12 research outputs found
Patterns and features of HIV-1 specific CD8+ T-cell responses during acute HIV-1 infection and their association with viral control.
Ph. D University of KwaZulu-Natal, Durban 2015.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
Nef-mediated down-regulation of CD4 and HLA class I in HIV-1 subtype C infection: association with disease progression and influence of immune pressure.
CAPRISA, 2014.Abstract available in pdf
Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study.
BACKGROUND: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa. METHODS: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD114 per year and 500 per disability-adjusted life years averted, and a discount rate of 3% per year. FINDINGS: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6-52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0-6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1-30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (-2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (-13 000 to -300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is 150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of 144 per year, in 52% at 114. INTERPRETATION: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health
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High Frequency of Transmitted HIV-1 Gag HLA Class I-Driven Immune Escape Variants but Minimal Immune Selection over the First Year of Clade C Infection
In chronic HIV infection, CD8+ T cell responses to Gag are associated with lower viral loads, but longitudinal studies of HLA-restricted CD8+ T cell-driven selection pressure in Gag from the time of acute infection are limited. In this study we examined Gag sequence evolution over the first year of infection in 22 patients identified prior to seroconversion. A total of 310 and 337 full-length Gag sequences from the earliest available samples (median = 14 days after infection [Fiebig stage I/II]) and at one-year post infection respectively were generated. Six of 22 (27%) individuals were infected with multiple variants. There was a trend towards early intra-patient viral sequence diversity correlating with viral load set point (p = 0.07, r = 0.39). At 14 days post infection, 59.7% of Gag CTL epitopes contained non-consensus polymorphisms and over half of these (35.3%) comprised of previously described CTL escape variants. Consensus and variant CTL epitope proportions were equally distributed irrespective of the selecting host HLA allele and most epitopes remained unchanged over 12 months post infection. These data suggest that intrapatient diversity during acute infection is an indicator of disease outcome. In this setting, there is a high rate of transmitted CTL escape variants and limited immune selection in Gag during the first year of infection. These data have relevance for vaccine strategies designed to elicit effective CD8+ T cell immune responses
Neighbour joining trees and Highlighter plots of longitudinal HIV-1 gag diversity from recently infected individuals.
<p>(A) Neighbour-joining phylogenetic tree of longitudinal (from 14 days to 1 year post infection) <i>gag</i> sequences from 22 recently infected HIV-1 participants and consensus subtype C reference sequence from the HIV database (<a href="http://www.hiv.lanl.gov" target="_blank">www.hiv.lanl.gov</a>). Gag sequences from the earliest time point are shown in red circles and in blue circles at 1 year post infection. (*) denotes samples sequenced later than 14 days post infection (AS3–0513, AS2–1037, AS2–0802, AS2–0945 and AS1–0876 were sequenced at 28, 34, 35, 46 and 101 days post-infection respectively). (B) Participant AS3_0513 with a highly homogeneous <i>gag</i> sequence population at screening (∼28 days post infection) displaying limited structure on a tree (left) and little or no nucleotide changes from the intrapatient consensus at 28 days post infection. (C) Participant AS3_0767 infected with four closely related <i>gag</i> populations based on the clustering of sequences. Heterogeneous, multiple variant <i>gag</i> sequences population at 14 days post infection visually represented by a phylogenetic tree (left) with extensive branching topology and Highlighter plots (right) with diverse pattern of nucleotide base mutations compared to consensus. Nucleotide polymorphisms are indicated by a colored tic mark (thymine in red, adenine in green, cytosine in blue and guanine in orange) and deletions are shown by gray tics in the Highlighter plots. (★) denotes the consensus sequence obtained from the earliest time point sequences.</p
Demographic and clinical characteristics of the study participants.
<p>*CD4+ cell counts were not performed at screening; the values given are for 2–4 weeks post screening</p><p>♦Viral loads were performed at screening</p><p>† CDC criteria followed for the interpretation of Western Blot results</p><p>Demographic and clinical characteristics of the study participants.</p
Percentage distribution of consensus and variant Gag sequence patterns in individuals over one year of HIV-1 infection.
<p>(A) Percentage of consensus, variant and known CTL variants within host specific epitopes from HLA class I alleles at one year post infection. Distribution of consensus, variant and percentage of variants as CTL variants within host-specific HLA restricted Gag epitopes in individuals possessing the selecting HLA-A (B), HLA-B (C) and HLA-C (D) allele and those individuals who do not possess the selecting HLA allele over one year of infection. (E) Overall distribution of adapted and non-adapted HLA-associated escape mutations within individuals that select and do not select for Gag polymorphisms by one year post infection. Distribution of adapted (F) and non-adapted (G) mutations expressing HLA-A, HLA-B and HLA-C alleles that select and do not select for Gag polymorphisms one year post infection.</p
Summary of reversion within CTL epitopes following transmission in the presence or absence of the selecting HLA type.
<p><i>a</i>Bold residues denotes known CTL escape mutation</p><p><i>b</i>(+): presence of HLA-association, (−): absence of previously identified HLA association</p><p>Underlining denotes the CTL epitope in the peptide sequence</p><p>Summary of reversion within CTL epitopes following transmission in the presence or absence of the selecting HLA type.</p
Multiple variant transmission and intrapatient diversity results in higher viral load set point.
<p>(A) Association of single versus multivariant transmission sequences versus viral load set point in individuals sequenced at the earliest time point (Student’s T test). (B) Significantly higher intrapatient diversity in individuals infected with multiple variants (Student’s T test). (C) Significantly higher intrapatient diversity within <i>gag</i> over one year of infection (Paired T test). (D) Intrapatient diversity of HIV-1 Gag at 14 days post infection correlation with viral load set point. Significant correlations of intrapatient diversity at 1 year versus viral load set point (E) and viral load at one year (F). (*) denotes statistical significant difference.</p
Summary of reversion of HLA associated mutations following transmission in the presence or absence of the selecting HLA type.
<p><i>a</i>"None" indicates no known HLA-association of mutation</p><p><i>b</i>(+): presence of HLA-association, (−): absence of previously identified HLA association</p><p>Bold restricting HLA indicates the HLA which is positively associted with the non-adapted mutation at one-year post infection</p><p>Summary of reversion of HLA associated mutations following transmission in the presence or absence of the selecting HLA type.</p