Aa
Chloroquine/autophagy suppression/apoptosis
HBV
Classification and Structure
HBV belongs to the Hepadnaviridae family. These viruses are characterized by having
a partial double-stranded DNA genome, with numerous overlapping genes in multiple
reading frames, which is copied through an RNA intermediate by a reverse
transcriptase enzyme. HBV infects primarily hepatocytes. For more complete reviews,
see (23-25). The HBV, also known as the Dane particle, is approximately 45nm in
diameter. The HBV genome is a circular DNA molecule of approximately 3200
nucleotides (Fig. 1A) that encodes 3 different-sized envelope proteins (HBsAg) as well
as several other structural and non-structural proteins (Fig. 1B, Table 1). At least one of
the non-structural proteins (HBx) has been suggested to have a role in autophagy. Tang
and colleagues found that HBx was involved in up-regulation of beclin-1 expression
during starvation-induced autophagy (26). Sir and colleagues demonstrated that HBV
infection induced early autophagy in the absence of autophagic protein degradation,
that autophagy enhanced HBV replication and that this was mediated by interaction
between HBx and PI3KC3 to enhance the latter’s activity (27). Other recent work by Li
and colleagues has confirmed that HBV induces autophagy and that this induction aids
virus replication. However, Li et al demonstrated, using a different vector construct and
HBV regulates and “hires” autophagy for its benefit to promote replication. A
recent report shows that HBV can enhance the autophagic process in hepatoma cells
without promoting the degradation of lysosomes (28). This report also demonstrates by
mutational analysis that HBV small surface proteins (HBsAg) are required to induce
autophagy. Transfection of HBsAg is sufficient enough to induce autophagy in
hepatoma cells. Autophagy machinery is activated during HBV infection and is
responsible for enhancement of HBV replication in the cells (28). Another experimental
finding shows that HBV transfected into the hepatoma cells induces an early autophagic
response without increasing the autophagic protein degradation (27). This autophagic
response enhances viral replication through the binding of HBV X protein (HBx) to
PI3KC3. These experimental studies provide evidence that the autophagy pathway can
be used as a target for the treatment of patients with HBV infection (26, 27). In the
report published by Tang and colleagues (26), HBVx protein when transfected into the
hepatocytes, leads to the increased activity of Beclin 1 protein expression, which in turn
leads to the enhancement of autophagy. These results certainly provide evidence that
HBV can induce autophagy in hepatocytes and thereby using this process for
enhancing its replication. In conclusion, the autophagy pathway can be a target for
designing drugs that better serve the purpose of patients with HBV infections in the
liver.
Classification and Structure
HBV belongs to the Hepadnaviridae family. These viruses are characterized by having
a partial double-stranded DNA genome, with numerous overlapping genes in multiple
reading frames, which is copied through an RNA intermediate by a reverse
transcriptase enzyme. HBV infects primarily hepatocytes. For more complete reviews,
see (23-25). The HBV, also known as the Dane particle, is approximately 45nm in
diameter. The HBV genome is a circular DNA molecule of approximately 3200
nucleotides (Fig. 1A) that encodes 3 different-sized envelope proteins (HBsAg) as well
as several other structural and non-structural proteins (Fig. 1B, Table 1). At least one of
the non-structural proteins (HBx) has been suggested to have a role in autophagy. Tang
and colleagues found that HBx was involved in up-regulation of beclin-1 expression
during starvation-induced autophagy (26). Sir and colleagues demonstrated that HBV
infection induced early autophagy in the absence of autophagic protein degradation,
that autophagy enhanced HBV replication and that this was mediated by interaction
between HBx and PI3KC3 to enhance the latter’s activity (27). Other recent work by Li
and colleagues has confirmed that HBV induces autophagy and that this induction aids
virus replication. However, Li et al demonstrated, using a different vector construct and
HBV regulates and “hires” autophagy for its benefit to promote replication. A
recent report shows that HBV can enhance the autophagic process in hepatoma cells
without promoting the degradation of lysosomes (28). This report also demonstrates by
mutational analysis that HBV small surface proteins (HBsAg) are required to induce
autophagy. Transfection of HBsAg is sufficient enough to induce autophagy in
hepatoma cells. Autophagy machinery is activated during HBV infection and is
responsible for enhancement of HBV replication in the cells (28). Another experimental
finding shows that HBV transfected into the hepatoma cells induces an early autophagic
response without increasing the autophagic protein degradation (27). This autophagic
response enhances viral replication through the binding of HBV X protein (HBx) to
PI3KC3. These experimental studies provide evidence that the autophagy pathway can
be used as a target for the treatment of patients with HBV infection (26, 27). In the
report published by Tang and colleagues (26), HBVx protein when transfected into the
hepatocytes, leads to the increased activity of Beclin 1 protein expression, which in turn
leads to the enhancement of autophagy. These results certainly provide evidence that
HBV can induce autophagy in hepatocytes and thereby using this process for
enhancing its replication. In conclusion, the autophagy pathway can be a target for
designing drugs that better serve the purpose of patients with HBV infections in the
liver.
interesting studies, chlorochine is probably useless monotherapy but like alinia, simvastatin might boost response to interferon.i hope to see in vivo studies on this too
Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2212941/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2212941/
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