Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage

BACKGROUND: LEDGF/p75 (LEDGF) is the main cellular cofactor of HIV-1 integrase (IN). It acts as a tethering factor for IN, and targets the integration of HIV in actively transcribed gene regions of chromatin. A recently developed class of IN allosteric inhibitors can inhibit the LEDGF-IN interaction. RESULTS: We describe a new series of IN-LEDGF allosteric inhibitors, the most active of which is Mut101. We determined the crystal structure of Mut101 in complex with IN and showed that the compound binds to the LEDGF-binding pocket, promoting conformational changes of IN which explain at the atomic level the allosteric effect of the IN/LEDGF interaction inhibitor on IN functions. In vitro, Mut101 inhibited both IN-LEDGF interaction and IN strand transfer activity while enhancing IN-IN interaction. Time of addition experiments indicated that Mut101 behaved as an integration inhibitor. Mut101 was fully active on HIV-1 mutants resistant to INSTIs and other classes of anti-HIV drugs, indicative that this compound has a new mode of action. However, we found that Mut101 also displayed a more potent antiretroviral activity at a post-integration step. Infectivity of viral particles produced in presence of Mut101 was severely decreased. This latter effect also required the binding of the compound to the LEDGF-binding pocket. CONCLUSION: Mut101 has dual anti-HIV-1 activity, at integration and post-integration steps of the viral replication cycle, by binding to a unique target on IN (the LEDGF-binding pocket). The post-integration block of HIV-1 replication in virus-producer cells is the mechanism by which Mut101 is most active as an antiretroviral. To explain this difference between Mut101 antiretroviral activity at integration and post-integration stages, we propose the following model: LEDGF is a nuclear, chromatin-bound protein that is absent in the cytoplasm. Therefore, LEDGF can outcompete compound binding to IN in the nucleus of target cells lowering its antiretroviral activity at integration, but not in the cytoplasm where post-integration production of infectious viral particles takes place

Supplemental material for Clinical and pathological dermatological features of Deficiency of Adenosine Deaminase 2: Multicenter retrospective observational study

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Spotlight on anifrolumab and its potential for the treatment of moderate-to-severe systemic lupus erythematosus: evidence to date

Renaud Felten,1–3 Florence Scher,4 Flora Sagez,1,2 François Chasset,5 Laurent Arnaud1,2,61Rheumatology Department, University Hospital of Strasbourg, Université de Strasbourg, Strasbourg, F-67000, France; 2National Reference Centre for Rare Systemic and Autoimmune Diseases East South-West (RESO), Strasbourg, France; 3Immunology Laboratory, “Immunopathologie et Chimie Thérapeutique”, Institut de Biologie Moléculaire et Cellulaire (IBMC), CNRS UPR3572, Strasbourg, F-67000, France; 4Pharmacy-Sterilisation Department, University Hospital of Strasbourg, University of Strasbourg, Strasbourg, France; 5Faculty of Medicine at Sorbonne University, AP-HP, Dermatology and Allergology Department, Tenon Hospital, Sorbonne University, Paris, F-75020, France; 6Immuno-Rheumatology Laboratory, “Laboratoire d‘ImmunoRhumatologie Moléculaire”, INSERM UMR_S1109, Strasbourg, F-67000, FranceAbstract: Previous reports have described the appearance of systemic lupus erythematosus (SLE) cases following interferon-α (IFN-α) therapy, IFN-regulated gene expression is significantly increased in SLE, and an association between SLE and gene variants belonging to IFN downstream pathways has been shown. Based on this, targeting of IFN and of their signaling pathways has appeared to be interesting developments within the field of SLE therapy. Different specific type I IFN antagonists have been studied in clinical trials and some of those have already reached Phase III. A potential approach would be to target IFN receptors rather than IFN themselves. Anifrolumab (previously MEDI-546) is a fully human monoclonal antibody (Ab) that binds to subunit 1 of the type I IFN receptor (IFNAR1), blocking the action of different type I IFNs (IFN-α, IFN-β and IFN-ω). This drug has been assessed in 11 clinical studies: 9 in SLE, 1 in systemic sclerosis and 1 in rheumatoid arthritis. In SLE, clinical development reached Phase I for 1 study and Phases II and III for 5 and 3 trials, respectively. The Phase IIb, randomized control trial (RCT), double-blind, placebo-controlled study of adults with moderate-to-severe SLE (MUSE trial) showed positive results on the composite primary endpoint SRI-4. Greater efficacy was seen in patients with high baseline IFN gene signature compared with those with low baseline IFN gene signature. Anifrolumab also demonstrated promising results on cutaneous and arthritic manifestations, especially among patients with a high IFN gene signature. The pivotal Treatment of Uncontrolled Lupus via the Interferon IFN Pathway (TULIP 1 and 2 studies are now completed. In August 2018, the promoter announced that the TULIP 1 Phase III trial did not reach its primary endpoint. The release of the completed but not yet published Phase II studies and of the TULIP pivotal trials results will further inform us on the actual therapeutic potential of anifrolumab.Keywords: systemic lupus erythematosus, interferon type I, interferon-alpha, anifrolumab, receptors interfero

Use of Anti-transcriptional Intermediary Factor-1 Gamma Autoantibody in Identifying Adult Dermatomyositis Patients with Cancer: A Systematic Review and Meta-analysis

International audienc

Is neutrophilic dermatosis a manifestation of familial Mediterranean fever?

International audienceObjectives: Familial Mediterranean fever (FMF) is the most frequent monogenic autoinflammatory disease. It is associated with MEFV mutations. Its main features are recurrent episodes of fever and serositis. Patients can display dermatological manifestations such as erysipelas-like erythema, generally considered as a neutrophilic dermatosis (ND). It has been suggested that FMF can be associated with other types of ND. Our aim was to perform a systematic review of the literature to assess the link between ND and FMF.Method: A systematic review of the literature was performed using MEDLINE from 1946 to 2018. Three independent investigators identified reports of non-erysipelas-like erythema neutrophilic dermatosis (NEND) associated with FMF, selected the criteria to establish the diagnosis of FMF and ND, and evaluated the link between the two conditions. FMF-associated NEND was supported by confirmation of both diagnoses and exclusion of other causes of ND.Results: Eighteen articles were selected. Nine articles reported FMF patients with the following NEND: neutrophilic panniculitis (n = 4), Sweet syndrome (n = 6), and pyoderma gangrenosum (n = 1). None of these cases was supported by histological confirmation, fulfilled diagnostic criteria for definitive or probable FMF, or confirmed the exclusion of all the most frequent diseases associated with NEND. As a result, there is insufficient evidence to support a potential relationship between NEND and FMF.Conclusions: The association between FMF and NEND remains unclear. In FMF patients with NEND, every differential diagnosis and alternative cause of NEND should be excluded before drawing any conclusions about a potential causal relationship