References of "Moutschen, Michel"
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See detailThe RIAD peptidomimetic inhibits HIV-1 replication in humanized NSG mice
Singh, Maneesh; Singh, Pratibha; Vaira, Dolores et al

in European Journal of Clinical Investigation (in press)

Background Increased intracellular concentration of cyclic AMP (cAMP) in T cells is associated with various immunodeficiency conditions including human immunodeficiency virus (HIV) infection. Several ... [more ▼]

Background Increased intracellular concentration of cyclic AMP (cAMP) in T cells is associated with various immunodeficiency conditions including human immunodeficiency virus (HIV) infection. Several reports indicate a critical role of activated protein kinase A (PKA) in the susceptibility of cells to HIV infection. We have used a cell permeable, stable peptidomimetic version (P3) of the RI-anchoring disruptor (RIAD), which prevents PKA interaction with A-kinase-anchoring proteins (AKAPs). It is known that RIAD peptide abrogates effects of localized cAMP signalling through anchored type I PKA in lymphocytes and prevents murine AIDS (MAIDS) infection when expressed as a transgene in mice. Methods and Results In vitro HIV-infected human peripheral blood mononuclear cells (PBMCs) show reduced levels of p24 and intracellular cAMP in T cells when treated with RIAD peptidomimetic (RIAD-P3). Humanized NOD/SCID/IL2cnull (NSG) mice infected with HIV-1 JRCSF and treated with RIAD-P3 (3􏰀5 mg) once every 2 weeks showed significantly reduced levels of viral load at +28, +42 and +56 days and increased CD4 numbers at +56 days after the start of treatment. RIAD-P3-treated humanized mice had lower levels of intracellular cAMP in T cells sorted from splenocytes. Conclusions Treatment with RIAD-P3 limits HIV-1 viral replication and stabilizes CD4 levels by mechanisms involving cAMP/PKA-I pathway in human PBMCs and humanized NSG mice. [less ▲]

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See detailObesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue
ESSER, Nathalie ULg; L'Homme, Laurent ULg; DE ROOVER, Arnaud ULg et al

in Diabetologia (2013), 56

Aims/hypothesis Obesity is a heterogeneous condition comprising both individuals who remain metabolically healthy (MHO) and those who develop metabolic disorders (metabolically unhealthy, MUO). Adipose ... [more ▼]

Aims/hypothesis Obesity is a heterogeneous condition comprising both individuals who remain metabolically healthy (MHO) and those who develop metabolic disorders (metabolically unhealthy, MUO). Adipose tissue is also heterogeneous in that its visceral component is more frequently associated with metabolic dysfunction than its subcutaneous component. The development of metabolic disorders is partly mediated by the NLR family pyrin domain containing-3 (NLRP3) inflammasome, which increases the secretion of inflammatory cytokines via activation of caspase-1. We compared the immunological profile and NLRP3 activity in adipose tissue between MUO and MHO individuals. Methods MHO and MUO phenotypes were defined, respectively, as the absence and the presence of the metabolic syndrome. Cellular composition and intrinsic inflammasome activity were investigated by flow cytometry, quantitative RTPCR and tissue culture studies in subcutaneous and visceral adipose tissue from 23 MUO, 21 MHO and nine lean individuals. Results We found significant differences between the three study groups, including an increased secretion of IL-1β, increased expression of IL1B and NLRP3, increased number of adipose tissue macrophages and decreased number of regulatory T cells in the visceral adipose tissue of MUO patients compared with MHO and lean participants. In macrophages derived from visceral adipose tissue, both caspase-1 activity and IL-1β levels were higher in MUO patients than in MHO patients. Furthermore, caspase-1 activity was higher in CD11c+CD206+ adipose tissue macrophages than in CD11c−CD206+ cells. Conclusions/interpretation The MUO phenotype seems to be associated with an increased activation of the NLPR3 inflammasome in macrophages infiltrating visceral adipose tissue, and a less favourable inflammatory profile compared with the MHO phenotype. [less ▲]

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See detailDifférences d’activité de l’inflammasome NLRP3 entre sujets obèses avec et sans anomalies métaboliques
Esser, Nathalie ULg; L'Homme, Laurent ULg; DE ROOVER, Arnaud ULg et al

in Diabètes & Métabolism (2013, March), 39(suppl 1), 102

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See detailRôle de la vitamine D dans l'infection par le VIH: revue des connaissances actuelles
Pirotte, Benoît ULg; Rassenfosse, Marie ULg; Collin, Romain ULg et al

in Revue Médicale de Liège (2013), 68(1), 25-31

La vitamine D possède des propriétés sur le métabolisme phosphocalcique mais aussi dans diverses pathologies telles que les maladies auto-immunes, les cancers, les maladies cardio-vasculaires, l’excès de ... [more ▼]

La vitamine D possède des propriétés sur le métabolisme phosphocalcique mais aussi dans diverses pathologies telles que les maladies auto-immunes, les cancers, les maladies cardio-vasculaires, l’excès de poids ou encore certaines infections. Nous nous intéressons ici aux relations frappantes qui existent entre la vitamine D et le VIH. Cette hormone joue assurément un rôle important dans l’infection par le VIH, tant au niveau squelettique qu’au niveau de l’évolution de la maladie elle-même. Nous remarquons en effet qu’un déficit en vitamine D est très souvent associé à l’infection par le VIH. De plus, un taux indétectable de cette hormone chez les patients séropositifs est associé à une infection cliniquement plus avancée et à une mortalité accrue. Ainsi, le déficit en vitamine D doit être considéré comme un cofacteur important de la progression de l’infection par le VIH. En effet, la vitamine D augmente l’activité des macrophages, entre autres via le processus d’autophagie, ce qui permet d’inhiber l’infection par le VIH-1. Nous parlerons ensuite de l’impact de certains traitements antirétroviraux sur l’altération du métabolisme de la vitamine D. Nous évaluerons enfin le bénéfice d’une supplémentation en vitamine D chez ces patients. [less ▲]

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See detailPerceptions de la pratique des essais cliniques sur le VIH/sida par les médecins prescripteurs des antirétroviraux agréés de Kinshasa (RD Congo)
Lubangi, MM; MOUTSCHEN, Michel ULg

in Bulletin de la Société de Pathologie Exotique (2012)

Le but de cette étude, réalisée entre novembre 2005 et janvier 2006 auprès des prescripteurs d’antirétroviraux (ARV), était de cerner leurs perceptions sur les enjeux contextuels liés à la pratique des ... [more ▼]

Le but de cette étude, réalisée entre novembre 2005 et janvier 2006 auprès des prescripteurs d’antirétroviraux (ARV), était de cerner leurs perceptions sur les enjeux contextuels liés à la pratique des essais sur le VIH/sida à Kinshasa. Pour effectuer le repérage de ces enjeux, un ques- tionnaire a été élaboré et finalisé à la suite de la phase explo- ratoire de notre enquête afin d’apprécier les points de vue des médecins agréés par le Programme national de lutte contre le sida du Congo (PNLS) et qui jouent le premier rôle dans le contexte de leur pratique professionnelle. Sur 50 médecins sollicités pour participer à notre enquête, 35 ont retourné le questionnaire, dix n’étaient pas disponibles au moment de l’enquête et cinq n’ont pas retourné le questionnaire à l’adresse et dans le délai que nous avions indiqués. Les résul- tats obtenus témoignent de la nécessité de renforcer les capa- cités des acteurs locaux. Un des objectifs visés par la conduite locale de ces essais étant le transfert des connais- sances, il est nécessaire, au vu des résultats, d’affirmer le rôle pédagogique du comité d’éthique local. Cela devra permettre de relever le défi de la contextualisation et de réduire les tensions susceptibles de compromettre le bon déroulement des essais cliniques. [less ▲]

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See detailHYGIENE ET PROBLEMES INFECTIEUX EN GERIATRIE
Moutschen, Michel ULg; FRIPPIAT, Frédéric ULg; CHRISTIAENS, Geneviève ULg et al

Conference (2012, June 14)

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See detailAn improved protocol for efficient engraftment in NOD/LTSZ-SCIDIL-2Rgammanull mice allows HIV replication and development of anti-HIV immune responses.
Singh, Maneesh; Singh, Pratibha; Gaudray, Gilles et al

in PloS one (2012), 7(6), 38491

Cord blood hematopoietic progenitor cells (CB-HPCs) transplanted immunodeficient NOD/LtsZ-scidIL2Rgamma(null) (NSG) and NOD/SCID/IL2Rgamma(null) (NOG) mice need efficient human cell engraftment for long ... [more ▼]

Cord blood hematopoietic progenitor cells (CB-HPCs) transplanted immunodeficient NOD/LtsZ-scidIL2Rgamma(null) (NSG) and NOD/SCID/IL2Rgamma(null) (NOG) mice need efficient human cell engraftment for long-term HIV-1 replication studies. Total body irradiation (TBI) is a classical myeloablation regimen used to improve engraftment levels of human cells in these humanized mice. Some recent reports suggest the use of busulfan as a myeloablation regimen to transplant HPCs in neonatal and adult NSG mice. In the present study, we further ameliorated the busulfan myeloablation regimen with fresh CB-CD34+cell transplantation in 3-4 week old NSG mice. In this CB-CD34+transplanted NSG mice engraftment efficiency of human CD45+cell is over 90% in peripheral blood. Optimal engraftment promoted early and increased CD3+T cell levels, with better lymphoid tissue development and prolonged human cell chimerism over 300 days. These humanized NSG mice have shown long-lasting viremia after HIV-1JRCSF and HIV-1Bal inoculation through intravenous and rectal routes. We also saw a gradual decline of the CD4+T cell count, widespread immune activation, up-regulation of inflammation marker and microbial translocation after HIV-1 infection. Humanized NSG mice reconstituted according to our new protocol produced, moderate cellular and humoral immune responses to HIV-1 postinfection. We believe that NSG mice reconstituted according to our easy to use protocol will provide a better in vivo model for HIV-1 replication and anti-HIV-1 therapy trials. [less ▲]

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See detailTreatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients.
Theys, Kristof; Deforche, Koen; Vercauteren, Jurgen et al

in Retrovirology (2012), 9

BACKGROUND: The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug ... [more ▼]

BACKGROUND: The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness and virulence in absence of therapy and major resistance mutations. We previously designed a modeling technique that quantifies genotypic footprints of in vivo treatment selective pressure, including both drug resistance mutations and polymorphic compensatory mutations, through the quantitative description of a fitness landscape from virus genetic sequences. RESULTS: Genotypic correlates of viral load and CD4 cell count were evaluated in subtype B sequences from recently diagnosed treatment-naive patients enrolled in the SPREAD programme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitness landscapes with baseline viral load and CD4 cell count was evaluated using regression techniques. Protease genotypic variability estimated to increase fitness during treatment was associated with higher viral load and lower CD4 cell counts also in treatment-naive patients, which could primarily be attributed to well-known compensatory mutations at highly polymorphic positions. By contrast, treatment-related mutations in reverse transcriptase could not explain viral load or CD4 cell count variability. CONCLUSIONS: These results suggest that polymorphic compensatory mutations in protease, reported to be selected during treatment, may improve the replicative capacity of HIV-1 even in absence of drug selective pressure or major resistance mutations. The presence of this polymorphic variation may either reflect a history of drug selective pressure, i.e. transmission from a treated patient, or merely be a result of diversity in wild-type virus. Our findings suggest that transmitted drug resistance has the potential to contribute to faster disease progression in the newly infected host and to shape the HIV-1 epidemic at a population level. [less ▲]

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See detailFidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials.
Crook, Derrick W.; Walker, A. Sarah; Kean, Yin et al

in Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America (2012), 55 Suppl 2

Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both ... [more ▼]

Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%-51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%-60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13-40 days), driven by 7 (1.2%) fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI. [less ▲]

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See detailAn Improved Protocol for Efficient Engraftment in NOD/ LTSZ-SCIDIL-2RcNULL Mice Allows HIV Replication and Development of Anti-HIV Immune Responses
Singh, Maneesh; Singh; Gaudray et al

in PLoS ONE (2012), 7(6), 38491

Cord blood hematopoietic progenitor cells (CB-HPCs) transplanted immunodeficient NOD/LtsZ-scidIL2Rcnull (NSG) and NOD/SCID/IL2Rcnull (NOG) mice need efficient human cell engraftment for long-term HIV-1 ... [more ▼]

Cord blood hematopoietic progenitor cells (CB-HPCs) transplanted immunodeficient NOD/LtsZ-scidIL2Rcnull (NSG) and NOD/SCID/IL2Rcnull (NOG) mice need efficient human cell engraftment for long-term HIV-1 replication studies. Total body irradiation (TBI) is a classical myeloablation regimen used to improve engraftment levels of human cells in these humanized mice. Some recent reports suggest the use of busulfan as a myeloablation regimen to transplant HPCs in neonatal and adult NSG mice. In the present study, we further ameliorated the busulfan myeloablation regimen with fresh CB-CD34+cell transplantation in 3–4 week old NSG mice. In this CB-CD34+transplanted NSG mice engraftment efficiency of human CD45+cell is over 90% in peripheral blood. Optimal engraftment promoted early and increased CD3+T cell levels, with better lymphoid tissue development and prolonged human cell chimerism over 300 days. These humanized NSG mice have shown long-lasting viremia after HIV-1JRCSF and HIV-1Bal inoculation through intravenous and rectal routes. We also saw a gradual decline of the CD4+T cell count, widespread immune activation, up-regulation of inflammation marker and microbial translocation after HIV-1 infection. Humanized NSG mice reconstituted according to our new protocol produced, moderate cellular and humoral immune responses to HIV-1 postinfection. We believe that NSG mice reconstituted according to our easy to use protocol will provide a better in vivo model for HIV-1 replication and anti-HIV-1 therapy trials. [less ▲]

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See detailDeleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity.
Lopez-Herrera, Gabriela; Tampella, Giacomo; Pan-Hammarstrom, Qiang et al

in American Journal of Human Genetics (2012), 90(6), 986-1001

Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive ... [more ▼]

Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity. [less ▲]

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See detailA national cohort of HIV-infected patients in Belgium: design and main characteristics.
Van Beckhoven, D.; Buve, A.; Ruelle, J. et al

in Acta Clinica Belgica (2012), 67(5), 333-7

In Belgium, individual laboratory and treatment data of all HIV-infected patients seen in the 9 AIDS Reference Centres and 7 AIDS Reference Laboratories are collected prospectively since 2006. We present ... [more ▼]

In Belgium, individual laboratory and treatment data of all HIV-infected patients seen in the 9 AIDS Reference Centres and 7 AIDS Reference Laboratories are collected prospectively since 2006. We present here an analysis of patients recorded in the cohort database between 1st of January 2006 and 31st of December 2008. During that period, 11982 patients were under medical follow-up in Belgium. Sixty-one percent of the patients were male and the median age was 39.8 at the time of first recorded viral load. Among the patients whose nationality or probable mode of transmission was recorded, nearly half (48.0%) were Belgian and 38.3% originated from Sub-Saharan Africa; heterosexual contacts were reported in the majority of cases (56.0%) followed by homosexual contacts (35.3%). A total of 145 deaths were reported. Around three quarters of the patients were on ART. The median CD4 cell count rose from 470 cells/mm3 in 2006 to 501 cells/mm3 in 2008. This cohort enabled us to obtain comprehensive information on the numbers and characteristics of HIV-infected patients currently being followed up in Belgium, and on trends in antiretroviral therapy and biological results. This will serve for planning purposes, evaluation of access to care and as a source of information for further studies. [less ▲]

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See detail[Gentetics, environment and determinants of autoimmune diseases].
MOUTSCHEN, Michel ULg

in Revue Médicale de Liège (2012), 67

We initiate this review article by a brief description of a few monogenic autoimmune diseases such as the APECED and the IPEX syndrome because they allow understand the fundamental mechanisms of self ... [more ▼]

We initiate this review article by a brief description of a few monogenic autoimmune diseases such as the APECED and the IPEX syndrome because they allow understand the fundamental mechanisms of self tolerance. Next we describe with more details the complex autoimmune diseases and discuss the recent data regarding the associated genetic and environmental factors and their modes of interaction. The conclusion of the article deals with the practical implications of this inherent complexity for the researcher and the clinician. [less ▲]

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See detailVitamine D et maladies infectieuses
CAVALIER, Etienne ULg; MOUTSCHEN, Michel ULg; Brunel, Elodie ULg

Conference (2011, November 24)

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See detailMucosal junctions: open doors to HPV and HIV infections?
Herfs, Michael ULg; Hubert, Pascale ULg; Moutschen, Michel ULg et al

in Trends in microbiology (2011), 19(3), 114-120

Throughout adult life, new developmental commitment of adult stem cells causes reversible epithelial replacements in various mucosal surfaces, including the uterine cervix and the anal canal. Located at ... [more ▼]

Throughout adult life, new developmental commitment of adult stem cells causes reversible epithelial replacements in various mucosal surfaces, including the uterine cervix and the anal canal. Located at the squamocolumnar junctions, these metaplastic conversions are associated with chronic inflammation and deregulated expression of soluble and cell-membrane factors important for antiviral immune response. In this paper, we propose that these histological and immunological features increase the susceptibility of these metaplastic microenvironments to human papillomavirus and human immunodeficiency virus infections. Identification of the anatomical sites and cell populations within the anogenital tract, which is the site primary infected by these viruses, is crucial for the understanding of the pathogenesis of viral disease and development of antiviral strategies. [less ▲]

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See detailMice with Disrupted Type I Protein Kinase A Anchoring in T Cells Resist Retrovirus-Induced Immunodeficiency
Mosenden, Randi; Singh, Pratibha; Cornez, Isabelle et al

in Journal of Immunology (2011), 186(9), 5119-30

Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C ... [more ▼]

Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C-terminal Src kinase. RI anchoring disruptor (RIAD) is a high-affinity competitor peptide that specifically displaces type I PKA from A-kinase anchoring proteins. In this study, we disrupted type I PKA anchoring in peripheral T cells by expressing a soluble ezrin fragment with RIAD inserted in place of the endogenous A-kinase binding domain under the lck distal promoter in mice. Peripheral T cells from mice expressing the RIAD fusion protein (RIAD-transgenic mice) displayed augmented basal and TCR-activated signaling, enhanced T cell responsiveness assessed as IL-2 secretion, and reduced sensitivity to PGE2- and cAMP-mediated inhibition of T cell function. Hyperactivation of the cAMP–type I PKA pathway is involved in the T cell dysfunction of HIV infection, as well as murine AIDS, a disease model induced by infection of C57BL/6 mice with LP-BM5, a mixture of attenuated murine leukemia viruses. LP-BM5–infected RIADtransgenic mice resist progression of murine AIDS and have improved viral control. This underscores the cAMP–type I PKA pathway in T cells as a putative target for therapeutic intervention in immunodeficiency diseases. [less ▲]

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See detailSyphilis treatment in the human immunodeficiency virus-infected patient: follow the guidelines.
FRIPPIAT, Frédéric ULg; Moutschen, Michel ULg

in Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America (2011), 53(8), 845

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