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Respiratory viruses, including influenza virus and SARS-CoV-2, are transmitted by the airborne route. Air filtration and ventilation mechanically reduce the concentration of airborne viruses and are necessary tools for disease mitigation. However, they ignore the potential impact of the chemical environment surrounding aerosolized viruses, which determines the aerosol pH. Atmospheric aerosol gravitates toward acidic pH, and enveloped viruses are prone to inactivation at strong acidity levels. Yet, the acidity of expiratory aerosol particles and its effect on airborne virus persistence have not been examined. Here, we combine pH dependent inactivation rates of influenza A virus (IAV) and SARSCoV-2 with microphysical properties of respiratory fluids using a biophysical aerosol model. We find that particles exhaled into indoor air (with relative humidity >= 50%) become mildly acidic (pH similar to 4), rapidly inactivating IAV within minutes, whereas SARSCoV-2 requires days. If indoor air is enriched with nonhazardous levels of nitric acid, aerosol pH drops by up to 2 units, decreasing 99%-inactivation times for both viruses in small aerosol particles to below 30 s. Conversely, unintentional removal of volatile acids from indoor air may elevate pH and prolong airborne virus persistence. The overlooked role of aerosol acidity has profound implications for virus transmission and mitigation strategies., Environmental Science & Technology, 57 (1), ISSN:0013-936X, ISSN:1520-5851

Objective: Persistence of the viral reservoir is the main barrier to curing HIV. Initiation of ART during acute HIV infection can limit the size and diversity of the reservoir. In depth characterization of the reservoir in individuals who initiate ART during acute infection will be critical for clinical trial design and cure strategies. Methods: Four cohortswith participantswhoinitiatedARTduring acute infection or during chronic infectionwere enrolled in a cross-sectional, noninterventional study.Viral reservoir was evaluated by the Intact Proviral DNA Assay (IPDA), the Total HIVDNA Assay (THDA) and the Quantitative Viral Outgrowth Assay (QVOA). Viral diversity and susceptibility to V3-glycan bNAbs were determined by genotyping of the viral envelope gene. Results: Participants who initiated ART during the acute Fiebig I-IV stages had lower level of total HIV DNA than participants who initiated ART during chronic infection whereas no difference was observed in intact HIV DNA or outgrowth virus. Participants who initiated ART during Fiebig I-IV also had lower viral diversity and appeared to have higher susceptibility to bNAbs than participants initiating ART during chronic infection. Conclusion: Individuals initiating ART during Fiebig I-IV had small viral reservoirs, low viral diversity, and high susceptibility to bNAbs, and would be an optimal target population for proof-of-concept HIV cure trials.

INTRODUCTION HIV infection leads to a persistent expansion of terminally CD8T cells and CD8T suppressor-cells, a marker of chronic immune activation leading to a low CD4:CD8 ratio that may persist in the presence of potent ART and regained CD4 helper cells. It remains unclear whether a low CD4:CD8 ratio is associated with cardiovascular diseases (CVD). METHODS We conducted an observational cohort study to investigate the association of immune depression and activation as characterized by the proxy of the CD4:CD8 ratio on the hazard of coronary heart disease (CHD) and stroke among treated individuals living with HIV, while accounting for viral load and known risk factors for CVD and exposure to abacavir or protease inhibitors. We used Cox proportional hazard models with time-dependent cumulative and lagged exposures to account for time-evolving risk factors and avoid reverse causality. RESULTS CD4, CD8 and CD4:CD8 immunological markers were not associated with an increased hazard for CHD. CD8 cell count lagged at 12 months above 1000 cells per μl increased the hazard of stroke, after adjusting for socio-demographics, cardiovascular risk factors and exposure to specific types of antiretroviral drugs. CONCLUSIONS This analysis of treated HIV infected individuals within a large cohort with long-term follow-up does not provide evidence for a prognostic role of immune dysregulation regarding CHD. However, increased CD8 cell count may be a moderate risk factor for stroke. Early detection and treatment of HIV-infected individuals are crucial for an optimal immune restoration and a limited CD8 cells expansion.

Pandemics are caused by novel pathogens to which pre-existing antibody immunity is lacking. Under these circumstances, the body must rely on innate interferon-mediated defenses to limit pathogen replication and allow development of critical humoral protection. Here, we highlight studies on disease susceptibility during H1N1 influenza and COVID-19 (SARS-CoV-2) pandemics. An emerging concept is that genetic and non-genetic deficiencies in interferon system components lead to uncontrolled virus replication and severe illness in a subset of people. Intriguingly, new findings suggest that individuals with autoantibodies neutralizing the antiviral function of interferon are at increased risk of severe COVID-19. We discuss key questions surrounding how such autoantibodies develop and function, as well as the general implications of diagnosing interferon deficiencies for personalized therapies.

Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies.

Background Several studies have reported suboptimal efficacy of direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV) subtypes endemic to sub-Saharan Africa (SSA) and Southeastern Asia (SEA). The extent of this issue in individuals with human immunodeficiency virus (HIV)/HCV from SSA or SEA residing in Europe is unknown. Methods We retrospectively analyzed data from several prospective European cohorts of people living with HIV. We included individuals with HIV/HCV who originated from SSA or SEA, were treated with interferon-free DAAs, and had an available HCV RNA result ≥12 weeks after the end of treatment. The primary outcome was sustained virological response at least 12 weeks after the end of treatment (SVR12). Results Of the 3293 individuals with HIV/HCV treated with DAA and with available SVR12 data, 142 were from SSA (n = 64) and SEA (n = 78). SVR12 was achieved by 60 (94% [95% confidence interval {CI}, 86%–98%]) individuals from SSA and 76 (97% [95% CI, 92%–99%]) from SEA. The genotypes of the 6 individuals failing DAA treatment were 2, 3a, 3h, 4a, 4c, and 6j. For 2 of the 4 unsuccessfully treated individuals with available sequence data at treatment failure, NS5A resistance-associated substitutions were present (30R/93S in an individual with genotype 4c and 31M in an individual with genotype 6j). Conclusions SVR12 rates were high in individuals with HIV/HCV residing in Europe and originating from regions where intrinsically NS5A-resistant HCV strains are endemic. HCV elimination for this population in Europe is unlikely to be hampered by suboptimal DAA efficacy.

BackgroundHepatitis delta virus (HDV) infection accelerates the progression of liver disease in persons living with HIV and hepatitis B virus (HBV) coinfection. We explored the association between HDV infection and alanine aminotransferase (ALT) elevation during tenofovir-containing antiretroviral treatment among persons living with HIV/HBV.Materials and methodsWe included persons living with HIV/HBV with and without HDV starting tenofovir-containing antiretroviral therapy (ART) in three European cohorts with at least 18 months of follow-up. We defined HDV infection as a positive anti-HDV antibody test. We assessed risk factors for ALT elevation ≥ 1.25x upper limit of normal after 5 years of tenofovir-treatment using multivariate logistic regression models. The difference in ALT trends between individuals with and without HDV was evaluated using linear mixed effects models.Results61/518 (11.8%) participants had an HDV infection. Among individuals with HDV, 63.9% had ALT elevation after 2 years and 55.6% after 5 years of tenofovir, whereas the estimates were 34.1% after two and 27.0% after 5 years in those without HDV. HDV coinfection (adjusted odds ratio 2.8, 95% confidence interval 1.4–5.8) and obesity at baseline (adjusted odds ratio 3.2, 95% confidence interval 1.2–8.0) were associated with ALT elevation after 5 years of tenofovir therapy. Mean ALT levels were consistently higher during follow-up in participants with HDV compared to those without HDV.ConclusionPersistent ALT elevation is common in persons living with HIV/HBV in Europe despite adequate HBV therapy. HDV coinfection and obesity are independent risk factors for persistent ALT elevation during long-term tenofovir treatment.

Background We previously showed that anticholinergic (ACH) medications contribute to self-reported neurocognitive impairment (NCI) in elderly people with human immunodeficiency virus (PWH). The current cross-sectional study further evaluated the effect of ACH and sedative drugs on neurocognitive function in PWH who underwent comprehensive neuropsychological evaluation. Methods A medication review was performed in PWH enrolled in the prospective Neurocognitive Assessment in Metabolic and Aging Cohort within the Swiss HIV Cohort Study. Neurocognitive functions were analyzed in 5 domains (motor skills, speed of information, attention/working memory, executive functions, and verbal learning memory). The effect of ACH and sedative medications on neurocognitive functioning was evaluated using linear regression models for the continuous (mean z-score) outcome and multivariable logistic regression models for the binary (presence/absence) outcome. Results A total of 963 PWH (80% male, 92% Caucasian, 96% virologically suppressed, median age 52) were included. Fourteen percent of participants were prescribed ≥1 ACH medication and 9% were prescribed ≥1 sedative medication. Overall, 40% of participants had NCI. Sedative medication use was associated with impaired attention/verbal learning and ACH medication use with motor skills deficits both in the continuous (mean z-score difference -0.26 to -0.14, P

Influenza A viruses (IAV) are a major burden for human health and thus the topic of intense research efforts. The entry of IAV into host cells is of particular interest as early infection steps are the ideal target for intervention strategies. Here, we review recent key findings in the field of IAV entry. Specifically, we discuss the identification of novel entry receptors, the emerging role of the viral neuraminidase in entry, as well as recent progress from structural studies on the viral hemagglutinin during the fusion process and the viral matrix protein involved in virus uncoating. We also highlight remaining gaps in our understanding of IAV entry and point out important questions for ongoing research efforts.

Proceedings of the National Academy of Sciences of the United States of America, 119 (39), ISSN:0027-8424, ISSN:1091-6490

The main obstacle to cure HIV-1 is the latent reservoir. Antiretroviral therapy effectively controls viral replication, however, it does not eradicate the latent reservoir. Latent CD4+ T cells are extremely rare in HIV-1 infected patients, making primary CD4+ T cell models of HIV-1 latency key to understanding latency and thus finding a cure. In recent years several primary CD4+ T cell models of HIV-1 latency were developed to study the underlying mechanism of establishing, maintaining and reversing HIV-1 latency. In the search of biomarkers, primary CD4+ T cell models of HIV-1 latency were used for bulk and single-cell transcriptomics. A wealth of information was generated from transcriptome analyses of different primary CD4+ T cell models of HIV-1 latency using latently- and reactivated HIV-1 infected primary CD4+ T cells. Here, we performed a pooled data-analysis comparing the transcriptome profiles of latently- and reactivated HIV-1 infected cells of 5 in vitro primary CD4+ T cell models of HIV-1 latency and 2 ex vivo studies of reactivated HIV-1 infected primary CD4+ T cells from HIV-1 infected individuals. Identifying genes that are differentially expressed between latently- and reactivated HIV-1 infected primary CD4+ T cells could be a more successful strategy to better understand and characterize HIV-1 latency and reactivation. We observed that natural ligands and coreceptors were predominantly downregulated in latently HIV-1 infected primary CD4+ T cells, whereas genes associated with apoptosis, cell cycle and HLA class II were upregulated in reactivated HIV-1 infected primary CD4+ T cells. In addition, we observed 5 differentially expressed genes that co-occurred in latently- and reactivated HIV-1 infected primary CD4+ T cells, one of which, MSRB2, was found to be differentially expressed between latently- and reactivated HIV-1 infected cells. Investigation of primary CD4+ T cell models of HIV-1 latency that mimic the in vivo state remains essential for the study of HIV-1 latency and thus providing the opportunity to compare the transcriptome profile of latently- and reactivated HIV-1 infected cells to gain insights into differentially expressed genes, which might contribute to HIV-1 latency., Frontiers in Immunology, 13, ISSN:1664-3224

Herpes simplex virus (HSV)-2 is a rare cause of hepatitis that can lead to acute liver failure (ALF) and often death. The earlier the initiation of acyclovir treatment the better the survival. With regard to ALF, controlled randomized data support the use of therapeutic plasma exchange (TPE) both as bridge to recovery or transplantation-possibly by modulating the systemic inflammatory response and by replacing coagulation factors. Seraph 100 Microbind Affinity Blood Filter (Seraph; Ex Thera Medical, Martinez, CA), a novel extracorporeal adsorption device, removes living pathogens by binding to a heparin-coated surface was shown to efficiently clear HSV-2 particles in vitro. Here, we tested the combination of Seraph with TPE to reduce a massive HSV-2 viral load to reach a situation in that liver transplantation would be feasible.Explorative study.Academic tertiary care transplant center.Single patient with HSV-2-induced ALF.TPE + Seraph 100 Microbind Affinity Blood Filter.We report Seraph clearance data of HSV-2 and of Epstein-Barr virus (EBV) in vivo as well as total viral elimination by TPE. Genome copies/mL of HSV-2 and EBV in EDTA plasma were measured by polymerase chain reaction every 60 minutes over 6 hours after starting Seraph both systemically and post adsorber. Also, HSV-2 and EBV were quantified before and after TPE and in the removed apheresis plasma. We found a total elimination of 1.81 × eTPE was able to remove circulating HSV-2 copies by 25% and EBV copies by 40% from the blood. On the other hand, clearance of HSV-2 by Seraph was clinically irrelevant, but Seraph seemed to be far more effective of removing EBV, implicating a possible use in EBV-associated pathologies, but this requires further study.

SHCS#879 is an ongoing Switzerland-wide multicenter observational study conducted within the Swiss HIV Cohort Study (SHCS) for the prospective follow-up of people living with HIV (PLWH) receiving long-acting injectable cabotegravir-rilpivirine (LAI-CAB/RPV). All adults under LAI-CAB/RPV and part of SHCS are enrolled in the project. The study addresses an integrated strategy of treatment monitoring outside the stringent frame of controlled clinical trials, based on relevant patient characteristics, clinical factors, potential drug-drug interactions, and measurement of circulating blood concentrations. So far, 91 blood samples from 46 PLWH have been collected. Most individuals are less than 50 years old, with relatively few comorbidities and comedications. The observed concentrations are globally in accordance with the available values reported in the randomized clinical trials. Yet, low RPV concentrations not exceeding twice the reported protein-adjusted 90% inhibitory concentration have been observed. Data available at present confirm a considerable between-patient variability overall. Based on the growing amount of PK data accumulated during this ongoing study, population pharmacokinetic analysis will characterize individual concentration-time profiles of LAI-CAB/RPV along with their variability in a real-life setting and their association with treatment response and tolerability, thus bringing key data for therapeutic monitoring and precision dosage adjustment of this novel long-acting therapy.

BACKGROUND The rapid course of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic calls for fast implementation of clinical trials to assess the effects of new treatment and prophylactic interventions. Building trial platforms embedded in existing data infrastructures is an ideal way to address such questions within well-defined subpopulations. METHODS We developed a trial platform building on the infrastructure of two established national cohort studies: the Swiss human immunodeficiency virus (HIV) Cohort Study (SHCS) and Swiss Transplant Cohort Study (STCS). In a pilot trial, termed Corona VaccinE tRiAL pLatform (COVERALL), we assessed the vaccine efficacy of the first two licensed SARS-CoV-2 vaccines in Switzerland and the functionality of the trial platform. RESULTS Using Research Electronic Data Capture (REDCap), we developed a trial platform integrating the infrastructure of the SHCS and STCS. An algorithm identifying eligible patients, as well as baseline data transfer ensured a fast inclusion procedure for eligible patients. We implemented convenient re-directions between the different data entry systems to ensure intuitive data entry for the participating study personnel. The trial platform, including a randomization algorithm ensuring balance among different subgroups, was continuously adapted to changing guidelines concerning vaccination policies. We were able to randomize and vaccinate the first trial participant the same day we received ethics approval. Time to enroll and randomize our target sample size of 380 patients was 22 days. CONCLUSION Taking the best of each system, we were able to flag eligible patients, transfer patient information automatically, randomize and enroll the patients in an easy workflow, decreasing the administrative burden usually associated with a trial of this size.

Viruses are the cause of a considerable burden to human, animal and plant health, while on the other hand playing an important role in regulating entire ecosystems. The power of new sequencing technologies combined with new tools for processing "Big Data" offers unprecedented opportunities to answer fundamental questions in virology. Virologists have an urgent need for virus-specific bioinformatics tools. These developments have led to the formation of the European Virus Bioinformatics Center, a network of experts in virology and bioinformatics who are joining forces to enable extensive exchange and collaboration between these research areas. The EVBC strives to provide talented researchers with a supportive environment free of gender bias, but the gender gap in science, especially in math-intensive fields such as computer science, persists. To bring more talented women into research and keep them there, we need to highlight role models to spark their interest, and we need to ensure that female scientists are not kept at lower levels but are given the opportunity to lead the field. Here we showcase the work of the EVBC and highlight the achievements of some outstanding women experts in virology and viral bioinformatics. ispartof: VIRUSES-BASEL vol:14 issue:7 ispartof: location:Switzerland status: published

CRISPR/dCas9-based activation systems (CRISPRa) enable sequence-specific gene activation and are therefore of particular interest for the ‘shock and kill’ cure approach against HIV-1 infections. This approach aims to activate the latent HIV-1 proviruses in infected cells and subsequently kill these cells. Several CRISPRa systems have been shown to specifically and effectively activate latent HIV-1 when targeted to the HIV-1 5′LTR promoter, making them a promising ‘shock’ strategy. Here, we aimed to evaluate the dCas9-VPR system for its applicability in reversing HIV-1 latency and identify the optimal gRNA target site in the HIV-1 5′LTR promoter leading to the strongest activation of the provirus with this system. We systematically screened the HIV-1 promoter by selecting 14 specific gRNAs that cover almost half of the HIV-1 promoter from the 3′ half of the U3 until the beginning of the R region. Screening in several latently HIV-1 infected cell lines showed that dCas9-VPR leads to a high activation of HIV-1 and that gRNA-V and -VII induce the strongest activation of replication competent latent provirus. This data indicates that the optimal activation region in the HIV-1 promoter for the dCas9-VPR system is located −165 to −106 bp from the transcription start site and that it is consistent with the optimal activation region reported for other CRISPRa systems. Our data demonstrates that the dCas9-VPR system is a powerful tool for HIV-1 activation and could be harnessed for the ‘shock and kill’ cure approach.

Motivation High-throughput sequencing technologies are used increasingly not only in viral genomics research but also in clinical surveillance and diagnostics. These technologies facilitate the assessment of the genetic diversity in intra-host virus populations, which affects transmission, virulence and pathogenesis of viral infections. However, there are two major challenges in analysing viral diversity. First, amplification and sequencing errors confound the identification of true biological variants, and second, the large data volumes represent computational limitations. Results To support viral high-throughput sequencing studies, we developed V-pipe, a bioinformatics pipeline combining various state-of-the-art statistical models and computational tools for automated end-to-end analyses of raw sequencing reads. V-pipe supports quality control, read mapping and alignment, low-frequency mutation calling, and inference of viral haplotypes. For generating high-quality read alignments, we developed a novel method, called ngshmmalign, based on profile hidden Markov models and tailored to small and highly diverse viral genomes. V-pipe also includes benchmarking functionality providing a standardized environment for comparative evaluations of different pipeline configurations. We demonstrate this capability by assessing the impact of three different read aligners (Bowtie 2, BWA MEM, ngshmmalign) and two different variant callers (LoFreq, ShoRAH) on the performance of calling single-nucleotide variants in intra-host virus populations. V-pipe supports various pipeline configurations and is implemented in a modular fashion to facilitate adaptations to the continuously changing technology landscape., Bioinformatics, 37 (12), ISSN:1367-4803, ISSN:1460-2059

Supplemental Digital Content is available in the text., Background and Purpose: Case series indicating cerebrovascular disorders in coronavirus disease 2019 (COVID-19) have been published. Comprehensive workups, including clinical characteristics, laboratory, electroencephalography, neuroimaging, and cerebrospinal fluid findings, are needed to understand the mechanisms. Methods: We evaluated 32 consecutive critically ill patients with COVID-19 treated at a tertiary care center from March 9 to April 3, 2020, for concomitant severe central nervous system involvement. Patients identified underwent computed tomography, magnetic resonance imaging, electroencephalography, cerebrospinal fluid analysis, and autopsy in case of death. Results: Of 32 critically ill patients with COVID-19, 8 (25%) had severe central nervous system involvement. Two presented with lacunar ischemic stroke in the early phase and 6 with prolonged impaired consciousness after termination of analgosedation. In all but one with delayed wake-up, neuroimaging or autopsy showed multiple cerebral microbleeds, in 3 with additional subarachnoid hemorrhage and in 2 with additional small ischemic lesions. In 3 patients, intracranial vessel wall sequence magnetic resonance imaging was performed for the first time to our knowledge. All showed contrast enhancement of vessel walls in large cerebral arteries, suggesting vascular wall pathologies with an inflammatory component. Reverse transcription-polymerase chain reactions for SARS-CoV-2 in cerebrospinal fluid were all negative. No intrathecal SARS-CoV-2-specific IgG synthesis was detectable. Conclusions: Different mechanisms of cerebrovascular disorders might be involved in COVID-19. Acute ischemic stroke might occur early. In a later phase, microinfarctions and vessel wall contrast enhancement occur, indicating small and large cerebral vessels involvement. Central nervous system disorders associated with COVID-19 may lead to long-term disabilities. Mechanisms should be urgently investigated to develop neuroprotective strategies.

Background: The primary hurdle for the eradication of HIV-1 is the establishment of a latent viral reservoir early after primary infection. Here, we investigated the potential influence of human genetic variation on the HIV-1 reservoir size and its decay rate during suppressive antiretroviral treatment. Setting: Genome-wide association study and exome sequencing study to look for host genetic determinants of HIV-1 reservoir measurements in patients enrolled in the Swiss HIV Cohort Study, a nation-wide prospective observational study. Methods: We measured total HIV-1 DNA in peripheral blood mononuclear cells from study participants, as a proxy for the reservoir size at 3 time points over a median of 5.4 years, and searched for associations between human genetic variation and 2 phenotypic readouts: the reservoir size at the first time point and its decay rate over the study period. We assessed the contribution of common genetic variants using genome-wide genotyping data from 797 patients with European ancestry enrolled in the Swiss HIV Cohort Study and searched for a potential impact of rare variants and exonic copy number variants using exome sequencing data generated in a subset of 194 study participants. Results: Genome-wide and exome-wide analyses did not reveal any significant association with the size of the HIV-1 reservoir or its decay rate on suppressive antiretroviral treatment. Conclusions: Our results point to a limited influence of human genetics on the size of the HIV-1 reservoir and its long-term dynamics in successfully treated individuals.

Background Vaccination may control the COVID-19 pandemic, including in nursing homes where many high-risk people live. We conducted extensive outbreak investigations. Methods We studied an outbreak at a nursing home in Switzerland where vaccination uptake of mRNA vaccines against SARS-CoV-2 was 82% among residents as of Jan 21/2021. After a vaccinated symptomatic HCW was diagnosed with COVID-19 on Feb 22, we did an outbreak investigations in house A (47 residents, 37 HCWs) using SARS-CoV-2-specific PCR in nasopharyngeal swabs. We performed whole-genome sequencing of SARS-CoV-2 and serological analyses. Results We identified 17 individuals with positive PCR tests; ten residents (five vaccinated) and seven HCWs (three vaccinated). Median age among residents was 86 years (interquartile range [IQR] 70-90) and 49 years (IQR 29-59) among HCWs. Among the five vaccinated residents, 60% had mild disease and had 40% no symptoms, whereas all five unvaccinated residents had mild to severe disease and two died. The vaccine effectiveness for the prevention of infection among the residents was 73.0% (95% Cl 24.7-90.1). The 12 available genomes were all alpha variants. Neutralizing titers were significantly higher in vaccinated individuals upon re-exposure (>1 week after diagnosis) than in vaccinated, unexposed HCWs (p=0.012). Transmission networks indicated four likely or possible transmissions from vaccinated to other individuals, and 12 transmission events from unvaccinated individuals. Conclusions COVID-19 outbreaks can occur in nursing homes, including transmission from vaccinated persons to others. Outbreaks might occur silently, underlining the need for continued testing and basic infection control measures in these high-risk settings.

Patients with type 2 diabetes and obesity have chronic activation of the innate immune system possibly contributing to the higher risk of hyperinflammatory response to SARS-CoV2 and severe COVID-19 observed in this population. We tested whether interleukin-1β (IL-1β) blockade using canakinumab improves clinical outcome.CanCovDia was a multicenter, randomised, double-blind, placebo-controlled trial to assess the efficacy of canakinumab plus standard-of-care compared with placebo plus standard-of-care in patients with type 2 diabetes and a BMI25 kg/mBetween October 17, 2020, and May 12, 2021, 116 patients were randomly assigned with 58 in each group. One participant dropped out in each group for the primary analysis. At the time of randomization, 85 patients (74·6 %) were treated with dexamethasone. The win-ratio of canakinumab vs placebo was 1·08 (95 % CI 0·69-1·69; p = 0·72). During four weeks, in the canakinumab vs placebo group 4 (7·0%) vs 7 (12·3%) participants died, 11 (20·0 %) vs 16 (28·1%) patients were on ICU, 12 (23·5 %) vs 11 (21·6%) were hospitalised for more than 3 weeks, respectively. Median ventilation time at four weeks in the canakinumab vs placebo group was 10 [IQR 6.0, 16.5] and 16 days [IQR 14.0, 23.0], respectively. There was no statistically significant difference in HbA1c after four weeks despite a lower number of anti-diabetes drug administered in patients treated with canakinumab. Finally, high-sensitive CRP and IL-6 was lowered by canakinumab. Serious adverse events were reported in 13 patients (11·4%) in each group.In patients with type 2 diabetes who were hospitalised with COVID-19, treatment with canakinumab in addition to standard-of-care did not result in a statistically significant improvement of the primary composite outcome. Patients treated with canakinumab required significantly less anti-diabetes drugs to achieve similar glycaemic control. Canakinumab was associated with a prolonged reduction of systemic inflammation.Swiss National Science Foundation

Objectives Characterizing features of the viral rebound trajectories and identifying host, virological, and immunological factors that are predictive of the viral rebound trajectories are central to HIV cure research. We investigate if key features of HIV viral decay and CD4 trajectories during antiretroviral therapy (ART) are associated with characteristics of HIV viral rebound following ART interruption. Methods Nonlinear mixed effect (NLME) models are used to model viral load trajectories before and following ART interruption, incorporating left censoring due to lower detection limits of viral load assays. A stochastic approximation EM (SAEM) algorithm is used for parameter estimation and inference. To circumvent the computational intensity associated with maximizing the joint likelihood, we propose an easy-to-implement three-step method. Results We evaluate the performance of the proposed method through simulation studies and apply it to data from the Zurich Primary HIV Infection Study. We find that some key features of viral load during ART (e.g., viral decay rate) are significantly associated with important characteristics of viral rebound following ART interruption (e.g., viral set point). Conclusions The proposed three-step method works well. We have shown that key features of viral decay during ART may be associated with important features of viral rebound following ART interruption.

Background Vaccines against SARS-CoV-2 have been rapidly approved. While pivotal studies were conducted in healthy volunteers, little information is available on safety and efficacy of mRNA vaccines in immunocompromised patients, including recipients of allogeneic hematopoietic cell transplantations (allo-HCT). Objectives Here, we used a novel assay to analyze patient- and transplant-related factors and their influence on immune responses over an extended period of time (up to 6 months) to the SARS-CoV-2 vaccination in a large and homogenous group of allo-HCT recipients at a single center in Switzerland. Study Design We examined longitudinal antibody responses to SARS-CoV-2 vaccination with BNT162b2 (BioNTech/Pfizer) or mRNA-1273 (Moderna) in 110 allo-HCT recipients and 86 healthy controls. Seroprofiling recording IgG, IgA, and IgM reactivities against SARS-CoV-2 antigens (receptor-binding domain (RBD), spike glycoprotein subunits S1 and S2, and nucleocapsid protein (N)) was performed prior to vaccination, prior to the 2nd dose, and 1, 3, and 6 months (m) after the 2nd dose. Patients were stratified to three groups (A) 3-6m post HCT; (B) 6-12m post HCT; and (C) >12m post HCT. Results Individuals early post allo-HCT (3-6 and 6-12m post HCT) developed significantly lower antibody titers after vaccination compared to patients >12m post allo-HCT and healthy controls (p65 years (p=0.030), those under immunosuppression for prevention or treatment of graft-vs-host disease (GVHD) (p=0.033), and/or with relapsed disease (p=0.014) displayed poor humoral immune response to the vaccine. In contrast, the intensity of the conditioning regimen, underlying disease (myeloid/lymphoid/other), and presence of chronic GVHD had no impact on antibody levels. Antibody titers achieved the highest levels 1m after the 2nd dose of the vaccine but substantially waned in all transplanted groups and healthy controls over time. Conclusions This analysis of long-term vaccine antibody response is of critical importance to allo-HCT recipients and transplant physicians to guide treatment decisions regarding re-vaccination and social behavior during the SARS-CoV-2 pandemic., Graphical Abstract Image, graphical abstract

Objective:Nosocomial transmission of influenza is a major concern for infection control. We aimed to dissect transmission dynamics of influenza, including asymptomatic transmission events, in acute care.Design:Prospective surveillance study during 2 influenza seasons.Setting:Tertiary-care hospital.Participants:Volunteer sample of inpatients on medical wards and healthcare workers (HCWs).Methods:Participants provided daily illness diaries and nasal swabs for influenza A and B detection and whole-genome sequencing for phylogenetic analyses. Contacts between study participants were tracked. Secondary influenza attack rates were calculated based on spatial and temporal proximity and phylogenetic evidence for transmission.Results:In total, 152 HCWs and 542 inpatients were included; 16 HCWs (10.5%) and 19 inpatients (3.5%) tested positive for influenza on 109 study days. Study participants had symptoms of disease on most of the days they tested positive for influenza (83.1% and 91.9% for HCWs and inpatients, respectively). Also, 11(15.5%) of 71 influenza-positive swabs among HCWs and 3 (7.9%) of 38 influenza-positive swabs among inpatients were collected on days without symptoms; 2 (12.5%) of 16 HCWs and 2 (10.5%) of 19 inpatients remained fully asymptomatic. The secondary attack rate was low: we recorded 1 transmission event over 159 contact days (0.6%) that originated from a symptomatic case. No transmission event occurred in 61 monitored days of contacts with asymptomatic influenza-positive individuals.Conclusions:Influenza in acute care is common, and individuals regularly shed influenza virus without harboring symptoms. Nevertheless, both symptomatic and asymptomatic transmission events proved rare. We suggest that healthcare-associated influenza prevention strategies that are based on preseason vaccination and barrier precautions for symptomatic individuals seem to be effective.

Due to the low stoichiometry and highly transient nature of protein phosphorylation it is challenging to capture the dynamics and complexity of phosphorylation events on a systems level. Here, we present an optimized protocol to measure virus-induced phosphorylation events with high sensitivity using label free quantification-based phosphoproteomics. Specifically, we describe filter assisted protein digestion (FASP), enrichment of phosphopeptides, mass spectrometry, and subsequent bioinformatic analysis. For complete details on the use and execution of this protocol, please refer to Hunziker et al. (2022)., STAR Protocols, 3 (1), ISSN:2666-1667

IntroductionSeroprevalence and transmission routes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents, especially in school setting, are not clear. Resulting uncertainty is reflected in very different decisions on school closures and reopenings across countries. The aim of this longitudinal cohort study is to assess the extent and patterns of seroprevalence of SARS-CoV-2 antibodies in school-attending children repeatedly. It will examine risk factors for infection, relationship between seropositivity and symptoms, and temporal persistence of antibodies. Additionally, it will include testing of school personnel and parents.Methods and analysisThe study (Ciao Corona) will enroll a regionally representative, random sample of schools in the canton of Zurich, where 18% of the Swiss population live. Children aged 5 to 16 years, attending classes in primary and secondary schools are invited. Venous blood and saliva samples are collected for SARS-CoV-2 serological testing after the first wave of infections (June/July 2020), in fall (October/November 2020), and after winter (March/April 2021). Venous blood is also collected for serological testing of parents and school personnel. Bi-monthly questionnaires to children, parents and school personnel cover SARS-CoV-2 symptoms and tests, health, preventive behavior, lifestyle and quality of life information. Total seroprevalence and cumulative incidence will be calculated. Hierarchical Bayesian logistic regression models will account for sensitivity and specificity of the serological test in the analyses and for the complex sampling structure, i.e., clustering within classes and schools.Ethics and disseminationThe study was approved by the Ethics Committee of the Canton of Zurich, Switzerland (2020-01336). The results of this study will be published in peer-reviewed journals and will be made available to study participants and participating schools, the Federal Office of Public Health, and the Educational Department of the canton of Zurich. Trial registration numberNCT04448717.Ciao Corona is a large, prospective school-based cohort study and will provide robust data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence, transmission routes and immunity over time in a representative sample of school children.The longitudinal design will allow describing temporal trends of immunity to SARS-CoV-2 infection and to evaluate effects of school structure and preventive measures.This study will inform goal-oriented policy decisions in school management during subsequent outbreaks.Participation bias, missing questionnaires, desirability bias, and loss of follow up may occur. The validity of serological tests may also hamper results.

International audience; Human immunodeficiency virus (HIV) infection is associated with an increased risk of non-Hodgkin lymphoma (NHL). Even in the era of suppressive antiretroviral treatment, HIV-infected individuals remain at higher risk of developing NHL compared to the general population. To identify potential genetic risk loci, we performed case-control genome-wide association studies and a meta-analysis across three cohorts of HIV+ patients of European ancestry, including a total of 278 cases and 1924 matched controls. We observed a significant association with NHL susceptibility in the C-X-C motif chemokine ligand 12 (CXCL12) region on chromosome 10. A fine mapping analysis identified rs7919208 as the most likely causal variant (P = 4.77e-11), with the G>A polymorphism creating a new transcription factor binding site for BATF and JUND. These results suggest a modulatory role of CXCL12 regulation in the increased susceptibility to NHL observed in the HIV-infected population.

Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology. The TIGIT pathway has been implicated in promoting T cell dysfunction in chronic viral infection. Importantly, TIGIT signaling is functionally linked to IL-10 expression, which has an effect on both virus control and maintenance of tissue homeostasis. However, whether TIGIT has a function in viral persistence or limiting tissue pathology is unclear. Here we report that TIGIT modulation effectively alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection, but does not affect virus control in vivo. Instead, TIGIT has an important effect in limiting immune pathology in peripheral organs by inducing IL-10. Our data therefore identify a function of TIGIT in limiting immune pathology that is independent of viral clearance., TIGIT is a lymphocyte co-inhibitory receptor that can limit type 1 and cytotoxic T cell responses and maintain immunological tolerance. Here the authors show that TIGIT also limits immune pathology during LCMV or influenza infections in mice by driving IL-10 expression without negatively affecting the viral load.

Background There are no reliable signs or symptoms that differentiate Mycoplasma pneumoniae (Mp) infection in community-acquired pneumonia (CAP) from other etiologies. Additionally, current diagnostic tests do not reliably distinguish between Mp infection and carriage. We previously determined that the measurement of Mp-specific immunoglobulin M antibody-secreting cells (ASCs) by enzyme-linked immunospot assay allowed for differentiation between infection and carriage. Using this new diagnostic test, we aimed to identify clinical and laboratory features associated with Mp infection. Methods This is a prospective cohort study of children, 3–18 years of age, with CAP from 2016 to 2017. Clinical features and biomarkers were compared between Mp-positive and -negative groups by Mann-Whitney U test or Fisher exact test, as appropriate. Area under the receiver operating characteristic curve (AUC) differences and optimal thresholds were determined by using the DeLong test and Youden J statistic, respectively. Results Of 63 CAP patients, 29 were Mp-positive (46%). Mp positivity was statistically associated with older age (median, 8.6 vs 4.7 years), no underlying disease, family with respiratory symptoms, prior antibiotic treatment, prolonged prodromal respiratory symptoms and fever, and extrapulmonary (skin) manifestations. Lower levels of C-reactive protein, white blood cell count, absolute neutrophil count, and procalcitonin (PCT), specifically PCT 5 years (AUC = 0.77), prodromal fever and respiratory symptoms >6 days (AUC = 0.79), and PCT, Community-acquired pneumonia (CAP) caused by Mycoplasma pneumoniae (Mp) is difficult to diagnose. A combination of clinical features and biomarkers may aid physicians in identifying patients at high risk for Mp CAP.

Binding of influenza virus to its receptor triggers signaling cascades that reprogram the cell for infection. To elucidate global virus-induced changes to the cellular signaling landscape, we conducted a quantitative phosphoproteomic screen with human and avian influenza viruses. Proteins with functions in cell adhesion and cytoskeletal remodeling are overrepresented among the hits, and the majority of factors undergoing phosphorylation changes have a significant impact on infection efficiency. We show that influenza virus induces the formation of filopodia through Cdc42 signaling, which results in enhanced virus endocytosis. The host cell counteracts this mechanism with cortactin, a regulator of actin polymerization that becomes phosphorylated in response to virus binding and translocates to the cell cortex, where it limits filopodia formation and virus uptake. Overall, our study reveals the signaling cascades induced by influenza virus receptor engagement and uncovers virus-induced filopodia formation that is counteracted by the host cell., Cell Reports, 38 (4), ISSN:2666-3864, ISSN:2211-1247