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Fig. 12.1
Life cycle of influenza A virus and possible targets for therapeutic intervention. IAV
enters the cell via receptor-mediated endocytosis and is internalized in endosomes. Endosomal
acidification alters the conformation of the viral hemagglutinin, leading to the release of viral
ribonucleoproteins (vRNPs) into the cytoplasm. Viral RNAs enter the nucleus via nuclear import,
where they are transcribed to generate mRNA required for the synthesis of viral proteins, and are
replicated by the viral RNA-dependent RNA polymerase complex. Newly generated viral vRNPs
shuttle to the cytoplasm and assemble with viral proteins, forming mature viruses that bud from the
cell surface. Two classes of antivirals are currently licensed for the treatment of influenza: M2
inhibitors, such as amantadine and rimantadine, which interfere with the viral M2 protein, thereby
inhibiting the release of vRNPs out of the endosomes; and inhibitors such as zanamivir and osel-
tamivir, which target the viral neuraminidase and prevent the release of newly generated virions.
Cellular pathways that are required for the IAV replication cycle and that have recently been
identified in global siRNA screens are shown in
red
. Adapted from Min and Subbarao [
6
]
blocking the viral M2 protein [
7
]. A single mutation in human and avian influenza
viruses, however, can confer resistance to amantadine [
3,
7
] . Therefore, the poten-
tial of amantadine and amantadine derivatives for controlling pandemics might be
limited. In contrast, anti-influenza neuraminidase (NA) inhibitors, such as oselta-
mivir and zanamivir preventing viral release from the cell membrane, have been
shown to efficiently inhibit influenza virus A and B strains in clinical studies [
9
] .
Although resistance to these compounds has been shown to emerge less frequently
than resistance to amantadine, resistant viruses have been identified
in vitro
[
10
]
and
in vivo
(Fig.
12.1
).
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