Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are ...monogenic autoinflammatory diseases characterized by recurrent fever flares.
We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab.
At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years).
In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).
Asymptomatic and pauci-symptomatic cases contribute to underestimating the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Moreover, we have few studies ...available on the longitudinal follow-up of SARS-CoV-2 antibodies after natural infection. We tested staff members of a Belgian tertiary academic hospital for SARS-CoV-2 IgG, IgM, and IgA antibodies. We analyzed the evolution of IgM and IgG after 6 weeks, and the persistence of IgG after 3 and 10 months. At the first evaluation, 409/3776 (10.8%) participants had a positive SARS-CoV-2 serology. Among initially seropositive participants who completed phases 2 and 3, IgM were still detected after 6 weeks in 53.1% and IgG persisted at 12 weeks in 82.0% (97.5% of those with more than borderline titers). IgG levels were higher and increased over time in symptomatic but were lower and stable in asymptomatic participants. After 10 months, 88.5% of participants had sustained IgG levels (97.0% of those with more than borderline titers).
The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and ...activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations exhibiting such a potent effect and represent a proof-of-concept for the co-administration of two different types of LRAs as a potential strategy to reduce the size of the latent HIV-1 reservoirs.
HIV-1 infection results in the activation of inflammasome that may facilitate viral spread and establishment of viral reservoirs. We evaluated the effects of the caspase-1 inhibitor VX-765 on HIV-1 ...infection in humanized NSG mice engrafted with human CD34
hematopoietic stem cells. Expression of caspase-1, NLRP3, and IL-1β was increased in lymph nodes and bone marrow between day 1 and 3 after HIV-1 infection (mean fold change (FC) of 2.08, 3.23, and 6.05, p<0.001, respectively). IFI16 and AIM2 expression peaked at day 24 and coincides with increased IL-18 levels (6.89 vs 83.19 pg/ml, p=0.004), increased viral load and CD4
T cells loss in blood (p<0.005 and p<0.0001, for the spleen respectively). Treatment with VX-765 significantly reduced TNF-α at day 11 (0.47 vs 2.2 pg/ml, p=0.045), IL-18 at day 22 (7.8 vs 23.2 pg/ml, p=0.04), CD4
T cells (44.3% vs 36,7%, p=0.01), viral load (4.26 vs 4.89 log 10 copies/ml, p=0.027), and total HIV-1 DNA in the spleen (1 054 vs 2 889 copies /10
cells, p=0.029). We demonstrated that targeting inflammasome activation early after infection may represent a therapeutic strategy towards HIV cure to prevent CD4
T cell depletion and reduce immune activation, viral load, and the HIV-1 reservoir formation.
•Post-coronavirus disease 2019 (COVID-19) conditions are common.•The prevalence of tiredness up to 6 months after COVID-19 is high.•The prevalence of shortness of breath up to 6 months after COVID-19 ...is high.•Pulmonary function tests improved during follow-up.•Chest computed tomography scan at 3 months after discharge showed that most images were improved.
Various symptoms and considerable organ dysfunction persist following infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Uncertainty remains about the potential mid- and long-term health sequelae. This prospective study of patients hospitalized with coronavirus disease 2019 (COVID-19) in Liège University Hospital, Belgium aimed to determine the persistent consequences of COVID-19.
Patients admitted to the University Hospital of Liège with moderate-to-severe confirmed COVID-19, discharged between 2 March and 1 October 2020, were recruited prospectively. Follow-up at 3 and 6 months after hospital discharge included demographic and clinical data, biological data, pulmonary function tests (PFTs) and high-resolution computed tomography (CT) scans of the chest.
In total, 199 individuals were included in the analysis. Most patients received oxygen supplementation (80.4%). Six months after discharge, 47% and 32% of patients still had exertional dyspnoea and fatigue. PFTs at 3-month follow-up revealed a reduced diffusion capacity of carbon monoxide (mean 71.6 ± 18.6%), and this increased significantly at 6-month follow-up (P<0.0001). Chest CT scans showed a high prevalence (68.9% of the cohort) of persistent abnormalities, mainly ground glass opacities. Duration of hospitalization, intensive care unit admission and mechanical ventilation were not associated with the persistence of symptoms 3 months after discharge.
The prevalence of persistent symptoms following hospitalization with COVID-19 is high and stable for up to 6 months after discharge. However, biological, functional and iconographic abnormalities improved significantly over time.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic pathology in Western countries. It encompasses a spectrum of conditions ranging from simple steatosis to more severe and ...progressive non-alcoholic steatohepatitis (NASH) that can lead to hepatocellular carcinoma (HCC). Obesity and related metabolic syndrome are important risk factors for the development of NAFLD, NASH and HCC. DUSP3 is a small dual-specificity protein phosphatase with a poorly known physiological function. We investigated its role in metabolic syndrome manifestations and in HCC using a mouse knockout (KO) model. While aging, DUSP3-KO mice became obese, exhibited insulin resistance, NAFLD and associated liver damage. These phenotypes were exacerbated under high fat diet (HFD). In addition, DEN administration combined to HFD led to rapid HCC development in DUSP3-KO compared to wild type (WT) mice. DUSP3-KO mice had more serum triglycerides, cholesterol, AST and ALT compared to control WT mice under both regular chow diet (CD) and HFD. The level of fasting insulin was higher compared to WT mice, though, fasting glucose as well as glucose tolerance were normal. At the molecular level, HFD led to decreased expression of DUSP3 in WT mice. DUSP3 deletion was associated with increased and consistent phosphorylation of the insulin receptor (IR) and with higher activation of the downstream signaling pathway. In conclusion, our results support a new role for DUSP3 in obesity, insulin resistance, NAFLD and liver damage.
Background. To date, there is no commercially available vaccine to prevent infectious mononucleosis, a disease frequently induced by Epstein-Barr virus (EBV) infection in adolescents or adults devoid ...of preexisting immunity to the virus. Methods. A total of 181 EBV-seronegative, healthy, young adult volunteers were randomized in a double-blind fashion to receive either placebo or a recombinant EBV subunit glycoprotein 350 (gp350)/aluminum hydroxide and 3-O-desacyl-4′-monophosphoryl lipid A (AS04) candidate vaccine in a 3-dose regimen. Results. The vaccine had demonstrable efficacy (mean efficacy rate, 78.0% 95% confidence interval {CI}, 1.0%–96.0%) in preventing the development of infectious mononucleosis induced by EBV infection, but it had no efficacy in preventing asymptomatic EBV infection. One month after receipt of the final dose of gp350 vaccine, 98.7% of subjects showed seroconversion to anti-gp350 antibodies (95% CI, 85.5%–97.9%), and they remained anti-gp350 antibody positive for >18 months. Furthermore, there were no concerns regarding the safety or reactogenicity of the gp350/AS04 vaccine. Conclusion. These data support the clinical feasibility of using an EBV vaccine to prevent infectious mononucleosis. Trial registration. ClinicalTrials.gov identifier: NCT00430534.
Background The dynamics of the spread of cholera epidemics in the Democratic Republic of the Congo (DRC), from east to west and within western DRC, have been extensively studied. However, the drivers ...of these spread processes remain unclear. We therefore sought to better understand the factors associated with these spread dynamics and their potential underlying mechanisms. Methods In this eco-epidemiological study, we focused on the spread processes of cholera epidemics originating from the shores of Lake Kivu, involving the areas bordering Lake Kivu, the areas surrounding the lake areas, and the areas out of endemic eastern DRC (eastern and western non-endemic provinces). Over the period 2000-2018, we collected data on suspected cholera cases, and a set of several variables including types of conflicts, the number of internally displaced persons (IDPs), population density, transportation network density, and accessibility indicators. Using multivariate ordinal logistic regression models, we identified factors associated with the spread of cholera outside the endemic eastern DRC. We performed multivariate Vector Auto Regressive models to analyze potential underlying mechanisms involving the factors associated with these spread dynamics. Finally, we classified the affected health zones using hierarchical ascendant classification based on principal component analysis (PCA). Findings The increase in the number of suspected cholera cases, the exacerbation of conflict events, and the number of IDPs in eastern endemic areas were associated with an increased risk of cholera spreading outside the endemic eastern provinces. We found that the increase in suspected cholera cases was influenced by the increase in battles at lag of 4 weeks, which were influenced by the violence against civilians with a 1-week lag. The violent conflict events influenced the increase in the number of IDPs 4 to 6 weeks later. Other influences and uni- or bidirectional causal links were observed between violent and non-violent conflicts, and between conflicts and IDPs. Hierarchical clustering on PCA identified three categories of affected health zones: densely populated urban areas with few but large and longer epidemics; moderately and accessible areas with more but small epidemics; less populated and less accessible areas with more and larger epidemics. Conclusion Our findings argue for monitoring conflict dynamics to predict the risk of geographic expansion of cholera in the DRC. They also suggest areas where interventions should be appropriately focused to build their resilience to the disease.
Abstract
Background
Combination antiretroviral therapy (cART) has dramatically extended the life expectancy of people living with HIV-1 and improved their quality of life. There is nevertheless no ...cure for HIV-1 infection since HIV-1 persists in viral reservoirs of latently infected CD4
+
T cells. cART does not eradicate HIV-1 reservoirs or restore cytotoxic natural killer (NK) cells which are dramatically reduced by HIV-1 infection, and express the checkpoint inhibitors NKG2A or KIR2DL upregulated after HIV-1 infection. Cytotoxic NK cells expressing the homing receptor CXCR5 were recently described as key subsets controlling viral replication.
Methods
We designed and evaluated the potency of “Natural killer activating Multimeric immunotherapeutic compleXes”, called as NaMiX, combining multimers of the IL-15/IL-15Rα complex with an anti-NKG2A or an anti-KIR single-chain fragment variable (scFv) to kill HIV-1 infected CD4
+
T cells. The oligomerization domain of the C4 binding protein was used to associate the IL-15/IL-15Rα complex to the scFv of each checkpoint inhibitor as well as to multimerize each entity into a heptamer (α form) or a dimer (β form). Each α or β form was compared in different in vitro models using one-way ANOVA and post-hoc Tukey’s tests before evaluation in humanized NSG tg-huIL-15 mice having functional NK cells.
Results
All NaMiX significantly enhanced the cytolytic activity of NK and CD8
+
T cells against Raji tumour cells and HIV-1
+
ACH-2 cells by increasing degranulation, release of granzyme B, perforin and IFN-γ. Targeting NKG2A had a stronger effect than targeting KIR2DL due to higher expression of NKG2A on NK cells. In viral inhibition assays, NaMiX initially increased viral replication of CD4
+
T cells which was subsequently inhibited by cytotoxic NK cells. Importantly, anti-NKG2A NaMiX enhanced activation, cytotoxicity, IFN-γ production and CXCR5 expression of NK cells from HIV-1 positive individuals. In humanized NSG tg-huIL-15 mice, we confirmed enhanced activation, degranulation, cytotoxicity of NK cells, and killing of HIV-1 infected cells from mice injected with the anti-NKG2A.α NaMiX, as compared to control mice, as well as decreased total HIV-1 DNA in the lung.
Conclusions
NK cell-mediated killing of HIV-1 infected cells by NaMiX represents a promising approach to support HIV-1 cure strategies.
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