Inhibition of viral replication
One of the main steps in the process of viral infection
is DNA and RNA genome replication of the virus.Additional examples of inhibition of viral replication by
siRNA originated from the study of positive RNA viruses
such as dengue (DENV), West Nile (WNV), and severe
acute respiratory syndrome (SARS) [32-36].In
another study, siRNA targeted to various domains of the
HAV internal ribosomal entry site (IRES) induced efficient
and sustained suppression of viral genome translation and
replication [30].An HCV replicon is derived from an
HCV consensus genome that was cloned from a viral RNA
isolated from an infected human and used to construct
subgenomic selectable replicons.siRNAs targeting the SARS-CoV RNA polymerase gene
inhibited viral RNA replication, protein synthesis and
reduced the viral cytopathic effects on Vero cells [36].Multiple siRNAs have
been used to target multiple conserved viral genes that
are essential for virus replication, including a long 5?-
non-coding region, a short 3?-non-coding region, the viral
protein VPg, the viral polymerase, and the viral capsid
protein VP4.In the hepatitis A virus (HAV) replicon-based system,
it has been reported that siRNAs targeting the regions
coding for the non-structural proteins of the virus give
rise to partial inhibition of HAV replication [28].siRNAs
targeting the 3?-UTR sequence of DENV, in a region
that is conserved in all the dengue serotypes, reduced
viral replication and infection in dendritic cells [32].Synthetic siRNA
targeted to the VP1 or to the viral polymerase showed
antiviral effects in infected HeLa cells by inducing a
significant reduction of viral replication [37].siRNAs targeting the viral polymerase NS5B
region reduced expression of NS5B-Luc chimera in mice
[27] or in the replicon system in vitro.Replication of DNA
viruses can be inhibited by targeting their viral mRNA,
whereas replication of RNA viruses can be inhibited by
targeting either their mRNAs or their viral RNA, as was
elegantly demonstrated for HIV [39].Other studies
that target other regions of the HCV genome reported a
significant decline in the level of HCV proteins and the
level of both the sense and antisense RNA strands [25].In that
study, two siRNAs specific for HAV sequences increased
rather than inhibited HAV replication.