Biomedical Engineering Reference
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Figure 7.1
The mediators of antiviral RNA interference (RNAi). Mediators
of viral suppression can be delivered in multiple formats. Short and long
hairpin RNAs (shRNA or lhRNA) can be expressed from viral or non-viral
vectors transcribed in the nucleus and are exported into the cytoplasm by
association with Exportin-5. The hairpin sequences are processed by Dicer,
to yield short interfering RNA (siRNAs). siRNAs can also be delivered directly
into the cytoplasm using nanocarriers. The guide strand of the siRNA gets
loaded onto the RNA-induce Silencing Complex (RISC); guiding RISC to the
target RNA, resulting in cleavage of the target by argonaute (AGO2). Anti-
sense oligonucleotides (ASOs) bind to the target RNA with a complementary
sequence and induce RNase H-mediated cleavage. Phosphorodiamidate
morpholino oligomers (PMOs) do not mediate cleavage of target RNAs,
they bind near the start codon and inhibit translation by blocking ribosome
binding.
Virus replication can be inhibited by targeting viral or cellular genes involved
in the viral lifecycle at various stages. (
a
) DNA viruses are susceptible to
degradation by RNAi machinery when their mRNA exits the nucleus and
enters the cytoplasm. (
b
) The (+) sense RNA genome is also the mRNA;
therefore upon uncoating it is susceptible to the eff ects of RNAi. (-) sense
RNA viruses must undergo RNA-dependent transcription to generate mRNA,
leaving both the negative genomic RNA and the newly generated mRNA
vulnerable to RNAi. (
c)
The genomic RNA of Retroviruses is targetable
upon uncoating in the cytoplasm. RNA that escapes degradation is reverse
transcribed into proviral DNA which enters the nucleus for integration and
transcription. The viral mRNA that is released into the cytoplasm can once
again be degraded by RNAi mechanisms. (
d
) Host factors essential for the
viral life cycle but not essential for the host can also be RNAi targets (i.e.,
CCR5 coreceptor ).
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