COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study

Background To date, few data on paediatric COVID-19 have been published, and most reports originate from China. This study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across Europe to inform physicians and health-care service planning during the ongoing pandemic. Methods This multicentre cohort study involved 82 participating health-care institutions across 25 European countries, using a well established research network—the Paediatric Tuberculosis Network European Trials Group (ptbnet)—that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. We included all individuals aged 18 years or younger with confirmed SARS-CoV-2 infection, detected at any anatomical site by RT-PCR, between April 1 and April 24, 2020, during the initial peak of the European COVID-19 pandemic. We explored factors associated with need for intensive care unit (ICU) admission and initiation of drug treatment for COVID-19 using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with ICU admission. Findings 582 individuals with PCR-confirmed SARS-CoV-2 infection were included, with a median age of 5·0 years (IQR 0·5–12·0) and a sex ratio of 1·15 males per female. 145 (25%) had pre-existing medical conditions. 363 (62%) individuals were admitted to hospital. 48 (8%) individuals required ICU admission, 25 (4%) mechanical ventilation (median duration 7 days, IQR 2–11, range 1–34), 19 (3%) inotropic support, and one (<1%) extracorporeal membrane oxygenation. Significant risk factors for requiring ICU admission in multivariable analyses were being younger than 1 month (odds ratio 5·06, 95% CI 1·72–14·87; p=0·0035), male sex (2·12, 1·06–4·21; p=0·033), pre-existing medical conditions (3·27, 1·67–6·42; p=0·0015), and presence of lower respiratory tract infection signs or symptoms at presentation (10·46, 5·16–21·23; p<0·0001). The most frequently used drug with antiviral activity was hydroxychloroquine (40 [7%] patients), followed by remdesivir (17 [3%] patients), lopinavir–ritonavir (six [1%] patients), and oseltamivir (three [1%] patients). Immunomodulatory medication used included corticosteroids (22 [4%] patients), intravenous immunoglobulin (seven [1%] patients), tocilizumab (four [1%] patients), anakinra (three [1%] patients), and siltuximab (one [<1%] patient). Four children died (case-fatality rate 0·69%, 95% CI 0·20–1·82); at study end, the remaining 578 were alive and only 25 (4%) were still symptomatic or requiring respiratory support. Interpretation COVID-19 is generally a mild disease in children, including infants. However, a small proportion develop severe disease requiring ICU admission and prolonged ventilation, although fatal outcome is overall rare. The data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed. Funding ptbnet is supported by Deutsche Gesellschaft für Internationale Zusammenarbeit

HIV latency: should we shock or lock?

Combinatory antiretroviral therapy (cART) increases the survival and quality of life of HIV-1-infected patients. However, interruption of therapy almost invariably leads to the re-emergence of detectable viral replication because HIV-1 persists in viral latent reservoirs. Improved understanding of the molecular mechanisms involved in HIV-1 latency has paved the way for innovative strategies that attempt to purge latent virus. In this article we discuss the results of the broadly explored ‘shock and kill’ strategy, and also highlight the major hurdles facing this approach. Finally, we present recent innovative works suggesting that locking out latent proviruses could be a potential alternative therapeutic strategy.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Preclinical shock strategies to reactivate latent HIV-1: an update

Purpose of review The 'shock and kill' strategy consists of activating HIV-1 expression to allow latently infected cells to die from viral cytopathic effects or host cytolytic immune effectors. This strategy relies on small molecules, called latency reversing agents, which activate HIV transcription. Recent findings Several mechanisms operating at the transcriptional level are involved in the establishment and maintenance of HIV-1 latency, including the absence of crucial inducible host transcription factors, epigenetic silencing, and the sequestration of the positive transcription elongation factor B. Progresses made toward the understanding of the molecular mechanisms of HIV-1 transcriptional repression have led to the identification of latency reversing agents that activate HIV transcription, such as histone deacetylase inhibitors or protein kinase C agonists. Multiple studies have recently pointed interesting ways to optimize the shock strategy by using combinations of latency reversing agents with an appropriate time schedule. Summary Combining latency reversing agents appears as one potential strategy for therapy against HIV-1 latency.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Role of Sp1 and CTIP2 in the transcriptional regulation of HTLV-1

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Role of post-translational modifications of CTIP2 in transcriptional regulation of HTLV-1.

- Introduction :Human T-lymphotropic Virus 1 (HTLV-1) infects 15-20 million people worldwide and is responsible of two major diseases :adult T cell leukemia and HTLV-1-associated myelopathy⁄tropical spastic paraparesis. HTLV-1 infection is characterized by viral latency in the large majority of infected cells and by the absence of viremia. These features are thought to be due to the transcriptional repression of viral expression in vivo. Latency, which results from transcriptional silencing in vivo, represents a viral strategy to escape from the host immune system and allow tumor development. Sp1 has been demonstrated as an important regulator of eukaryotic promoter transcriptional activity, we here analyzed the HTLV-1 Long Terminal Repeat (LTR) sequence for other potential Sp1 sites and studied the role of all the Sp1 sites in a nucleosomal context and in both HTLV-1 sense and antisense LTR promoter activity. In the context of HIV-1 latency, our laboratory have shown that the co-factor CTIP2 (COUP-TF interacting Factor 2)/Bcl11b (B-cell CLL/lymphoma 11b), a transcriptional factor involved in the development and lymphomagenesis, is recruited to the HIV-1 and p21 promoter via its association with the transcription factor Sp1 thereby silencing genes transcription through interactions with HDACs and the HMT SUV39H1. Recently, we have reported that CTIP2 interacts with and inhibits the positive transcription elongation factor b complex (P-TEFb, composed of CDK9 and human cyclin T1 or T2) for which deregulations are associated with various type of human malignancies and cardiomyocytes hypertrophy. Moreover, we showed that HMGA1 (High Mobility Group A1), a protein highly expressed during embryogenesis and in virtually all aggressive human cancers studied to date, is involved in the recruitment of the P-TEFb repressor CTIP2 and/or the CTIP2-repressed P-TEFb snRNP (small nuclear ribonucleo-protein complex) to target promoters. - Aims :The aim of this study is to further characterize the epigenetic control of the HTLV-1 gene expression in latently-infected cells with a special emphasis on the role of Sp1, CTIP-2 and their cofactors.- Methods and results :In silico analysis of the nucleotide sequence of the HTLV-1 LTR promoter revealed the presence of two additional potential Sp1 binding sites within the R region. We demonstrated that the Sp1 and Sp3 transcription factors bound in vitro to these sites by EMSAs and supershift experiments. By competition assays, we compared the binding affinity for Sp1 of all six different HTLV-1 Sp1 binding sites and demonstrated, by chromatin immunprecipitation experiments, Sp1 recruitment in vivo to the newly identified Sp1 sites. We demonstrated in the nucleosomal context of an episomal reporter vector that the Sp1 sites interfered with both the sense and antisense LTR transcription. Interestingly, we showed that the two Sp1 binding sites located in the R region of the LTR exhibited together a repressor effect on the LTR sense transcriptional activity but had no effect on the LTR antisense activity. Interestingly, our preliminary results demonstrated that CTIP2 is able to repress the TAXHTLV-1- mediated transactivation of the HTLV-1 promoters by luciferase reporter assays. CTIP2 interacts with the HAT p300 and is involved in transcriptional activation of the IL-2 promoter in T lymphocytes. We postulate that the function of CTIP2 might be modulated by posttranslational modifications of the protein. To test this hypothesis, we evaluated posttranslational modifications of overexpressed CTIP2 protein by western blot using antibodies directed against acetylated lysine and we identified by mass spectrometry at least 5 acetylated residues. Interestingly, our preliminary results showed that the substitution of a single acetylable residue by an arginine, a non-acetylable residue that mimics a constitutively hypoacetylated lysine, impede the global acetylation of CTIP2. Moreover, this substitution also interferes with the ability of CTIP2 to inhibit the Tax-mediated transactivation of the HTLV-1 promoters. Furthermore, we have demonstrated by ChIP assays the recruitment in vivo of CTIP2 to the HTLV-1 LTR in a latently-infected cell line (TL-Om1) but not in a HTLV-1 productive cell line (SLB1).- Conclusions :Taken together, our results demonstrate the presence of two new functional Sp1 binding sites located in the R region of the HTLV-1 LTR, which act as negative cis-regulatory elements of sense transcription. Furthermore, our recent data suggest that CTIP2 is a major regulator of the viral transcription and may be important for the viral latency potentially involving the multienzymatic complexes that interact with CTIP2.info:eu-repo/semantics/nonPublishe