Monocytes Contribute to Differential Immune Pressure on R5 versus X4 HIV through the Adipocytokine Visfatin/NAMPT

Background: The immune system exerts a diversifying selection pressure on HIV through cellular, humoral and innate mechanisms. This pressure drives viral evolution throughout infection. A better understanding of the natural immune pressure on the virus during infection is warranted, given the clinical interest in eliciting and sustaining an immune response to HIV which can help to control the infection. We undertook to evaluate the potential of the novel HIV-induced, monocyte-derived factor visfatin to modulate viral infection, as part of the innate immune pressure on viral populations. Results: We show that visfatin is capable of selectively inhibiting infection by R5 HIV strains in macrophages and resting PBMC in vitro, while at the same time remaining indifferent to or even favouring infection by X4 strains. Furthermore, visfatin exerts a direct effect on the relative fitness of R5 versus X4 infections in a viral competition setup. Direct interaction of visfatin with the CCR5 receptor is proposed as a putative mechanism for this differential effect. Possible in vivo relevance of visfatin induction is illustrated by its association with the dominance of CXCR4-using HIV in the plasma. Conclusions: As an innate factor produced by monocytes, visfatin is capable of inhibiting infections by R5 but not X4 strains, reflecting a potential selective pressure against R5 viruses. © 2012 Van den Bergh et al.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Analysis of infectious virus clones from two HIV-1 superinfection cases suggests that the primary strains have lower fitness

<p>Abstract</p> <p>Background</p> <p>Two HIV-1 positive patients, L and P, participating in the Amsterdam Cohort studies acquired an HIV-1 superinfection within half a year from their primary HIV-1 infection (Jurriaans <it>et al</it>., <it>JAIDS </it>2008, <b>47:</b>69-73). The aim of this study was to compare the replicative fitness of the primary and superinfecting HIV-1 strains of both patients. The use of isolate-specific primer sets indicated that the primary and secondary strains co-exist in plasma at all time points after the moment of superinfection.</p> <p>Results</p> <p>Biological HIV-1 clones were derived from peripheral blood CD4 + T cells at different time point, and identified as the primary or secondary virus through sequence analysis. Replication competition assays were performed with selected virus pairs in PHA/IL-2 activated peripheral blood mononuclear cells (PBMC's) and analyzed with the Heteroduplex Tracking Assay (HTA) and isolate-specific PCR amplification. In both cases, we found a replicative advantage of the secondary HIV-1 strain over the primary virus. Full-length HIV-1 genomes were sequenced to find possible explanations for the difference in replication capacity. Mutations that could negatively affect viral replication were identified in the primary infecting strains. In patient L, the primary strain has two insertions in the LTR promoter, combined with a mutation in the <it>tat </it>gene that has been associated with decreased replication capacity. The primary HIV-1 strain isolated from patient P has two mutations in the LTR that have been associated with a reduced replication rate. In a luciferase assay, only the LTR from the primary virus of patient P had lower transcriptional activity compared with the superinfecting virus.</p> <p>Conclusions</p> <p>These preliminary findings suggest the interesting scenario that superinfection occurs preferentially in patients infected with a relatively attenuated HIV-1 isolate.</p

The preclinical pharmacology of the high affinity anti-IL-6R Nanobody (R) ALX-0061 supports its clinical development in rheumatoid arthritis

Introduction: The pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody (R) with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology. Methods: ALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control. Results: ALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration. Conclusions: ALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA

Virgo Detector Characterization and Data Quality during the O3 run

The Advanced Virgo detector has contributed with its data to the rapid growth of the number of detected gravitational-wave signals in the past few years, alongside the two LIGO instruments. First, during the last month of the Observation Run 2 (O2) in August 2017 (with, most notably, the compact binary mergers GW170814 and GW170817) and then during the full Observation Run 3 (O3): an 11 months data taking period, between April 2019 and March 2020, that led to the addition of about 80 events to the catalog of transient gravitational-wave sources maintained by LIGO, Virgo and KAGRA. These discoveries and the manifold exploitation of the detected waveforms require an accurate characterization of the quality of the data, such as continuous study and monitoring of the detector noise. These activities, collectively named {\em detector characterization} or {\em DetChar}, span the whole workflow of the Virgo data, from the instrument front-end to the final analysis. They are described in details in the following article, with a focus on the associated tools, the results achieved by the Virgo DetChar group during the O3 run and the main prospects for future data-taking periods with an improved detector.Comment: 86 pages, 33 figures. This paper has been divided into two articles which supercede it and have been posted to arXiv on October 2022. Please use these new preprints as references: arXiv:2210.15634 (tools and methods) and arXiv:2210.15633 (results from the O3 run

Virgo Detector Characterization and Data Quality: results from the O3 run

The Advanced Virgo detector has contributed with its data to the rapid growth of the number of detected gravitational-wave (GW) signals in the past few years, alongside the two Advanced LIGO instruments. First during the last month of the Observation Run 2 (O2) in August 2017 (with, most notably, the compact binary mergers GW170814 and GW170817), and then during the full Observation Run 3 (O3): an 11-months data taking period, between April 2019 and March 2020, that led to the addition of about 80 events to the catalog of transient GW sources maintained by LIGO, Virgo and now KAGRA. These discoveries and the manifold exploitation of the detected waveforms require an accurate characterization of the quality of the data, such as continuous study and monitoring of the detector noise sources. These activities, collectively named {\em detector characterization and data quality} or {\em DetChar}, span the whole workflow of the Virgo data, from the instrument front-end hardware to the final analyses. They are described in details in the following article, with a focus on the results achieved by the Virgo DetChar group during the O3 run. Concurrently, a companion article describes the tools that have been used by the Virgo DetChar group to perform this work.Comment: 57 pages, 18 figures. To be submitted to Class. and Quantum Grav. This is the "Results" part of preprint arXiv:2205.01555 [gr-qc] which has been split into two companion articles: one about the tools and methods, the other about the analyses of the O3 Virgo dat

Virgo Detector Characterization and Data Quality: tools

Detector characterization and data quality studies -- collectively referred to as {\em DetChar} activities in this article -- are paramount to the scientific exploitation of the joint dataset collected by the LIGO-Virgo-KAGRA global network of ground-based gravitational-wave (GW) detectors. They take place during each phase of the operation of the instruments (upgrade, tuning and optimization, data taking), are required at all steps of the dataflow (from data acquisition to the final list of GW events) and operate at various latencies (from near real-time to vet the public alerts to offline analyses). This work requires a wide set of tools which have been developed over the years to fulfill the requirements of the various DetChar studies: data access and bookkeeping; global monitoring of the instruments and of the different steps of the data processing; studies of the global properties of the noise at the detector outputs; identification and follow-up of noise peculiar features (whether they be transient or continuously present in the data); quick processing of the public alerts. The present article reviews all the tools used by the Virgo DetChar group during the third LIGO-Virgo Observation Run (O3, from April 2019 to March 2020), mainly to analyse the Virgo data acquired at EGO. Concurrently, a companion article focuses on the results achieved by the DetChar group during the O3 run using these tools.Comment: 44 pages, 16 figures. To be submitted to Class. and Quantum Grav. This is the "Tools" part of preprint arXiv:2205.01555 [gr-qc] which has been split into two companion articles: one about the tools and methods, the other about the analyses of the O3 Virgo dat

The Advanced Virgo+ status

The gravitational wave detector Advanced Virgo+ is currently in the commissioning phase in view of the fourth Observing Run (O4). The major upgrades with respect to the Advanced Virgo configuration are the implementation of an additional recycling cavity, the Signal Recycling cavity (SRC), at the output of the interferometer to broaden the sensitivity band and the Frequency Dependent Squeezing (FDS) to reduce quantum noise at all frequencies. The main difference of the Advanced Virgo + detector with respect to the LIGO detectors is the presence of marginally stable recycling cavities, with respect to the stable recycling cavities present in the LIGO detectors, which increases the difficulties in controlling the interferometer in presence of defects (both thermal and cold defects). This work will focus on the interferometer commissioning, highlighting the control challenges to maintain the detector in the working point which maximizes the sensitivity and the duty cycle for scientific data taking

Open Data from the Third Observing Run of LIGO, Virgo, KAGRA, and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in 2019 April and lasting six months, O3b starting in 2019 November and lasting five months, and O3GK starting in 2020 April and lasting two weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main data set, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages

A Joint Fermi-GBM and Swift-BAT Analysis of Gravitational-wave Candidates from the Third Gravitational-wave Observing Run

We present Fermi Gamma-ray Burst Monitor (Fermi-GBM) and Swift Burst Alert Telescope (Swift-BAT) searches for gamma-ray/X-ray counterparts to gravitational-wave (GW) candidate events identified during the third observing run of the Advanced LIGO and Advanced Virgo detectors. Using Fermi-GBM onboard triggers and subthreshold gamma-ray burst (GRB) candidates found in the Fermi-GBM ground analyses, the Targeted Search and the Untargeted Search, we investigate whether there are any coincident GRBs associated with the GWs. We also search the Swift-BAT rate data around the GW times to determine whether a GRB counterpart is present. No counterparts are found. Using both the Fermi-GBM Targeted Search and the Swift- BAT search, we calculate flux upper limits and present joint upper limits on the gamma-ray luminosity of each GW. Given these limits, we constrain theoretical models for the emission of gamma rays from binary black hole mergers