Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers

Objective: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. Methods: HICs were identified in COHERE on the basis of \ue2\u89\ua55 consecutive viral loads (VL) \ue2\u89\ua4500 copies/mL over \ue2\u89\ua51 year whilst ART-naive, with the last VL \ue2\u89\ua4500 copies/mL measured \ue2\u89\ua55 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. Results: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. Discussion: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs

ABIN-2, un nouvel activateur de NF-kappaB en réponse aux agents génotoxiques : implication de la poly-ubiquitination

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers

Objective: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. Methods: HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. Results: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. Discussion: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.0SCOPUS: ar.jinfo:eu-repo/semantics/publishe

First Description of a Yersinia pseudotuberculosis Clonal Outbreak in France, Confirmed Using a New Core Genome Multilocus Sequence Typing Method

International audienceYersinia pseudotuberculosis is an enteric pathogen causing mild enteritis that can lead to mesenteric adenitis in children and septicemia in elderly patients. Most cases are sporadic, but outbreaks have already been described in different countries. We report for the first time a Y. pseudotuberculosis clonal outbreak in France, that occurred in 2020. An epidemiological investigation based on food queries pointed toward the consumption of tomatoes as the suspected source of infection. The Yersinia National Reference Laboratory (YNRL) developed a new cgMLST scheme with 1,921 genes specific to Y. pseudotuberculosis that identified the clustering of isolates associated with the outbreak and allowed to perform molecular typing in real time. In addition, this method allowed to retrospectively identify isolates belonging to this cluster from earlier in 2020. This method, which does not require specific bioinformatic skills, is now used systematically at the YNRL and proves to display an excellent discriminatory power and is available to the scientific community

A20-binding Inhibitor of Nuclear Factor-κB (NF-κB)-2 (ABIN-2) Is an Activator of Inhibitor of NF-κB (IκB) Kinase α (IKKα)-mediated NF-κB Transcriptional Activity

International audienceNF-κB transcription factors are pivotal players in controlling inflammatory and immune responses, as well as cell proliferation and apoptosis. Aberrant regulation of NF-κB and the signaling pathways that regulate its activity have been involved in various pathologies, particularly cancers, as well as inflammatory and autoimmune diseases. NF-κB activation is tightly regulated by the IκB kinase (IKK) complex, which is composed of two catalytic subunits IKKα and IKKβ, and a regulatory subunit IKKγ/NEMO. Although IKKα and IKKβ share structural similarities, IKKα has been shown to have distinct biological functions. However, the molecular mechanisms that modulate IKKα activity have not yet been fully elucidated. To understand better the regulation of IKKα activity, we purified IKKα-associated proteins and identified ABIN-2. Here, we demonstrate that IKKα and IKKβ both interact with ABIN-2 and impair its constitutive degradation by the proteasome. Nonetheless, ABIN-2 enhances IKKα-but not IKKβ-mediated NF-κB activation by specifically inducing IKKα autophosphorylation and kinase activity. Furthermore, we found that ABIN-2 serine 146 is critical for the ABIN-2-dependent IKKα transcriptional up-regulation of specific NF-κB target genes. These results imply that ABIN-2 acts as a positive regulator of NF-κB-dependent transcription by activating IKKα

Colonization of Extended-Spectrum- β -Lactamase-and NDM-1-Producing Enterobacteriaceae among Pregnant Women in the Community in a Low-Income Country: a Potential Reservoir for Transmission of Multiresistant Enterobacteriaceae to Neonates

International audienceThe spread of extended-spectrum-␤-lactamase-producing Enterobacteriaceae (ESBL-PE) in low-income countries, where the burden of neonatal sepsis is high, may have a serious impact on neonatal mortality rates. Given the potential for mother-to-child transmission of multiresistant bacteria, this study investigated the ESBL-PE rectal colonization among pregnant women at delivery in the community in Madagascar and estimated a prevalence of 18.5% (95% confidence interval, 14.5% to 22.6%). One strain of Klebsiella pneumoniae isolated was also a New Delhi metallo-␤-lactamase-1 (NDM-1) producer. S evere bacterial infections are responsible for a large number of neonatal deaths in low-income countries (LICs) (1, 2), with Enterobacteriaceae most frequently isolated in neonatal sepsis (3, 4). The production of plasmid-borne extended-spectrum ␤-lacta-mases (ESBL) is the main mechanism of resistance against expanded spectrum cephalosporins (ESC) among Enterobacteria-ceae, with the CTX-M-15 variant being the most common enzyme (5). In LICs, where neonatal sepsis caused by ESBL-producing Enterobacteriaceae (ESBL-PE) may be associated with higher fatality rates (6), colonized mothers could represent a source of transmission to neonates. The objectives of this study were to estimate the prevalence of ESBL-PE rectal colonization among pregnant women in Madagascar in an urban area, Antananarivo, and a semirural area, Moramanga, and to identify associated risk factors. This study was conducted in the context of an international pediatric cohort, the BIRDY (bacterial infections and antibiotic resistance disease among young children in low-income countries) program, approved by the Ethics Committees of Ministry of Health, Madagascar, and Institut Pasteur, France. All pregnant women living in the study areas were identified by medical or community workers and enrolled after giving written informed consent. A stool sample was taken at delivery for ESBL-PE screening. Among the women enrolled, 356 gave birth between June 2013 and March 2014 and were included in the present study. A risk factor analysis was conducted on a subset of 231 women who delivered during a 6-month period (. Sociodemographic characteristics, previous health care exposure, and antibiotic consumption (collected with prescription documents, remaining tablets, or visual aid) were recorded. Fresh stools were plated onto Drigalski agar supplemented with 3 mg/liter of ceftriaxone at the clinical laboratory of Institut Pasteur of Madagascar. Plates were incubated for 24 to 48 h at 37°C. Every oxidase and Gram-negative colony type wa

Evolution of outcomes for patients hospitalised during the first 9 months of the SARS-CoV-2 pandemic in France: A retrospective national surveillance data analysis.

Background: As SARS-CoV-2 continues to spread, a thorough characterisation of healthcare needs and patient outcomes, and how they have changed over time, is essential to inform planning. Methods: We developed a probabilistic framework to analyse detailed patient trajectories from 198,846 hospitalisations in France during the first nine months of the pandemic. Our model accounts for the varying age- and sex- distribution of patients, and explore changes in outcome probabilities as well as length of stay. Findings: We found that there were marked changes in the age and sex of hospitalisations over the study period. In particular, the proportion of hospitalised individuals that were >80y varied between 27% and 48% over the course of the epidemic, and was lowest during the inter-peak period. The probability of hospitalised patients entering ICU dropped from 0·25 (0·24-0·26) to 0·13 (0·12-0·14) over the four first months as case numbers fell, before rising to 0·19 (0·19-0·20) during the second wave. The probability of death followed a similar trajectory, falling from 0·25 (0·24-0·26) to 0·10 (0·09-0·11) after the first wave before increasing again during the second wave to 0·19 (0·18-0·19). Overall, we find both the probability of death and the probability of entering ICU were significantly correlated with COVID-19 ICU occupancy. Interpretation: There are large scale trends in patients outcomes by age, sex and over time. These need to be considered in ongoing healthcare planning efforts. Funding: INCEPTION

Evolution of outcomes for patients hospitalised during the first 9 months of the SARS-CoV-2 pandemic in France: A retrospective national surveillance data analysis.

BACKGROUND: As SARS-CoV-2 continues to spread, a thorough characterisation of healthcare needs and patient outcomes, and how they have changed over time, is essential to inform planning. METHODS: We developed a probabilistic framework to analyse detailed patient trajectories from 198,846 hospitalisations in France during the first nine months of the pandemic. Our model accounts for the varying age- and sex- distribution of patients, and explore changes in outcome probabilities as well as length of stay. FINDINGS: We found that there were marked changes in the age and sex of hospitalisations over the study period. In particular, the proportion of hospitalised individuals that were >80y varied between 27% and 48% over the course of the epidemic, and was lowest during the inter-peak period. The probability of hospitalised patients entering ICU dropped from 0·25 (0·24-0·26) to 0·13 (0·12-0·14) over the four first months as case numbers fell, before rising to 0·19 (0·19-0·20) during the second wave. The probability of death followed a similar trajectory, falling from 0·25 (0·24-0·26) to 0·10 (0·09-0·11) after the first wave before increasing again during the second wave to 0·19 (0·18-0·19). Overall, we find both the probability of death and the probability of entering ICU were significantly correlated with COVID-19 ICU occupancy. INTERPRETATION: There are large scale trends in patients outcomes by age, sex and over time. These need to be considered in ongoing healthcare planning efforts. FUNDING: INCEPTION

Frequent engagement of RelB activation is critical for cell survival in multiple myeloma.

The NF-κB family of transcription factors has emerged as a key player in the pathogenesis of multiple myeloma (MM). NF-κB is activated by at least two major signaling pathways. The classical pathway results in the activation of mainly RelA containing dimers, whereas the alternative pathway leads to the activation of RelB/p52 and RelB/p50 heterodimers. Activating mutations in regulators of the alternative pathway have been identified in 17% of MM patients. However, the status of RelB activation per se and its role in the regulation of cell survival in MM has not been investigated. Here, we reveal that 40% of newly diagnosed MM patients have a constitutive RelB DNA-binding activity in CD138(+) tumor cells, and we show an association with increased expression of a subset of anti-apoptotic NF-κB target genes, such as cIAP2. Furthermore, we demonstrate that RelB exerts a crucial anti-apoptotic activity in MM cells. Our findings indicate that RelB activation is key for promoting MM cell survival through the upregulation of anti-apoptotic proteins. Altogether, our study provides the framework for the development of new molecules targeting RelB in the treatment of MM

Hyperspectral imaging for the evaluation of lithology and the monitoring of hydrocarbons in environmental samples

International audienc