination between
polymerization and encapsidation Therefore, a promoter for encapsidation must
exist near their 5'-end to initiate the concomitant encapsidation of the growing
RNA.
Before viral budding, transcription arid replication are inhibited. Simultaneously,
there is intense condensation and coiling of the ribonucleocapsids. These
events take place in speclfrc areas of the cell membrane where transmembrane G
have been concentrated. The vir~on
prote~ns
leaves the cell by budding, the lipidic
envelope being pulled out from the host-cell membrane.
The ribonucleocapsid complex, which consists of the RNA genome and the N,
M1 and L proteins, is the niininial virion structure exhibiting RNA synthesis. The
respective role of each viral polypeptide in this process has been studied less
deeply than the mechanisms themselves. On the bass of studies on VSV, it is
known that the M1 and L proteins are the catalytic elements involved in the
polyrnerase function. The L protein is the actual RNA-dependent RNA polymerase
possessing most of the required enzymatic activities, including RNA synthesis,
capping, polyadenylaton, and partial kination of the N and M1 proteins. The role
of the M1 protein is probably more regulatory: it helps the RNA-dependent RNA
polymerase so that it binds correctly to the promoter for polymerization; it possibly
uncoats the RNA template upstream of the polymerization complex; and it checks
the amount of N protein available for encapsidation.
The N protein plays a major structural role in encapsidating the RNA genome
and antigenome. It is therefore involved in the switch between transcription and
replication, as suggested by several studies on VSV. These studies indicate that
replication cannot begin in the absence of sufficient quantities of N protein to
encapsidate the growing template. As long as the amount of N protein remains
below a certain level, the transcription complex recognizes a stop signal (T) at the.
end of the leader gene and releases the leader RNA. It then recognizes the start
and stop signals flanking the N, Ml, M2. G and L genes and produces the naked
mRNAs When there are sufficient amounts of N protein, the transcription complex
participates in a concurrent assembly of the growing template and somehow is
responsible for the polymerase ignoring the stop signal. This event corresponds to
the switch between transcription and replication The viral polymerase then
becomes unable to recognize the other start and stop transcription signals. Since
the leader RNA is no longer produced, the promoter for encapsidation remains
linked to the 5'-end of the growing genome, which is progressively encapsidated in
a cooperative manner.
The M2 protein plays an important role during the latter stages of infection,
notably dur~ng morphogenesis. Its position, between the ribonucleocapsid and the
membrane, permits its interaction with both internal (N protein) and external
(cytoplasmic tail of the G protein) proteins. It is able to inhibit RNA synthesis,
mediate the coiling of the ribonucleocapsid, and concentrate the G protein, all of
which are required before the virion buds out of the infected cell.
Viral proteins involved in the host immune response
Although all the viral proteins show antigenicty, they do not all play the same role
in protection (32). The purified G protein has been shown to protect against an