Transmitted drug resistance, selection of resistance mutations and moderate antiretroviral efficacy in HIV-2: Analysis of the HIV-2 Belgium and Luxembourg database

BACKGROUND: Guidelines established for the treatment of HIV-1 infection and genotype interpretation do not apply for HIV-2. Data about antiretroviral (ARV) drug efficacy and resistance mutations is scarce. METHODS: Clinical data about HIV-2 infected patients in Belgium and Luxembourg were collected and the effect of ARV therapy on plasma viral load and CD4 counts were analysed. Viral RNA encoding for protease (PR) and reverse transcriptase (RT) from ARV-naive and treated patients were sequenced. RESULTS: Sixty-five HIV-2 infected patients were included in this cohort. Twenty patients were treated with 25 different ARV combinations in a total of 34 regimens and six months after the start of ARV therapy, only one third achieved viral load suppression. All of these successful regimens bar one contained protease inhibitors (PIs). Mean CD4 gains in the group of viral load suppressors and the group of patients treated with PI-containing regimens were respectively significantly higher than in the group of non-suppressors and the group of PI-sparing regimens. The most frequent mutations selected under therapy (compared to HIV-2 ROD) were V71I, L90M and I89V within PR. Within RT, they were M184V, Q151M, V111I and K65R. All of these mutations, except K65R and M184V, were also found in variable proportions in ARV-naive patients. CONCLUSION: Despite a high rate of ARV treatment failure, better virological and immunological results were achieved with PI-containing regimens. The analysis of polymorphic positions and HIV-2 specific mutations selected during therapy showed for the first time that transmission of drug resistant viruses has occurred in Belgium and Luxembourg. The high heterogeneity in ARV combinations reflects a lack of guidelines for the treatment of HIV-2 infection

Objective assessment of stored blood quality by deep learning

Stored red blood cells (RBCs) are needed for life-saving blood transfusions, but they undergo continuous degradation. RBC storage lesions are often assessed by microscopic examination or biochemical and biophysical assays, which are complex, time-consuming, and destructive to fragile cells. Here we demonstrate the use of label-free imaging flow cytometry and deep learning to characterize RBC lesions. Using brightfield images, a trained neural network achieved 76.7% agreement with experts in classifying seven clinically relevant RBC morphologies associated with storage lesions, comparable to 82.5% agreement between different experts. Given that human observation and classification may not optimally discern RBC quality, we went further and eliminated subjective human annotation in the training step by training a weakly supervised neural network using only storage duration times. The feature space extracted by this network revealed a chronological progression of morphological changes that better predicted blood quality, as measured by physiological hemolytic assay readouts, than the conventional expert-assessed morphology classification system. With further training and clinical testing across multiple sites, protocols, and instruments, deep learning and label-free imaging flow cytometry might be used to routinely and objectively assess RBC storage lesions. This would automate a complex protocol, minimize laboratory sample handling and preparation, and reduce the impact of procedural errors and discrepancies between facilities and blood donors. The chronology-based machine-learning approach may also improve upon humans’ assessment of morphological changes in other biomedically important progressions, such as differentiation and metastasis

State-of-the-art microscopy to understand islets of Langerhans:what to expect next?

The discovery of Langerhans and microscopic description of islets in the pancreas were crucial steps in the discovery of insulin. Over the past 150 years, many discoveries in islet biology and type 1 diabetes have been made using powerful microscopic techniques. In the past decade, combination of new probes, animal and tissue models, application of new biosensors and automation of light and electron microscopic methods and other (sub)cellular imaging modalities have proven their potential in understanding the beta cell under (patho)physiological conditions. The imaging evolution, from fluorescent jellyfish to real-time intravital functional imaging, the revolution in automation and data handling and the increased resolving power of analytical imaging techniques are now converging. Here, we review innovative approaches that address islet biology from new angles by studying cells and molecules at high spatiotemporal resolution and in live models. Broad implementation of these cellular imaging techniques will shed new light on cause/consequence of (mal)function in islets of Langerhans in the years to come

HIV-2 Integrase Variation in Integrase Inhibitor-Naïve Adults in Senegal, West Africa

Antiretroviral therapy for HIV-2 infection is hampered by intrinsic resistance to many of the drugs used to treat HIV-1. Limited studies suggest that the integrase inhibitors (INIs) raltegravir and elvitegravir have potent activity against HIV-2 in culture and in infected patients. There is a paucity of data on genotypic variation in HIV-2 integrase that might confer intrinsic or transmitted INI resistance.We PCR amplified and analyzed 122 HIV-2 integrase consensus sequences from 39 HIV-2-infected, INI-naive adults in Senegal, West Africa. We assessed genetic variation and canonical mutations known to confer INI-resistance in HIV-1.No amino acid-altering mutations were detected at sites known to be pivotal for INI resistance in HIV-1 (integrase positions 143, 148 and 155). Polymorphisms at several other HIV-1 INI resistance-associated sites were detected at positions 72, 95, 125, 154, 165, 201, 203, and 263 of the HIV-2 integrase protein.Emerging genotypic and phenotypic data suggest that HIV-2 is susceptible to the new class of HIV integrase inhibitors. We hypothesize that intrinsic HIV-2 integrase variation at "secondary" HIV-1 INI-resistance sites may affect the genetic barrier to HIV-2 INI resistance. Further studies will be needed to assess INI efficacy as part of combination antiretroviral therapy in HIV-2-infected patients

Neurocognition and quality of life after reinitiating antiretroviral therapy in children randomized to planned treatment interruption

Objective: Understanding the effects of antiretroviral treatment (ART) interruption on neurocognition and quality of life (QoL) are important for managing unplanned interruptions and planned interruptions in HIV cure research. Design: Children previously randomized to continuous (continuous ART, n=41) vs. planned treatment interruption (PTI, n=47) in the Pediatric European Network for Treatment of AIDS (PENTA) 11 study were enrolled. At study end, PTI children resumed ART. At 1 and 2 years following study end, children were assessed by the coding, symbol search and digit span subtests of Wechsler Intelligence Scale for Children (6-16 years old) or Wechsler Adult Intelligence Scale ( 6517 years old) and by Pediatrics QoL questionnaires for physical and psychological QoL. Transformed scaled scores for neurocognition and mean standardized scores for QoL were compared between arms by t-test and Mann-Whitney U test, respectively. Scores indicating clinical concern were compared (<7 for neurocognition and <70 for QoL tests). Results: Characteristics were similar between arms with a median age of 12.6 years, CD4 + of 830 cells/\u3bcl and HIV RNA of 1.7 log 10 copies/ml. The median cumulative ART exposure was 9.6 in continuous ART vs. 7.7 years in PTI (P=0.02). PTI children had a median of 12 months off ART and had resumed ART for 25.2 months at time of first assessment. Neurocognitive scores were similar between arms for all tests. Physical and psychological QoL scores were no different. About 40% had low neurocognitive and QoL scores indicating clinical concern. Conclusion: No differences in information processing speed, sustained attention, short-term memory and QoL functioning were observed between children previously randomized to continuous ART vs. PTI in the PENTA 11 trial

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Contribution de l'analyse RBS pour la caractérisation de couches minces PVD-PCVD utilisées dans des applications mécaniques

27-30 Sept. 2016International audienceno abstrac

Differential Gene Expression in Response to Mechanical Wounding and Insect Feeding in Arabidopsis

Wounding in multicellular eukaryotes results in marked changes in gene expression that contribute to tissue defense and repair. Using a cDNA microarray technique, we analyzed the timing, dynamics, and regulation of the expression of 150 genes in mechanically wounded leaves of Arabidopsis. Temporal accumulation of a group of transcripts was correlated with the appearance of oxylipin signals of the jasmonate family. Analysis of the coronatine-insensitive coi1-1 Arabidopsis mutant that is also insensitive to jasmonate allowed us to identify a large number of COI1-dependent and COI1-independent wound-inducible genes. Water stress was found to contribute to the regulation of an unexpectedly large fraction of these genes. Comparing the results of mechanical wounding with damage by feeding larvae of the cabbage butterfly (Pieris rapae) resulted in very different transcript profiles. One gene was specifically induced by insect feeding but not by wounding; moreover, there was a relative lack of water stress–induced gene expression during insect feeding. These results help reveal a feeding strategy of P. rapae that may minimize the activation of a subset of water stress–inducible, defense-related genes

Immunovirological response to triple nucleotide reverse-transcriptase inhibitors and ritonavir-boosted protease inhibitors in treatment-naive HIV-2-infected patients: The ACHIEV2E Collaboration Study Group

Contains fulltext : 97014.pdf (publisher's version ) (Open Access)BACKGROUND: Triple nucleoside reverse-transcriptase inhibitors (NRTIs) are recommended by the World Health Organization as first-line regimen in treatment-naive HIV-2-infected patients. However, ritonavir-boosted protease inhibitor (PI/r)-containing regimens are frequently prescribed. In the absence of previous randomized trials, we retrospectively compared these regimens in observational cohorts. METHODS: HIV-2-infected patients from 7 European cohorts who started triple NRTI or PI/r since January 1998 were included. Piecewise linear models were used to estimate CD4 cell count and plasma HIV-2 RNA level slopes, differentiating an early phase (until end of month 3) and a second phase (months 4-12). On-treatment analyses censored data at major treatment modification and systematically at month 12. RESULTS: Forty-four patients started triple NRTI therapy and 126 started PI/r therapy. Overall, the median CD4 cell count was 191 cells/mm(3) and the median plasma HIV-2 RNA level was >/=2.7 log(10) copies/ml in 61% of the patients at combination antiretroviral therapy (cART) initiation; the median duration of the first cART was 20 months, not differing between groups. PI/r regimens were associated with better CD4 cell count and HIV-2 RNA level outcomes, compared with NRTI regimens. Estimated CD4 cell count slopes were +6 and +12 cells/mm(3)/month during the early phase (P = .22), and -60 cells/mm(3)/year versus +76 cells/mm(3)/year during the second phase (P = .002), for triple NRTI and PI/r, respectively. Estimated mean HIV-2 RNA levels at month 12 in patients with detectable viremia at cART initiation were 4.0 and 2.2 log(10) copies/ml, respectively (P = .005). CONCLUSIONS: In this observational study, PI/r-containing regimens showed superior efficacy over triple NRTI regimens as first-line therapy in HIV-2-infected patients

PVD aluminium alloy coatings: Environmentally friendly alternative to protect steel parts against corrosion

International audienceIn the automotive and aeronautic industries, security is of prime importance and so corrosion prevention is essential. Steel parts were once protected with deposits such as cadmium or zinc-nickel produced using a chromatation treatment but recent environmental directives dictate that these methods are no longer acceptable. Aluminium sacrificial coatings have excellent corrosion behaviour but unfortunately they have poor mechanical characteristics and a fast dissolution rate. The present study investigated a possible solution: alloying the aluminium with a more noble element, chromium, in order to decrease the sacrificial galvanic effect of the deposit and therefore improve its lifetime. The corrosion protection afforded by such coatings in relation to their structure and mechanical properties was investigated. The coatings were produced on carbon steel by a vacuum PVD arc evaporation process at a pilot scale. Intrinsic electrochemical properties were determined on pure materials and on layers deposited on glass strip. Several elaboration configurations (pure as well as composite targets) were investigated. In most cases the coatings were stratified and composed of pure aluminium and numerous hardened AlxCry intermetallic phases. Chromium enrichment of aluminium based coatings induces not only a beneficial hardening effect on the surface characteristics (> 700 HV) but also significantly improves the corrosion behaviour of the coated pieces (increasing lifetime by up to three times compared to pure Aluminium)