Impact du petit inhibiteur temsavir sur la conformation des glycoprotéines d’enveloppe du VIH-1

Un obstacle important dans l’éradication du virus de l’immunodéfience humaine (VIH-1) est l’établissement de réservoirs viraux où le virus reste à l’état latent ainsi que l’absence de vaccin efficace. Bien que les molécules antivirales actuelles permettent d’augmenter l’espérance de vie des personnes vivant avec le VIH-1 (PLWH) ainsi que de diminuer la réplication virale chez cellesci, elles ne contribuent pas à l’élimination de ces réservoirs. La hausse de résistance envers ces molécules inhibitrices nécessite le développement constant de nouvelles molécules. L’une d’entre elles, temsavir (BMS-626529), est un nouvel inhibiteur d’attachement approuvé par la FDA depuis 2020. Sa cible, la glycoprotéine d’enveloppe (Env), est le seul antigène viral présent à la surface des cellules infectées et des virions, représentant donc la cible idéale des anticorps. L’Env mature se trouve sous forme d’hétérodimère (gp120 et gp41) suite au clivage de son précurseur gp160. Temsavir lie sous la boucle β20-β21 de la gp120 et prévient donc, par compétition, l’interaction entre l’Env et le récepteur CD4 de l’hôte. En plus de son rôle en tant qu’inhibiteur d’attachement, temsavir permet de stabiliser le trimère dans sa conformation dite «fermée». Un ancien analogue de temsavir, BMS-806, a montré réduire l’addition de glycans ainsi que de diminuer le clivage du précurseur gp160. Nos études démontrent que temsavir possède également un impact sur ces mécanismes impliqués dans la maturation et la flexibilité de l’Env de plusieurs souches du VIH-1. De ce fait, nous avons investigué l’effet de cette altération sur la conformation des différentes Env. Nos observations montrent que l’effet de temsavir sur le clivage protéolytique est associé à une diminution de la reconnaissance de l’Env par des anticorps ciblant différentes régions de celle-ci. Cette modification de la reconnaissance de l’Env est également associée à l’efficacité de la réponse cytotoxique cellulaire dépendante des anticorps (ADCC) à éliminer les cellules infectées. Les résultats présentés dans ce mémoire, notamment l’effet de temsavir sur la conformation de l’Env, devrait être considéré lors du développement d’immunothérapies ciblant le réservoir viral.An important obstacle in the eradication of the human immunodeficiency virus (HIV-1) is the establishment of viral reservoirs where the virus remains in a latent state and the absence of a potent vaccine. Although current antiretroviral molecules increase the life expectancy of people living with HIV-1 (PLWH) as well as reduce viral replication, they do not contribute to the elimination of these reservoirs. Also, the increase in drugs resistances towards these inhibitory molecules requires the constant development of new molecules. One of them, temsavir (BMS-626529), is a new attachment inhibitor approved by the FDA since 2020. Its target, the envelope glycoprotein (Env), is the only viral antigen present at the surface of infected cells and virions and thus, is also the main target of antibodies. This mature Env consists of three gp120-gp41 heterodimers after the proteolytic cleavage of its gp160 precursor. Temsavir binds under the β20-β21 loop of gp120 and prevents the interaction between Env and the host CD4 receptor. In addition to its role as an attachment inhibitor, temsavir stabilizes the trimer in its "closed" conformation. A previous analog of temsavir, BMS-806, has been shown to affect the addition of glycans as well as the cleavage of the gp160 precursor. Our studies demonstrate that temsavir also has an impact on these mechanisms involved in the maturation and flexibility of Env of several strains of HIV-1. Therefore, we investigated the effect of this alteration on the conformation of different Env. Our observations showed that the effect of temsavir on proteolytic cleavage is associated with a decrease in Env recognition by antibodies targeting different regions of Env. This modification in Env recognition also appears to be associated with the efficacy of antibody to mediate potent antibody-dependent cellular cytotoxicity (ADCC) against infected-cells. The results presented in this master thesis, should be considered when developing immunotherapies aimed at targeting the viral reservoir in Fostemsavir-treated individuals

Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

peer reviewedDespite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain–specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA’s predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Environmental effect on health: Air pollution and smoke

This review has discussed various topics related to environmental health. The major findings highlighted are air pollution, children and adult vulnerability, cytokines related to interleukin-33, thymic stromal lymphopoietin, tobacco smoke related to neonates, women, and their families, and perinatal outcomes. The Emergency Department was also highlighted related to asthma and air pollution concentrations within the emergency department, admissions for respiratory effects in pediatrics, and in patients with asthma that often present to the emergency department for treatment for acute exacerbations

Biomarkers, Trauma, and Sepsis in Pediatrics: A Review

Context: There is a logical connection with biomarkers, trauma, and sepsis. This review paper provides new information and clinical practice implications. Biomarkers are very important especially in pediatrics. Procalcitonin and other biomarkers are helpful in identifying neonatal sepsis, defense mechanisms of the immune system. Pediatric trauma and sepsis is very important both in infants and in children. Stress management both in trauma is based upon the notion that stress causes an immune imbalance in susceptible individuals. Evidence Acquisition: Data sources included studies indexed in PubMed, a meta- analysis, predictive values, research strategies, and quality assessments. A recent paper by one of the authors stated marked increase in serum procalcitonin during the course of a septic process often indicates an exacerbation of the illness, and a decreasing level is a sign of improvement. A review of epidemiologic studies on pediatric soccer patients was also addressed. Keywords for searching included biomarkers, immunity, trauma, and sepsis. Results: Of 50 reviewed articles, 34 eligible articles were selected including biomarkers, predictive values for procalcitonin, identifying children at risk for intra-abdominal injuries, blunt trauma, and epidemiology, a meta-analysis. Of neonatal associated sepsis, the NF-kappa B pathway by inflammatory stimuli in human neutrophils, predictive value of gelsolin for the outcomes of preterm neonates, a meta-analysis interleukin-8 for neonatal sepsis diagnosis. Conclusions: Biomarkers are very important especially in pediatrics. Procalcitonin and other biomarkers are helpful in identifying neonatal sepsis, defense mechanisms, and physiological functions of the immune system. Pediatric trauma and sepsis is very important both in infants and in children. Various topics were covered such as biomarkers, trauma, sepsis, inflammation, innate immunity, role of neutrophils and IL-8, reactive oxygen species, neonatal hypoxia, NF-kappa B related to inflammation. These topics are clearly linked and are very important for pediatricians, pulmonologists, and immunologists in academic centers and in practice

Biomarkers, Trauma, and Sepsis in Pediatrics: A Review

Context: There is a logical connection with biomarkers, trauma, and sepsis. This review paper provides new information and clinical practice implications. Biomarkers are very important especially in pediatrics. Procalcitonin and other biomarkers are helpful in identifying neonatal sepsis, defense mechanisms of the immune system. Pediatric trauma and sepsis is very important both in infants and in children. Stress management both in trauma is based upon the notion that stress causes an immune imbalance in susceptible individuals. Evidence Acquisition: Data sources included studies indexed in PubMed, a meta- analysis, predictive values, research strategies, and quality assessments. A recent paper by one of the authors stated marked increase in serum procalcitonin during the course of a septic process often indicates an exacerbation of the illness, and a decreasing level is a sign of improvement. A review of epidemiologic studies on pediatric soccer patients was also addressed. Keywords for searching included biomarkers, immunity, trauma, and sepsis. Results: Of 50 reviewed articles, 34 eligible articles were selected including biomarkers, predictive values for procalcitonin, identifying children at risk for intra-abdominal injuries, blunt trauma, and epidemiology, a meta-analysis. Of neonatal associated sepsis, the NF-kappa B pathway by inflammatory stimuli in human neutrophils, predictive value of gelsolin for the outcomes of preterm neonates, a meta-analysis interleukin-8 for neonatal sepsis diagnosis. Conclusions: Biomarkers are very important especially in pediatrics. Procalcitonin and other biomarkers are helpful in identifying neonatal sepsis, defense mechanisms, and physiological functions of the immune system. Pediatric trauma and sepsis is very important both in infants and in children. Various topics were covered such as biomarkers, trauma, sepsis, inflammation, innate immunity, role of neutrophils and IL-8, reactive oxygen species, neonatal hypoxia, NF-kappa B related to inflammation. These topics are clearly linked and are very important for pediatricians, pulmonologists, and immunologists in academic centers and in practice

Stress, Trauma, Sepsis, Inflammation, Management in Asthma

This review paper covered stress, management related to asthma, trauma, sepsis, inflammation along with anxiety, and depression that occurs both in women with asthma, traumatic children and adult patients. These areas, induce immune function changes, which can lead to both trauma and pro inflammatory activation known as systemic inflammation response syndrome (SIRS). Related to sepsis.Stress management in trauma is based upon the notion that stress causes an immune imbalance in susceptible individuals. Various topics also covered were the neuroimmune system, oxidative stress, inflammation, innate immunity, the role of NF-kappa B related to inflammation, cytokines, procalcitonin related to sepsis.</p

Review: Immunology of Sinusitis, Trauma, Asthma, and Sepsis

Background This review article is important for allergists/immunologists and otolaryngologists. It discussed chronic rhinosinusitis, epidemiology, pathogenesis, innate adaptive immunology, nuclear factor–kappa B related to inflammation, sepsis, complement, reactive oxygen species, asthma, sinusitis, elderly pathogenesis, oxidative stress, depression, seasonal variation, vitamin D, genetic susceptibility and sepsis, hereditary angioedema related to trauma and stress. Objective The objective of this review is to link chronic rhinosinusitis, epidemiology, innate and adaptive immunology, NF-kappa B related to inflammation, sepsis, complement, reactive oxygen species, asthma and sinusitis. Methods A literature search was conducted from several articles, prospective studies, recent reviews and earlier reports. A synergistic relationship develops between activation of the innate immune system and the loss of organ barrier functions. Many complex factors, such as genetics, physical agents, mediators in the development of organ failure both in asthma, sinusitis, stress, depression and trauma, leading to posttraumatic organ failure. Asthma and sepsis, a common condition encountered in hospital environments remains an important cause of death at intensive care units where allergists/immunologists and otolaryngologists are frequently consulted. The patient's immune surveillance could fail to eliminate the pathogen, allowing it to spread and there is a proinflammatory mediator release with inappropriate activation. Conclusion This review discussed chronic rhinosinusitis, sinusitis related to trauma, the innate and adaptive immunology, NF-kappa B related to inflammation, sepsis, complement, inflammation, reactive oxygen species, asthma pathogenesis, and asthma in the elderly, oxidative stress, depression, seasonal variation and vitamin D, cytokines, genetic susceptibility related to sepsis, hereditary angioedema related to trauma and stress

News and controversies regarding essential tremor

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Is glutamate decarboxylase 2 (GAD2) a genetic link between low birth weight and subsequent development of obesity in children?

Low birth weight is a risk factor for obesity and type 2 diabetes. The fetal insulin hypothesis proposes that low birth weight might be mediated partly by genetic factors that impair insulin secretion/sensitivity during the fetal stage, as shown for glucokinase, the ATP-sensitive K+ channel subunit Kir6.2, and the small heterodimer partner genes. Glutamic acid decarboxylase 2 gene (GAD2) overexpression impairs insulin secretion in animals. Recently, polymorphisms in the GAD2 gene were associated with adult morbid obesity. In the present study, we investigated potential effects of the functional -243 A-->G polymorphism in the 5' promoter region of the GAD2 gene on fetal growth, insulin secretion, food intake, and risk of obesity in 635 French Caucasian severely obese children from three different medical centers. The case/control study confirmed the association between the GAD2 single-nucleotide polymorphism (SNP) -243 A-->G and obesity (odds ratio, 1.25; P = 0.04). In addition, SNP -243 GG children carriers showed a 270 g lower birth weight and a 1.5 cm lower birth height compared with AA carriers (P = 0.009 and P = 0.013, respectively). The relation between birth weight and Z score of BMI was linear in AA carrier children (P = 0.00001) and quadratic (U-shaped curve) in AG/GG carrier children (P = 0.0009). G allele children carriers presented a trend toward lower insulinogenic index with 25% reduction of insulin secretion in response to glucose load compared with A carriers (P = 0.09). Eighteen percent of GG obese carriers vs. 5.7% of AA carriers reported binge eating phenotype (P = 0.04). These results confirm the association between GAD2-243 promoter SNP and the risk for obesity and suggest that GAD2 may be a polygenic component of the complex mechanisms linking birth weight to further risk for metabolic diseases, possibly involving the pleiotropic effect of insulin on fetal growth and later on feeding behavior