The HIV-specific cytotoxic T lymphocyte (CTL) response is a critical component in controlling viral replication in vivo, but ultimately fails in its ability to eradicate the virus. Our intent in ...these studies is to develop ways to enhance and restore the HIV-specific CTL response to allow long-term viral suppression or viral clearance. In our approach, we sought to genetically manipulate human hematopoietic stem cells (HSCs) such that they differentiate into mature CTL that will kill HIV infected cells. To perform this, we molecularly cloned an HIV-specific T cell receptor (TCR) from CD8+ T cells that specifically targets an epitope of the HIV-1 Gag protein. This TCR was then used to genetically transduce HSCs. These HSCs were then introduced into a humanized mouse containing human fetal liver, fetal thymus, and hematopoietic progenitor cells, and were allowed to differentiate into mature human CD8+ CTL. We found human, HIV-specific CTL in multiple tissues in the mouse. Thus, genetic modification of human HSCs with a cloned TCR allows proper differentiation of the cells to occur in vivo, and these cells migrate to multiple anatomic sites, mimicking what is seen in humans. To determine if the presence of the transgenic, HIV-specific TCR has an effect on suppressing HIV replication, we infected with HIV-1 mice expressing the transgenic HIV-specific TCR and, separately, mice expressing a non-specific control TCR. We observed significant suppression of HIV replication in multiple organs in the mice expressing the HIV-specific TCR as compared to control, indicating that the presence of genetically modified HIV-specific CTL can form a functional antiviral response in vivo. These results strongly suggest that stem cell based gene therapy may be a feasible approach in the treatment of chronic viral infections and provide a foundation towards the development of this type of strategy.
A unique aspect of human monocytes, compared to monocytes from many other species, is that they express the CD4 molecule. However, the role of the CD4 molecule in human monocyte development and ...function is not known. We determined that the activation of CD4 via interaction with major histocompatibility complex class II (MHC-II) triggers cytokine expression and the differentiation of human monocytes into functional mature macrophages. Importantly, we determined that CD4 activation induces intracellular signaling in monocytes and that inhibition of the MAPK and Src family kinase pathways blocked the ability of CD4 ligation to trigger macrophage differentiation. We observed that ligation of CD4 by MHC-II on activated endothelial cells induced CD4-mediated macrophage differentiation of blood monocytes. Finally, CD4 ligation by MHC-II increases the susceptibility of blood-derived monocytes to HIV binding and subsequent infection. Altogether, our studies have identified a novel function for the CD4 molecule on peripheral monocytes and suggest that a unique set of events that lead to innate immune activation differ between humans and mice. Further, these events can have effects on HIV infection and persistence in the macrophage compartment.
The CD4 molecule, as the primary receptor for HIV, plays an important role in HIV pathogenesis. There are many cell types that express CD4 other than the primary HIV target, the CD4(+) T cell. Other than allowing HIV infection, the role of the CD4 molecule on human monocytes or macrophages is not known. We were interested in determining the role of CD4 in human monocyte/macrophage development and function and the potential effects of this on HIV infection. We identified a role for the CD4 molecule in triggering the activation and development of a monocyte into a macrophage following its ligation. Activation of the monocyte through the CD4 molecule in this manner increases the ability of monocytes to bind to and become infected with HIV. Our studies have identified a novel function for the CD4 molecule on peripheral monocytes in triggering macrophage development that has direct consequences for HIV infection.
We described earlier a dual-combination anti-HIV type 1 (HIV-1) lentiviral vector (LVsh5/C46) that downregulates CCR5 expression of transduced cells via RNAi and inhibits HIV-1 fusion via cell ...surface expression of cell membrane-anchored C46 antiviral peptide. This combinatorial approach has two points of inhibition for R5-tropic HIV-1 and is also active against X4-tropic HIV-1. Here, we utilize the humanized bone marrow, liver, thymus (BLT) mouse model to characterize the in vivo efficacy of LVsh5/C46 (Cal-1) vector to engineer cellular resistance to HIV-1 pathogenesis. Human CD34+ hematopoietic stem/progenitor cells (HSPC) either nonmodified or transduced with LVsh5/C46 vector were transplanted to generate control and treatment groups, respectively. Control and experimental groups displayed similar engraftment and multilineage hematopoietic differentiation that included robust CD4+ T-cell development. Splenocytes isolated from the treatment group were resistant to both R5- and X4-tropic HIV-1 during ex vivo challenge experiments. Treatment group animals challenged with R5-tropic HIV-1 displayed significant protection of CD4+ T-cells and reduced viral load within peripheral blood and lymphoid tissues up to 14 weeks postinfection. Gene-marking and transgene expression were confirmed stable at 26 weeks post-transplantation. These data strongly support the use of LVsh5/C46 lentiviral vector in gene and cell therapeutic applications for inhibition of HIV-1 infection.
Jet energy scale measurements and their systematic uncertainties are reported for jets measured with the ATLAS detector using proton-proton collision data with a center-of-mass energy of s=13 TeV, ...corresponding to an integrated luminosity of 3.2 fb−1 collected during 2015 at the LHC. Jets are reconstructed from energy deposits forming topological clusters of calorimeter cells, using the anti-kt algorithm with radius parameter R=0.4. Jets are calibrated with a series of simulation-based corrections and in situ techniques. In situ techniques exploit the transverse momentum balance between a jet and a reference object such as a photon, Z boson, or multijet system for jets with 20<pT<2000 GeV and pseudorapidities of |η|<4.5, using both data and simulation. An uncertainty in the jet energy scale of less than 1% is found in the central calorimeter region (|η|<1.2) for jets with 100<pT<500 GeV. An uncertainty of about 4.5% is found for low-pT jets with pT=20 GeV in the central region, dominated by uncertainties in the corrections for multiple proton-proton interactions. The calibration of forward jets (|η|>0.8) is derived from dijet pT balance measurements. For jets of pT=80 GeV, the additional uncertainty for the forward jet calibration reaches its largest value of about 2% in the range |η|>3.5 and in a narrow slice of 2.2<|η|<2.4.
The performance of the missing transverse momentum (
E
T
miss
) reconstruction with the ATLAS detector is evaluated using data collected in proton–proton collisions at the LHC at a centre-of-mass ...energy of 13 TeV in 2015. To reconstruct
E
T
miss
, fully calibrated electrons, muons, photons, hadronically decaying
τ
-leptons
, and jets reconstructed from calorimeter energy deposits and charged-particle tracks are used. These are combined with the soft hadronic activity measured by reconstructed charged-particle tracks not associated with the hard objects. Possible double counting of contributions from reconstructed charged-particle tracks from the inner detector, energy deposits in the calorimeter, and reconstructed muons from the muon spectrometer is avoided by applying a signal ambiguity resolution procedure which rejects already used signals when combining the various
E
T
miss
contributions. The individual terms as well as the overall reconstructed
E
T
miss
are evaluated with various performance metrics for scale (linearity), resolution, and sensitivity to the data-taking conditions. The method developed to determine the systematic uncertainties of the
E
T
miss
scale and resolution is discussed. Results are shown based on the full 2015 data sample corresponding to an integrated luminosity of
3.2
fb
-
1
.
A measurement of the mass of the
W
boson is presented based on proton–proton collision data recorded in 2011 at a centre-of-mass energy of 7 TeV with the ATLAS detector at the LHC, and corresponding ...to
4.6
fb
-
1
of integrated luminosity. The selected data sample consists of
7.8
×
10
6
candidates in the
W
→
μ
ν
channel and
5.9
×
10
6
candidates in the
W
→
e
ν
channel. The
W
-boson mass is obtained from template fits to the reconstructed distributions of the charged lepton transverse momentum and of the
W
boson transverse mass in the electron and muon decay channels, yielding
m
W
=
80370
±
7
(
stat.
)
±
11
(
exp. syst.
)
±
14
(
mod. syst.
)
MeV
=
80370
±
19
MeV
,
where the first uncertainty is statistical, the second corresponds to the experimental systematic uncertainty, and the third to the physics-modelling systematic uncertainty. A measurement of the mass difference between the
W
+
and
W
-
bosons yields
m
W
+
-
m
W
-
=
-
29
±
28
MeV.
A measurement of the associated production of a top-quark pair (tt¯) with a vector boson (W, Z) in proton-proton collisions at a center-of-mass energy of 13 TeV is presented, using 36.1 fb−1 of ...integrated luminosity collected by the ATLAS detector at the Large Hadron Collider. Events are selected in channels with two same- or opposite-sign leptons (electrons or muons), three leptons or four leptons, and each channel is further divided into multiple regions to maximize the sensitivity of the measurement. The tt¯Z and tt¯W production cross sections are simultaneously measured using a combined fit to all regions. The best-fit values of the production cross sections are σtt¯Z=0.95±0.08stat±0.10syst pb and σtt¯W=0.87±0.13stat±0.14syst pb in agreement with the Standard Model predictions. The measurement of the tt¯Z cross section is used to set constraints on effective field theory operators which modify the tt¯Z vertex.
The luminosity determination for the ATLAS detector at the LHC during
pp
collisions at
s
=
8 TeV in 2012 is presented. The evaluation of the luminosity scale is performed using several luminometers, ...and comparisons between these luminosity detectors are made to assess the accuracy, consistency and long-term stability of the results. A luminosity uncertainty of
δ
L
/
L
=
±
1.9
%
is obtained for the
22.7
fb
-
1
of
pp
collision data delivered to ATLAS at
s
=
8 TeV in 2012.
A
bstract
A search for Higgs boson pair production in the
b
b
¯
b
b
¯
final state is carried out with up to 36.1 fb
−1
of LHC proton-proton collision data collected at
s
=
13
TeV with the ATLAS ...detector in 2015 and 2016. Three benchmark signals are studied: a spin-2 graviton decaying into a Higgs boson pair, a scalar resonance decaying into a Higgs boson pair, and Standard Model non-resonant Higgs boson pair production. Two analyses are carried out, each implementing a particular technique for the event reconstruction that targets Higgs bosons reconstructed as pairs of jets or single boosted jets. The resonance mass range covered is 260–3000 GeV. The analyses are statistically combined and upper limits on the production cross section of Higgs boson pairs times branching ratio to
b
b
¯
b
b
¯
are set in each model. No significant excess is observed; the largest deviation of data over prediction is found at a mass of 280 GeV, corresponding to 2.3 standard deviations globally. The observed 95% confidence level upper limit on the non-resonant production is 13 times the Standard Model prediction.
Combined analyses of the Higgs boson production and decay rates as well as its coupling strengths to vector bosons and fermions are presented. The combinations include the results of the analyses of ...the
H
→
γ
γ
,
Z
Z
∗
,
W
W
∗
,
Z
γ
,
b
b
¯
,
τ
τ
and
μ
μ
decay modes, and the constraints on the associated production with a pair of top quarks and on the off-shell coupling strengths of the Higgs boson. The results are based on the LHC proton-proton collision datasets, with integrated luminosities of up to 4.7
fb
-
1
at
s
=
7
TeV and 20.3
fb
-
1
at
s
=
8
TeV, recorded by the ATLAS detector in 2011 and 2012. Combining all production modes and decay channels, the measured signal yield, normalised to the Standard Model expectation, is
1
.
18
-
0.14
+
0.15
. The observed Higgs boson production and decay rates are interpreted in a leading-order coupling framework, exploring a wide range of benchmark coupling models both with and without assumptions on the Higgs boson width and on the Standard Model particle content in loop processes. The data are found to be compatible with the Standard Model expectations for a Higgs boson at a mass of 125.36 GeV for all models considered.
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