Patterns and features of HIV-1 specific CD8+ T-cell responses during acute HIV-1 infection and their association with viral control.
Date
2015
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Evidence suggests that
CD8+
T-‐cells
play
a
major
role
in
the
control
of
HIV-‐1
viremia
and
apply
significant
immune
pressure
on
HIV-‐1
replication.
However,
the
presence
of
virus-‐specific
CD8+
T-‐cells
in
individuals
with
varying
levels
of
viral
control
suggests
that
CD8+
T-‐cells
may
differ
in
their
antiviral
function
or
efficacy.
The
mechanisms
underlying
differences
in
the
control
of
viremia,
particularly
the
reasons
why
particular
individuals
experience
more
effective
acute
viremia
resolution,
which
is
a
good
correlate
of
the
subsequent
rate
of
disease
progression,
are
still
not
well
understood.
In
order
to
uncover
some
of
the
features
of
CD8+
T-‐cell
subsets
responsible
for
the
control
of
HIV
replication,
particularly
during
the
critical
early
infection
phase,
we
investigated
the
patterns
and
features
of
HIV-‐1-‐specific
CD8+
T-‐
cell
responses
during
acute
and
primary
HIV-‐1
infection
and
their
association
with
viral
control.
We
also
sought
to
determine
the
impact
of
acute
phase
immune
activation
on
the
acute
HIV-‐1-‐specific
CD8+
T-‐cell
response
and
on
disease
progression.
We
hypothesized
that
protein-‐specific
and
epitope-‐specific
immunodominance
patterns
during
the
first
12
weeks
of
HIV-‐1
infection
are
associated
with
subsequent
disease
progression.
Our
data
show
the
presence
of
HIV-‐1
specific
CD8+
T-‐cells
with
limited
breadth
during
acute
HIV-‐1
infection
and
also
demonstrate
that
the
magnitude
and
breadth
of
interferon
gamma
(IFN-‐γ)
ELISPOT
assay
responses
measured
within
12
weeks
post-‐infection
are
unrelated
to
the
course
of
disease
in
the
first
year
of
infection.
During
the
first
weeks
of
infection
Nef
protein
was
most
frequently
recognized
by
T-‐
xv
cells
and
was
the
target
for
the
earliest
response.
Although
initially
subdominant,
there
was
a
broadening
of
the
Gag-‐specific
T-‐cell
immune
response
such
that
these
responses
became
immunodominant
by
one
year
post
infection.
The
broadening
and
preservation
of
early
Gag–specific
T-‐cell
responses
during
the
follow
up
period
was
associated
with
better
control
of
viremia
and
lower
viral
load
set
point.
Although
many
of
the
acute/early
HIV-‐1-‐specific
IFN-‐γ
enzyme
linked
immunospot
assay
(ELISPOT)
CD8+
T-‐cell
responses
targeting
Gag
and
Pol
persisted,
the
majority
of
acute
and
early
T-‐cell
responses
targeting
Env,
Nef
and
other
regulatory
proteins
waxed
and
waned
over
time
and
could
not
be
detected
at
the
last
time
point
evaluated.
Some
of
the
early
T-‐cell
responses
which
where
no
longer
detectable
when
using
overnight
ELISPOT
assay
were
detectable
when
PBMCs
were
stimulated
with
corresponding
peptides
and
cultured
for
10
days
before
measuring
IFN-‐γ
secretion
via
the
ELISPOT
assay.
The
presence
of
these
cultured
ELISPOT
central
memory
type
T-‐cell
responses
targeting
epitopes
in
Pol,
Env,
Nef,
Regulatory
and
Accessory
proteins
were
not
significantly
associated
with
viral
set
point.
However,
cultured
ELISPOT
Gag-‐specific
responses
correlated
with
low
plasma
viremia,
thus
further
providing
evidence
for
the
favourable
role
of
Gag-‐specific
T-‐cell
responses
in
the
control
of
viral
replication.
We
also
show
that
three
cytokines
IL-‐10,
IP-‐10
and
IL-‐
12
were
associated
with
changes
in
viral
load
set
point
and/or
CD4+
T-‐cell
dynamics
during
the
first
year
of
HIV-‐1
infection.
Interestingly,
the
activation
of
the
PD-‐1
inhibitory
pathway
in
acute
HIV-‐1
infection
was
associated
with
a
slower
disease
progression.
Description
Ph. D University of KwaZulu-Natal, Durban 2015.
Keywords
HIV infections--Immunological aspects., HIV infections--Complications., T cells--Immunology., Theses--Immunology., HIV-1 infection., Viral control.