Biology Reference
In-Depth Information
gene expression as well as apop-
tosis,
44
while cytopathogenic HAV strains induce apoptosis.
45
The
dominant property of noncytopathogenic strains preserves the sites of
viral replication for a longer time, thus allowing the establishment of
viral infection. The HBV enhancer I/X gene promoter was found to
contain a functional interferon-stimulated regulatory element (ISRE)
that was responsive to IRF1 and IRF7; however, IFN
of HAV inhibit dsRNA-induced IFN
β
and the IRFs
showed minimal effects on HBV transcription and replication in the
context of the whole genome in cell culture.
46
Another major pathway of interferon action is the induction of
α
2
linked
oligoadenylate molecules. This leads to the activation of RNase L and
degradation of cellular RNA in infected cells. Surprisingly, only mini-
mal effects of hepatitis viruses have been observed on this pathway of
interferon action. While the HCV core protein was shown to activate
OAS transcription
47
′
,5
′
-oligoA synthetase (OAS) resulting in synthesis of 2
′
and 5
′
therapy, the
NS5A protein appeared to affect OAS activity.
48
Microarray analysis
of IFN-induced genes in liver cells expressing the HCV NS5A protein
showed reduced induction of the OAS p69 gene, an effect that
appeared to be mediated by the cytokine IL8.
49
The Mx family includes interferon-inducible proteins with antivi-
ral activity. These proteins are GTPases that belong to the dynamin-
like GTPase superfamily.
50,51
IFN-
in HCV patients undergoing IFN
α
, induce the
Mx family of proteins. The spectrum of antiviral activities of the Mx
proteins and the molecular mechanisms by which they inhibit viral
replication depend on the specific Mx protein and its subcellular local-
ization. The antiviral effects of MxA are dependent upon its
oligomerization, GTP binding and hydrolysis.
52
Chronic HBV infec-
tion is associated with defective virus particles generated as a result of
alternatively spliced HBV RNA.
53
This leads to cytoplasmic accumu-
lation of the viral capsid protein. The MxA protein normally accumu-
lates in the cytoplasm of IFN-treated cells and blocks RNA synthesis.
Expression of defective capsid protein has a suppressive effect on the
MxA promoter, thereby reducing the antiviral effect of IFN. The
HCV core protein down-regulates the MxA gene promoter, leading
to decreased MxA levels.
54
α
and
β
, but not IFN-
γ
