Hepatitis
C
VIruS
(HCY)
infection
is
characterized
by
a
broad
spectrum
of
clinical
outcomes.
An
estimated
14%-46%
of
individuals
exposed
to
HCY
are
able
to
clear
the
virus,
while
the
other
portion
develops
chronic
(persistent)
infections.
Among
the
individuals
with
chronic
HCY
who
are
treated
with
interferon-based
therapies,
only
a
portion
are
able
experience
sustained
virological
suppression.
Similarly,
a
number
of
chronically
infected
individuals
have
autoimmune
extrahepatic
manifestations
such
as
the
presence
of
autoantibodies.
The
pathological
mechanisms
behind
these
phenomena
are
not
known,
but
it
is
believed
that
host
genetic
factors
may
playa
role.
This
thesis
examines
the
hypothesis
that
host
genetic
factors
may
contribute
to
the
diverse
spectrum
of
HCY
clinical
outcomes.
In
addition,
it
examines
the
pathogenesis
of
antinuclear
antibodies
(ANA)
in
chronic
HCY,
and
the
effect
of
ANA
positivity
on
the
natural
history
of
HCY.
Correlations
were
observed
between
female
gender
and
geographic
location
and
ANA
positivity.
No
relationships
were
observed
for
an
effect
of
ANA
positivity
on
response
rates
to
interferon
therapy.
We
observed
a
trend
of
ANA
positivity
with
faster
progression
of
HCY-related
fibrosis,
although
t
his
failed
to
achieve
statistical
significance.
ANA-positive
individuals
tended
to
have
more
plasma
cells
in
their
liver
than
ANA-negative
individuals.
This
study
also
observed
a
number
of
correlations
between
genotypes
of
the
interferon
induced
genes
encoding
the
myxovirus
resistance
1
protein
(MxA),
2'-5'0Iigo-adenylate
synthase
1
(OAS-
I),
and
protein
kinase
(PKR),
as
well
as
genes
encoding
cytotoxic
T
-lymphocyte
antigen-s
(CTLA4),
and
inducible
nitric
oxide
synthase
(iNOS)
(encoded
by
the
NOS2A
gene)
with
several
outcomes
including
self-limiting
versus
chronic
HCY
infection,
along
with
the
response
to
interferon
therapy.
This
study
identified
several
factors
to
be
correlated
with
ANA
positivity
in
HCY.
These
factors
may
serve
as
future
points
for
investigation
by
basic
scientists
understanding
the
mechanisms
ofHCY-mediated
autoimmunity.
Importantly,
this
study
suggests
that
low
titre
ANA
positivity
should
not
be
a
contraindication
to
therapy.
This
study
also
highlighted
the
importance
of
several
genetic
pathways
in
HCY
infection.
These
may
serve
as
targets
for
future
pharmacologic
interventions
or
genetic
tests
designed
to
screen
for
those
who
will
not
benefit
from
interferon
therapies