Caractérisation du profil lymphocytaire B et de la réponse vaccinale des enfants exposés non infectés par le virus de l'immunodéficience humaine

En bas âge, les enfants exposés au VIH mais non infectés (ENI) ont des risques de morbidité et de mortalité plus élevés. Des perturbations dans le profil immunitaire ont été mises en évidence et associées, en outre, aux paramètres maternels relatifs à l’infection au VIH y compris l’exposition au VIH, aux agents antirétroviraux et au milieu placentaire pro-inflammatoire. Ici, nous avons caractérisé le compartiment cellulaire B et la réponse vaccinale antitétanique d’enfants ENI durant leur 1re année de vie. Les enfants ENI (n = 68) de la cohorte du CMIS ont été stratifiés selon le zénith de la charge virale (CV; ≤40 vs. >40 copies/ml plasma) et le nadir du compte de CD4 (<500 vs. ≥500 cellules/mm3) de la mère en grossesse. Les nouveau-nés ont reçu une prophylaxie (AZT/3TC) 12 h après la naissance et jusqu'à leur 4e ou 6e semaine d’âge. Les cellules mononucléées de sang ont été isolées à la naissance, à 6 et à 12 mois d’âge. Les sous-populations de cellules B (naïves; transitionnelles T1/T2; plasmablastes; mémoires classiques, activées et atypiques) ont été analysées par cytométrie en flux grâce à un marquage pour CD10, CD20, CD21, CD27 et l’IgM de surface. Les cellules B spécifiques au tétanos et la capacité de sécrétion d'IgG de la fraction mémoire ont été étudiées à l’aide d’oligomères fluorescents du fragment C du toxoïde tétanique (TTCF) et d’une détection immunoenzymatique des IgG par ELISpot. Les nourrissons nés de mères avec une CV détectable en grossesse avaient une proportion élevée de plasmablastes (p=0,0449) et diminuée de cellules B CD19+ (p=0,0174) à la naissance en plus d'une proportion accrue de cellules B mémoires classiques IgM+ à 12 mois (p=0,0367). Ceux dont les mères avaient une immunité lymphocytaire T CD4+ altérée en grossesse (<500 cellules/mm3) présentaient des fréquences augmentées de plasmablastes (p=0,0458) et de cellules B mémoires activées IgM+ (p=0,0071) à la naissance et à 6 mois de vie respectivement. Ces résultats suggèrent une maturation précoce du compartiment cellulaire B et une altération dans la commutation de classe chez les bambins nés de mères avec une CV détectable et/ou un compte de CD4 sous-optimal. Aucune différence majeure n'a été notée dans la réponse vaccinale antitétanique des enfants ENI. Dans l’ensemble, nos résultats indiquent que la gravité des paramètres maternels en terme de CV et de compte de CD4 n’a que peu d'impact sur l'ontogénie des cellules B chez les enfants ENI et leur capacité à répondre à une vaccination.In early life, HIV-exposed uninfected (HEU) children experience higher rates of morbidity and mortality. Studies revealed evidences of alterations in their immunological profile that are associated, in part, with maternal parameters related to HIV infection including in utero exposure to HIV, antiretroviral therapy (ART) and the pro-inflammatory placental environment. Here, we performed a longitudinal profiling of the B cell subsets and response to tetanus vaccine in HEU children during their 1st year of life. HEU children (n = 68) from the CMIS Cohort were stratified based on the zenith of the maternal viral load (VL; ≤40 vs. >40 copies/ml plasma) and the nadir of the maternal CD4 count (<500 vs. ≥500 cells/mm3) during pregnancy. Newborns received prophylactic ART (AZT/3TC) from 12h after birth until week 4 or 6. Blood mononuclear cells were isolated at birth, 6, and 12 months of age. CD19+ B cell subsets (naïve; transitional T1/T2; classical, activated and atypical memory; plasmablasts) were analysed by flow cytometry using CD10, CD20, CD21, CD27 and surface IgM markers. Tetanus-specific B cells and the IgG secreting activity of the memory fraction were studied using fluorescent tetanus toxoid C fragment (TTCF) oligomers and an ELISpot assay. HEU infants born to mothers with a detectable VL during pregnancy had increased proportions of plasmablasts (p=0,0449) and a lower frequency of CD19+ B cells (p=0,0174) at birth in addition to having an expanded percentage of IgM+ classical memory B cells at 12 months (p=0,0367). Infants whose mothers had an impaired CD4 immunity throughout pregnancy (<500 cells/mm3) presented with greater frequencies of plasmablasts (p=0,0458) and IgM+ activated memory B cells (p=0,0071) at birth and 6 months respectively. These results suggest an early maturation of the B cell compartment and an alteration of the class switching mechanism in infants born to mothers with either a detectable VL or a low CD4 count. No relevant difference was noted in the TTCF-specific B cell subsets and the ability of memory B cells to generated specific antibodies. Overall, the severity of the maternal parameters in terms of VL and CD4 count had little impact on the ontogeny of the B cells subsets and their capacity to respond to vaccination

LILAC pilot study : effects of metformin on mTOR activation and HIV reservoir persistence during antiretroviral therapy

Background: Chronic inflammation and residual HIV transcription persist in people living with HIV (PLWH) receiving antiretroviral therapy (ART), thus increasing the risk of developing non-AIDS co-morbidities. The mechanistic target of rapamycin (mTOR) is a key regulator of cellular metabolism and HIV transcription, and therefore represents an interesting novel therapeutic target. Methods: The LILAC pilot clinical trial, performed on non-diabetic ART-treated PLWH with CD4+ /CD8+ T-cell ratios <0.8, evaluated the effects of metformin (12 weeks oral administration; 500-850 mg twice daily), an indirect mTOR inhibitor, on the dynamics of immunological/virological markers and changes in mTOR activation/phosphorylation in blood collected at Baseline, Week 12, and 12 weeks after metformin discontinuation (Week 24) and sigmoid colon biopsies (SCB) collected at Baseline and Week 12. Findings: CD4+ T-cell counts, CD4+ /CD8+ T-cell ratios, plasma markers of inflammation/gut damage, as well as levels of cell-associated integrated HIV-DNA and HIV-RNA, and transcriptionally-inducible HIV reservoirs, underwent minor variations in the blood in response to metformin. The highest levels of mTOR activation/ phosphorylation were observed in SCB at Baseline. Consistently, metformin significantly decreased CD4+ Tcell infiltration in the colon, as well as mTOR activation/phosphorylation, especially in CD4+ T-cells expressing the Th17 marker CCR6. Also, metformin decreased the HIV-RNA/HIV-DNA ratios, a surrogate marker of viral transcription, in colon-infiltrating CD4+ T-cells of 8/13 participants

Repurposing Metformin in Nondiabetic People With HIV:Influence on Weight and Gut Microbiota

Background. People with HIV (PWH) taking antiretroviral therapy (ART) may experience weight gain, dyslipidemia, increased risk of non-AIDS comorbidities, and long-term alteration of the gut microbiota. Both low CD4/CD8 ratio and chronic inflammation have been associated with changes in the gut microbiota of PWH. The antidiabetic drug metformin has been shown to improve gut microbiota composition while decreasing weight and inflammation in diabetes and polycystic ovary syndrome. Nevertheless, it remains unknown whether metformin may benefit PWH receiving ART, especially those with a low CD4/CD8 ratio. Methods. In the Lilac pilot trial, we recruited 23 nondiabetic PWI I receiving ART for more than 2 years with a low CD4/CD8 ratio ( Results. Metformin decreased weight in PWH, and weight loss was inversely correlated with plasma levels of the satiety factor GDF-15. Furthermore, metformin changed the gut microbiota composition by increasing the abundance of anti-inflammatory bacteria such as butyrate-producing species and the protective Akkermansia muciniphila. Conclusions. Our study provides the first evidence that a 12-week metformin treatment decreased weight and favored anti-inflammatory bacteria abundance in the microbiota of nondiabetic ART-treated PWH. Larger randomized placebo-controlled clinical trials with longer metformin treatment will be needed to further investigate the role of metformin in reducing inflammation and the risk of non-AIDS comorbidities in ART-treated PWH

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Les droits disciplinaires des fonctions publiques : « unification », « harmonisation » ou « distanciation ». A propos de la loi du 26 avril 2016 relative à la déontologie et aux droits et obligations des fonctionnaires

The production of tt‾ , W+bb‾ and W+cc‾ is studied in the forward region of proton–proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98±0.02 fb−1 . The W bosons are reconstructed in the decays W→ℓν , where ℓ denotes muon or electron, while the b and c quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions.The production of $t\overline{t}$, $W+b\overline{b}$ and $W+c\overline{c}$ is studied in the forward region of proton-proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98 $\pm$ 0.02 \mbox{fb}^{-1}. The $W$ bosons are reconstructed in the decays $W\rightarrow\ell\nu$, where $\ell$ denotes muon or electron, while the $b$ and $c$ quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions

Physics case for an LHCb Upgrade II - Opportunities in flavour physics, and beyond, in the HL-LHC era

The LHCb Upgrade II will fully exploit the flavour-physics opportunities of the HL-LHC, and study additional physics topics that take advantage of the forward acceptance of the LHCb spectrometer. The LHCb Upgrade I will begin operation in 2020. Consolidation will occur, and modest enhancements of the Upgrade I detector will be installed, in Long Shutdown 3 of the LHC (2025) and these are discussed here. The main Upgrade II detector will be installed in long shutdown 4 of the LHC (2030) and will build on the strengths of the current LHCb experiment and the Upgrade I. It will operate at a luminosity up to 2×1034 cm−2s−1, ten times that of the Upgrade I detector. New detector components will improve the intrinsic performance of the experiment in certain key areas. An Expression Of Interest proposing Upgrade II was submitted in February 2017. The physics case for the Upgrade II is presented here in more depth. CP-violating phases will be measured with precisions unattainable at any other envisaged facility. The experiment will probe b → sl+l−and b → dl+l− transitions in both muon and electron decays in modes not accessible at Upgrade I. Minimal flavour violation will be tested with a precision measurement of the ratio of B(B0 → μ+μ−)/B(Bs → μ+μ−). Probing charm CP violation at the 10−5 level may result in its long sought discovery. Major advances in hadron spectroscopy will be possible, which will be powerful probes of low energy QCD. Upgrade II potentially will have the highest sensitivity of all the LHC experiments on the Higgs to charm-quark couplings. Generically, the new physics mass scale probed, for fixed couplings, will almost double compared with the pre-HL-LHC era; this extended reach for flavour physics is similar to that which would be achieved by the HE-LHC proposal for the energy frontier

LHCb upgrade software and computing : technical design report

This document reports the Research and Development activities that are carried out in the software and computing domains in view of the upgrade of the LHCb experiment. The implementation of a full software trigger implies major changes in the core software framework, in the event data model, and in the reconstruction algorithms. The increase of the data volumes for both real and simulated datasets requires a corresponding scaling of the distributed computing infrastructure. An implementation plan in both domains is presented, together with a risk assessment analysis

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article

Observation of the B0 → ρ0ρ0 decay from an amplitude analysis of B0 → (π+π−)(π+π−) decays

Proton–proton collision data recorded in 2011 and 2012 by the LHCb experiment, corresponding to an integrated luminosity of 3.0 fb−1 , are analysed to search for the charmless B0→ρ0ρ0 decay. More than 600 B0→(π+π−)(π+π−) signal decays are selected and used to perform an amplitude analysis, under the assumption of no CP violation in the decay, from which the B0→ρ0ρ0 decay is observed for the first time with 7.1 standard deviations significance. The fraction of B0→ρ0ρ0 decays yielding a longitudinally polarised final state is measured to be fL=0.745−0.058+0.048(stat)±0.034(syst) . The B0→ρ0ρ0 branching fraction, using the B0→ϕK⁎(892)0 decay as reference, is also reported as B(B0→ρ0ρ0)=(0.94±0.17(stat)±0.09(syst)±0.06(BF))×10−6