Sustained aviraemia despite anti-retroviral therapy non-adherence in male children following in utero hiv transmission.

Following sporadic reports of post-treatment control of HIV in children who initiated combination antiretroviral therapy (cART) early, we here prospectively studied 284 very early cART-treated children from KwaZulu-Natal, South Africa after vertical HIV transmission to assess control of viraemia. 84% of the children achieved aviraemia on cART but aviraemia persisting to >36m was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (p=0.01). Unexpectedly, a subset (n=5) of males maintained aviraemia despite unscheduled complete discontinuation of cART lasting 3m-10m (n=4), or intermittent cART adherence during 17m loss to follow up (n=1). We further observed in vertically transmitted viruses a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (p<0.0001), that was markedly stronger for males than females (r=-0.51 versus r=-0.07 for IFNα). While viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (p<0.0001 and p=0.0003), the viruses transmitted to the five males maintaining cART-free aviraemia had significantly lower replication capacity (p<0.0001). These data suggest that viraemic control can occur in some infants with in utero acquired HIV infection after early cART initiation, and may be associated with innate immune sex differences.

Targeting Viral Transcription for HIV Cure Strategies.

Combination antiretroviral therapy (ART) suppresses viral replication to undetectable levels, reduces mortality and morbidity, and improves the quality of life of people living with HIV (PWH). However, ART cannot cure HIV infection because it is unable to eliminate latently infected cells. HIV latency may be regulated by different HIV transcription mechanisms, such as blocks to initiation, elongation, and post-transcriptional processes. Several latency-reversing (LRA) and -promoting agents (LPA) have been investigated in clinical trials aiming to eliminate or reduce the HIV reservoir. However, none of these trials has shown a conclusive impact on the HIV reservoir. Here, we review the cellular and viral factors that regulate HIV-1 transcription, the potential pharmacological targets and genetic and epigenetic editing techniques that have been or might be evaluated to disrupt HIV-1 latency, the role of miRNA in post-transcriptional regulation of HIV-1, and the differences between the mechanisms regulating HIV-1 and HIV-2 expression.

The Arabidopsis thioredoxin TRXh5regulates the S-nitrosylation pattern of the TIRK receptor being both proteins essential in the modulation of defences to Tetranychus urticae.

The interaction between plants and phytophagous arthropods encompasses a complex network of molecules, signals, and pathways to overcome defences generated by each interacting organism. Although most of the elements and modulators involved in this interplay are still unidentified, plant redox homeostasis and signalling are essential for the establishment of defence responses. Here, focusing on the response of Arabidopsis thaliana to the spider mite Tetranychus urticae, we demonstrate the involvement in plant defence of the thioredoxin TRXh5, a small redox protein whose expression is induced by mite infestation. TRXh5 is localized in the cell membrane system and cytoplasm and is associated with alterations in the content of reactive oxygen and nitrogen species. Protein S-nitrosylation signal in TRXh5 over-expression lines is decreased and alteration in TRXh5 level produces changes in the JA/SA hormonal crosstalk of infested plants. Moreover, TRXh5 interacts and likely regulates the redox state of an uncharacterized receptor-like kinase, named THIOREDOXIN INTERACTING RECEPTOR KINASE (TIRK), also induced by mite herbivory. Feeding bioassays performed withTRXh5 over-expression plants result in lower leaf damage and reduced egg accumulation after T. urticae infestation than in wild-type (WT) plants. In contrast, mites cause a more severe injury in trxh5 mutant lines where a greater number of eggs accumulates. Likewise, analysis of TIRK-gain and -loss-of-function lines demonstrate the defence role of this receptor in Arabidopsis against T. urticae. Altogether, our findings demonstrate the interaction between TRXh5 and TIRK and highlight the importance of TRXh5 and TIRK in the establishment of effective Arabidopsis defences against spider mite herbivory.

Exploring the HIV-1 Rev Recognition Element (RRE)-Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs.

Human immunodeficiency virus-type 1 (HIV-1) remains one of the leading contributors to the global burden of disease, and novel antiretroviral agents with alternative mechanisms are needed to cure this infection. Here, we describe an exploratory attempt to optimize the antiretroviral properties of benfluron, a cytostatic agent previously reported to exhibit strong anti-HIV activity likely based on inhibitory actions on virus transcription and Rev-mediated viral RNA export. After obtaining six analogs designed to modify the benzo[c]fluorenone system of the parent molecule, we examined their antiretroviral and toxicity properties together with their capacity to recognize the Rev Recognition Element (RRE) of the virus RNA and inhibit the RRE-Rev interaction. The results indicated that both the benzo[c] and cyclopentanone components of benfluron are required for strong RRE-Rev target engagement and antiretroviral activity and revealed the relative impact of these moieties on RRE affinity, RRE-Rev inhibition, antiviral action and cellular toxicity. These data provide insights into the biological properties of the benzo[c]fluorenone scaffold and contribute to facilitating the design of new anti-HIV agents based on the inhibition of Rev function.

Caecum OX40+CD4 T-cell subset associates with mucosal damage and key markers of disease in treated HIV-infection.

BACKGROUND: Blood OX40-expressing CD4 T-cells from antiretroviral (ART)-treated people living with HIV (PWH) were found to be enriched for clonally-expanded HIV sequences, hence contributing to the HIV reservoir. OX40-OX40L is also a checkpoint regulator of inflammation in multiple diseases. We explored gut mucosal OX40+CD4+ T-cells and their potential significance in HIV disease. METHODS: Biopsies of caecum and terminal-ileum of ART-treated PWH (n = 32) were obtained and mucosal damage and HIV reservoir were assessed. Mucosal OX40+ and Ki67+ CD4 T-cell subsets, as well as several tissue T-cell subsets modulating mucosal integrity and homeostasis (Th17, Th22, Treg, Tc17, Tc22, IL17+TCRγδ, IL22+TCRγδ) were quantified. Inflammatory-related markers, T-cell activation and thymic output were also determined in blood samples. Correlations were explored using Spearman rank test and corrected for multiple comparisons by Benjamini-Hochberg. RESULTS: Compared to healthy controls, a high frequency of mucosal, mainly caecum, CD4 T-cells were OX40+ in PWH. Such frequency strongly correlated with nadir CD4 (r = -0.836; p < 0.0001), CD4/CD8 ratio (r = -0.630; p = 0.002), caecum mucosal damage (r = 0.606; p = 0.008), caecum Th22 (r = -0.635; p = 0.002), caecum Th17 (r = 0.474; p = 0.03) and thymic output (r = -0.686; p < 0.001). It also correlated with Neutrophil-to-Lymphocyte Ratio and blood CD4 T-cell activation and tended to with mucosal HIV reservoir. CONCLUSION: High frequencies of caecum OX40+CD4 T-cells are found in people with HIV (PWH) and successful viral control. Interestingly, this cellular subset reflects key markers of disease and peripheral T-cell activation, as well as HIV-driven mucosal damage. OX40+CD4 T-cells deserve further investigation since they could expand because of T-cell homeostatic proliferation and relate to the Th22/Th17 gut mucosal ratio.

Reactive oxygen species- and nitric oxide-dependent regulation of ion and metal homeostasis in plants.

Deterioration and impoverishment of soil, caused by environmental pollution and climate change, result in reduced crop productivity. To adapt to hostile soils, plants have developed a complex network of factors involved in stress sensing, signal transduction, and adaptive responses. The chemical properties of reactive oxygen species (ROS) and reactive nitrogen species (RNS) allow them to participate in integrating the perception of external signals by fine-tuning protein redox regulation and signal transduction, triggering specific gene expression. Here, we update and summarize progress in understanding the mechanistic basis of ROS and RNS production at the subcellular level in plants and their role in the regulation of ion channels/transporters at both transcriptional and post-translational levels. We have also carried out an in silico analysis of different redox-dependent modifications of ion channels/transporters and identified cysteine and tyrosine targets of nitric oxide in metal transporters. Further, we summarize possible ROS- and RNS-dependent sensors involved in metal stress sensing, such as kinases and phosphatases, as well as some ROS/RNS-regulated transcription factors that could be involved in metal homeostasis. Understanding ROS- and RNS-dependent signaling events is crucial to designing new strategies to fortify crops and improve plant tolerance of nutritional imbalance and metal toxicity.

Impact of Obefazimod on Viral Persistence, Inflammation, and Immune Activation in People With Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy.

BACKGROUND: Persistence of viral reservoirs has been observed in people with human immunodeficiency virus (HIV), despite long-term antiretroviral therapy (ART), and likely contributes to chronic immune activation and inflammation. Obefazimod is a novel drug that inhibits human immunodeficiency virus type 1 (HIV-1) replication and reduces inflammation. Here we assess whether obefazimod is safe and might impact HIV-1 persistence, chronic immune activation, and inflammation in ART-suppressed people with HIV. METHODS: We evaluated obefazimod-related adverse events, changes in cell-associated HIV-1 DNA and RNA, residual viremia, immunophenotype, and inflammation biomarkers in blood and rectal tissue. We compared 24 ART-suppressed people with HIV who received daily doses of 50 mg obefazimod for 12 weeks (n = 13) or 150 mg for 4 weeks (n = 11) and 12 HIV-negative individuals who received 50 mg for 4 weeks. RESULTS: The 50- and 150-mg doses of obefazimod were safe, although the 150-mg dose showed inferior tolerability. The 150-mg dose reduced HIV-1 DNA (P = .008, median fold change = 0.6) and residual viremia in all individuals with detectable viremia at baseline. Furthermore, obefazimod upregulated miR-124 in all participants and reduced the activation markers CD38, HLA-DR, and PD-1 and several inflammation biomarkers. CONCLUSIONS: The effect of obefazimod by reducing chronic immune activation and inflammation suggests a potential role for the drug in virus remission strategies involving other compounds that can activate immune cells, such as latency-reversing agents.

Nitric Oxide and Globin Glb1 Regulate Fusarium oxysporum Infection of Arabidopsis thaliana.

Plants continuously interact with fungi, some of which, such as Fusarium oxysporum, are lethal, leading to reduced crop yields. Recently, nitric oxide (NO) has been found to play a regulatory role in plant responses to F. oxysporum, although the underlying mechanisms involved are poorly understood. In this study, we show that Arabidopsis mutants with altered levels of phytoglobin 1 (Glb1) have a higher survival rate than wild type (WT) after infection with F. oxysporum, although all the genotypes analyzed exhibited a similar fungal burden. None of the defense responses that were analyzed in Glb1 lines, such as phenols, iron metabolism, peroxidase activity, or reactive oxygen species (ROS) production, appear to explain their higher survival rates. However, the early induction of the PR genes may be one of the reasons for the observed survival rate of Glb1 lines infected with F. oxysporum. Furthermore, while PR1 expression was induced in Glb1 lines very early on the response to F. oxysporum, this induction was not observed in WT plants.

Understanding the neurological implications of acute and long COVID using brain organoids.

As early as in the acute phase of the coronavirus disease 2019 (COVID-19) pandemic, the research community voiced concerns about the long-term implications of infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), like many other viruses, can trigger chronic disorders that last months or even years. Long COVID, the chronic and persistent disorder lasting more than 12 weeks after the primary infection with SARS-CoV-2, involves a variable number of neurological manifestations, ranging from mild to severe and even fatal. In vitro and in vivo modeling suggest that SARS-CoV-2 infection drives changes within neurons, glia and the brain vasculature. In this Review, we summarize the current understanding of the neuropathology of acute and long COVID, with particular emphasis on the knowledge derived from brain organoid models. We highlight the advantages and main limitations of brain organoids, leveraging their human-derived origin, their similarity in cellular and tissue architecture to human tissues, and their potential to decipher the pathophysiology of long COVID.

Standard Hypercaloric, Hyperproteic vs. Leucine-Enriched Oral Supplements in Patients with Cancer-Induced Sarcopenia, a Randomized Clinical Trial.

(1) Background: Malnutrition frequently affects patients with cancer, and it negatively impacts treatment tolerance, clinical outcomes and survival. Thus, appropriate nutritional screening and early nutrition support are extremely recommended. Currently, a significant number of oral supplements (OS) are commercially available; despite this, there is a lack of evidence for recommending specific OS, including leucine-enriched OS, for nutritional support in patients with cancer. (2) Aim: To compare the clinical evolution of patients with cancer (undergoing systemic treatment) that received standard hypercaloric, whey protein-based hyperproteic oral supplements vs. hypercaloric, hyperproteic leucine-enriched OS using a novel morphofunctional nutritional evaluation. (3) Patients and methods: This paper details an open-label, controlled clinical study in which patients were randomly assigned to receive nutritional treatment with whey protein-based hyperproteic oral supplements (control group) vs. hypercaloric, hyperproteic leucine-enriched OS (intervention group) during a twelve-week period. Forty-six patients were included; epidemiological, clinical, anthropometric, ultrasound (muscle echography of the rectus femoris muscle of the quadriceps and abdominal adipose tissue) and biochemical evaluation were performed. All patients received additional supplementation with vitamin D. (4) Results: Nutritional parameters (including bioimpedance, anthropometric, ultrasound and biochemical variables) of all included patients remained stable after the nutritional intervention. Extracellular mass tended to increase in the patients that received the leucine-enriched formula. Functionality (evaluated through the stand-up test) improved in both groups (p < 0.001). Prealbumin, transferrin levels and superficial adipose tissue increased in the control group (p < 0.05), while self-reported quality of life improved in all the evaluated patients (p < 0.001). (5) Conclusions: Nutritional support with hypercaloric, hyperproteic (with whey protein) OS and vitamin D supplementation were associated with the maintenance of body composition and improvements in functionality and in quality of life in the patients with cancer undergoing systemic treatment. No significant benefits were observed when a leucine-enriched formula was used.

Deciphering peroxisomal reactive species interactome and redox signalling networks.

Plant peroxisomes are highly dynamic organelles with regard to metabolic pathways, number and morphology and participate in different metabolic processes and cell responses to their environment. Peroxisomes from animal and plant cells house a complex system of reactive oxygen species (ROS) production associated to different metabolic pathways which are under control of an important set of enzymatic and non enzymatic antioxidative defenses. Nitric oxide (NO) and its derivate reactive nitrogen species (RNS) are also produced in these organelles. Peroxisomes can regulate ROS and NO/RNS levels to allow their role as signalling molecules. The metabolism of other reactive species such as carbonyl reactive species (CRS) and sulfur reactive species (SRS) in peroxisomes and their relationship with ROS and NO have not been explored in depth. In this review, we define a peroxisomal reactive species interactome (PRSI), including all reactive species ROS, RNS, CRS and SRS, their interaction and effect on target molecules contributing to the dynamic redox/ROS homeostasis and plasticity of peroxisomes, enabling fine-tuned regulation of signalling networks associated with peroxisome-dependent H2O2. Particular attention will be paid to update the information available on H2O2-dependent peroxisomal retrograde signalling and to discuss a specific peroxisomal footprint.

Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial.

Attempts to reduce the human immunodeficiency virus type 1 (HIV-1) reservoir and induce antiretroviral therapy (ART)-free virologic control have largely been unsuccessful. In this phase 1b/2a, open-label, randomized controlled trial using a four-group factorial design, we investigated whether early intervention in newly diagnosed people with HIV-1 with a monoclonal anti-HIV-1 antibody with a CD4-binding site, 3BNC117, followed by a histone deacetylase inhibitor, romidepsin, shortly after ART initiation altered the course of HIV-1 infection ( NCT03041012 ). The trial was undertaken in five hospitals in Denmark and two hospitals in the United Kingdom. The coprimary endpoints were analysis of initial virus decay kinetics and changes in the frequency of CD4+ T cells containing intact HIV-1 provirus from baseline to day 365. Secondary endpoints included changes in the frequency of infected CD4+ T cells and virus-specific CD8+ T cell immunity from baseline to day 365, pre-ART plasma HIV-1 3BNC117 sensitivity, safety and tolerability, and time to loss of virologic control during a 12-week analytical ART interruption that started at day 400. In 55 newly diagnosed people (5 females and 50 males) with HIV-1 who received random allocation treatment, we found that early 3BNC117 treatment with or without romidepsin enhanced plasma HIV-1 RNA decay rates compared to ART only. Furthermore, 3BNC117 treatment accelerated clearance of infected cells compared to ART only. All groups had significant reductions in the frequency of CD4+ T cells containing intact HIV-1 provirus. At day 365, early 3BNC117 + romidepsin was associated with enhanced HIV-1 Gag-specific CD8+ T cell immunity compared to ART only. The observed virological and immunological effects of 3BNC117 were most pronounced in individuals whose pre-ART plasma HIV-1 envelope sequences were antibody sensitive. The results were not disaggregated by sex. Adverse events were mild to moderate and similar between the groups. During a 12-week analytical ART interruption among 20 participants, 3BNC117-treated individuals harboring sensitive viruses were significantly more likely to maintain ART-free virologic control than other participants. We conclude that 3BNC117 at ART initiation enhanced elimination of plasma viruses and infected cells, enhanced HIV-1-specific CD8+ immunity and was associated with sustained ART-free virologic control among persons with 3BNC117-sensitive virus. These findings strongly support interventions administered at the time of ART initiation as a strategy to limit long-term HIV-1 persistence.

Gene network downstream plant stress response modulated by peroxisomal H2O2.

Reactive oxygen species (ROS) act as secondary messengers that can be sensed by specific redox-sensitive proteins responsible for the activation of signal transduction culminating in altered gene expression. The subcellular site, in which modifications in the ROS/oxidation state occur, can also act as a specific cellular redox network signal. The chemical identity of ROS and their subcellular origin is actually a specific imprint on the transcriptome response. In recent years, a number of transcriptomic studies related to altered ROS metabolism in plant peroxisomes have been carried out. In this study, we conducted a meta-analysis of these transcriptomic findings to identify common transcriptional footprints for plant peroxisomal-dependent signaling at early and later time points. These footprints highlight the regulation of various metabolic pathways and gene families, which are also found in plant responses to several abiotic stresses. Major peroxisomal-dependent genes are associated with protein and endoplasmic reticulum (ER) protection at later stages of stress while, at earlier stages, these genes are related to hormone biosynthesis and signaling regulation. Furthermore, in silico analyses allowed us to assign human orthologs to some of the peroxisomal-dependent proteins, which are mainly associated with different cancer pathologies. Peroxisomal footprints provide a valuable resource for assessing and supporting key peroxisomal functions in cellular metabolism under control and stress conditions across species.

IRF7 expression correlates with HIV latency reversal upon specific blockade of immune activation.

The persistence of latent HIV reservoirs allows for viral rebound upon antiretroviral therapy interruption, hindering effective HIV-1 cure. Emerging evidence suggests that modulation of innate immune stimulation could impact viral latency and contribute to the clearing of HIV reservoir. Here, the latency reactivation capacity of a subclass of selective JAK2 inhibitors was characterized as a potential novel therapeutic strategy for HIV-1 cure. Notably, JAK2 inhibitors reversed HIV-1 latency in non-clonal lymphoid and myeloid in vitro models of HIV-1 latency and also ex vivo in CD4+ T cells from ART+ PWH, albeit its function was not dependent on JAK2 expression. Immunophenotypic characterization and whole transcriptomic profiling supported reactivation data, showing common gene expression signatures between latency reactivating agents (LRA; JAK2i fedratinib and PMA) in contrast to other JAK inhibitors, but with significantly fewer affected gene sets in the pathway analysis. In depth evaluation of differentially expressed genes, identified a significant upregulation of IRF7 expression despite the blockade of the JAK-STAT pathway and downregulation of proinflammatory cytokines and chemokines. Moreover, IRF7 expression levels positively correlated with HIV latency reactivation capacity of JAK2 inhibitors and also other common LRAs. Collectively, these results represent a promising step towards HIV eradication by demonstrating the potential of innate immune modulation for reducing the viral reservoir through a novel pathway driven by IRF7.

Synthesis of a Zinc Hydroxystannate/Sepiolite Hybrid Additive to Avoid Fire Propagation and Reduce Smoke Emission of EPDM Rubber Nanocomposites.

A zinc hydroxystannate/sepiolite (SEPZHS) hybrid additive was successfully prepared following a facile wet chemical route synthesis where zinc hydroxystannate (ZHS) nanoparticles were grown on the sepiolite's surface. SEPZHS particles have a fibrillar structure with ZHS nanoparticles homogeneously dispersed and with significantly smaller particle sizes than the synthesized ZHS nanoparticles alone. Sepiolite and SEPZHS were organically modified and introduced in a basic ethylene propylene diene monomer rubber (EPDM) formulation for cable to evaluate the nanocomposite behavior under direct fire sources. The results confirmed the synergistic effect of the hybrid SEPZHS additive in the formation of a most stable and efficient char barrier, thus improving the flame-retardant behavior of EPDM nanocomposite in terms of heat emission, with reductions of more than 40% in the peak of Heat Release Rate (cone calorimeter test), and smoke suppression, with more than 25% reduction in the Total Smoke Production and Smoke Density parameters (smoke chamber test). Moreover, the addition of sepiolite-based additives increased the mechanical properties (hardness) of the nanocomposites, as a result of the matrix reinforcement. This suggests that the SEPZHS hybrid additive may provide a promising option for a new, cost-effective, eco-friendly, yet efficient flame-retardant solution.

Gut microbiome signatures linked to HIV-1 reservoir size and viremia control.

BACKGROUND: The potential role of the gut microbiome as a predictor of immune-mediated HIV-1 control in the absence of antiretroviral therapy (ART) is still unknown. In the BCN02 clinical trial, which combined the MVA.HIVconsv immunogen with the latency-reversing agent romidepsin in early-ART treated HIV-1 infected individuals, 23% (3/13) of participants showed sustained low-levels of plasma viremia during 32 weeks of a monitored ART pause (MAP). Here, we present a multi-omics analysis to identify compositional and functional gut microbiome patterns associated with HIV-1 control in the BCN02 trial. RESULTS: Viremic controllers during the MAP (controllers) exhibited higher Bacteroidales/Clostridiales ratio and lower microbial gene richness before vaccination and throughout the study intervention when compared to non-controllers. Longitudinal assessment indicated that the gut microbiome of controllers was enriched in pro-inflammatory bacteria and depleted in butyrate-producing bacteria and methanogenic archaea. Functional profiling also showed that metabolic pathways related to fatty acid and lipid biosynthesis were significantly increased in controllers. Fecal metaproteome analyses confirmed that baseline functional differences were mainly driven by Clostridiales. Participants with high baseline Bacteroidales/Clostridiales ratio had increased pre-existing immune activation-related transcripts. The Bacteroidales/Clostridiales ratio as well as host immune-activation signatures inversely correlated with HIV-1 reservoir size. CONCLUSIONS: The present proof-of-concept study suggests the Bacteroidales/Clostridiales ratio as a novel gut microbiome signature associated with HIV-1 reservoir size and immune-mediated viral control after ART interruption. Video abstract.

On the single and multiple associations of COVID-19 post-acute sequelae: 6-month prospective cohort study.

Medical research is progressing to clarify the full spectrum of sub-acute and long-term effects of the post-COVID-19 syndrome. However, most manuscripts published to date only analyze the effects of post-COVID-19 in patients discharged from hospital, which may induce significant bias. Here, we propose a pioneering study to analyze the single and multiple associations between post-COVID-19 characteristics with up to 6-months of follow-up in hospitalized and non-hospitalized COVID-19 patients. The cohort study was conducted from May to October 2020 at the University Hospital Virgen de la Nieves, the leading hospital assigned for patients with COVID-19 in Granada, Spain. A total of 372 and 217 patients-with 217 and 207 included in the first and second follow-up visits-were referred 2 and 6 months after diagnosing COVID-19, respectively. We find out that post-COVID-19 clinical and mental health impairment symptoms are correlated with patient gender. Logistic adjustments showed strong statistically robust single and multiple associations of demographic, clinical, mental health, X-ray, laboratory indices, and pulmonary function variables. The functional lung tests are good predictors of chest CT imaging abnormalities in elderly patients. Bilateral lung involvement, subpleural reticulum, ground-glass opacity, peripheral lung lesions, and bronchiectasis were the most common findings of the high-resolution computed tomography images. Non-hospitalized patients suffer more severe thromboembolic events and fatigue than those hospitalized.

Epigenetic landscape in the kick-and-kill therapeutic vaccine BCN02 clinical trial is associated with antiretroviral treatment interruption (ATI) outcome.

BACKGROUND: The BCN02-trial combined therapeutic vaccination with a viral latency reversing agent (romidepsin, RMD) in HIV-1-infected individuals and included a monitored antiretroviral pause (MAP) as an efficacy read-out identifying individuals with an early or late (< or > 4weeks) viral-rebound. Integrated -omics analyses were applied prior treatment interruption to identify markers of virus control during MAP. METHODS: PBMC, whole-genome DNA methylation and transcriptomics were assessed in 14 BCN02 participants, including 8 Early and 4 Late viral-rebound individuals. Chromatin state, histone marks and integration analysis (histone-3 acetylation (H3Ac), viral load, proviral levels and HIV-specific T cells responses) were included. REDUC-trial samples (n = 5) were included as a control group for RMD administration alone. FINDINGS: DNA methylation imprints after receiving the complete intervention discriminated Early versus Late viral-rebound individuals before MAP. Also, differential chromatin accessibility and histone marks at DNA methylation level were detected. Importantly, the differential DNA methylation positions (DMPs) between Early and Late rebounders before MAP were strongly associated with viral load, proviral levels as well as the HIV-specific T-cell responses. Most of these DMPs were already present prior to the intervention and accentuated after RMD infusion. INTERPRETATION: This study identifies host DNA methylation profiles and epigenetic cascades that are predictive of subsequent virus control in a kick-and-kill HIV cure strategy. FUNDING: European Union Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement N°681137-EAVI2020 and N°847943-MISTRAL, the Ministerio de Ciencia e Innovación (SAF2017_89726_R), and the National Institutes of Health-National Institute of Allergy and Infectious Diseases Program Grant P01-AI131568.

Morphofunctional and Molecular Assessment of Nutritional Status in Head and Neck Cancer Patients Undergoing Systemic Treatment: Role of Inflammasome in Clinical Nutrition.

Malnutrition in patients with head and neck cancer is frequent, multifactorial and widely associated with clinical evolution and prognosis. Accurate nutritional assessments allow for early identification of patients at risk of malnutrition in order to start nutritional support and prevent sarcopenia. We aimed to perform a novel morphofunctional nutritional evaluation and explore changes in inflammasome-machinery components in 45 patients with head and neck cancer who are undergoing systemic treatment. To this aim, an epidemiological/clinical/anthropometric/biochemical evaluation was performed. Serum RCP, IL6 and molecular expression of inflammasome-components and inflammatory-associated factors (NOD-like-receptors, inflammasome-activation-components, cytokines and inflammation/apoptosis-related components, cell-cycle and DNA-damage regulators) were evaluated in peripheral-blood mononuclear-cells (PBMCs). Clinical-molecular correlations/associations were analyzed. Coherent and complementary information was obtained in the morphofunctional nutritional assessment of the patients when bioimpedance, anthropometric and ultrasound data were analyzed. These factors were also correlated with different biochemical and molecular parameters, revealing the complementary aspect of the whole evaluation. Serum reactive C protein (RCP) and IL6 were the most reliable parameters for determining patients with decreased standardized phase angle, which is associated with increased mortality in patients with solid malignancies. Several inflammasome-components were dysregulated in patients with malnutrition, decreased phase angle and dependency grade or increased circulating inflammation markers. A molecular fingerprint based on gene-expression of certain inflammasome factors (p27/CCL2/ASC) in PBMCs accurately differentiated patients with and without malnutrition. In conclusion, malnutrition induces a profound alteration in the gene-expression pattern of inflammasome-machinery components in PBMCs. A comprehensive nutritional assessment including novel morphofunctional techniques and molecular markers allows a broad characterization of the nutritional status in cancer patients. Profile of certain inflammasome-components should be further studied as potential targets for nutrition-focused treatment strategies in cancer patients.