References of "Moutschen, Michel"
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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 detailGentetics, 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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See detailComparison of phenotypic and genotypic tropism determination in triple-class-experienced HIV patients eligible for maraviroc treatment.
Vandekerckhove, Linos; Verhofstede, Chris; Demecheleer, Els et al

in Journal of Antimicrobial Chemotherapy (2011), 66(2), 265-72

BACKGROUND: Determination of HIV-1 tropism is a pre-requisite to the use of CCR5 antagonists. This study evaluated the potential of population genotypic tropism tests (GTTs) in clinical practice, and the ... [more ▼]

BACKGROUND: Determination of HIV-1 tropism is a pre-requisite to the use of CCR5 antagonists. This study evaluated the potential of population genotypic tropism tests (GTTs) in clinical practice, and the correlation with phenotypic tropism tests (PTTs) in patients accessing routine HIV care. METHODS: Forty-nine consecutive plasma samples for which an original Trofile(TM) assay was performed were obtained from triple-class-experienced patients in need of a therapy change. Viral tropism was defined as the consensus of three or more tropism calls obtained from the combination of two independent population PTT assays (Trofile Biosciences, San Francisco, CA, USA, and Virco, Beerse, Belgium), population GTTs and GTTs based on ultra-deep sequencing. If no consensus was reached, a clonal PTT was performed in order to finalize the tropism call. This two-step approach allowed the definition of a reference tropism call. RESULTS: According to the reference tropism result, 35/49 samples were CCR5 tropic (R5) (patients eligible for maraviroc treatment) and 14/49 were assigned as non-R5 tropic. The non-R5 samples [patients not eligible for maraviroc treatment according to the FDA/European Medicines Agency (EMEA) label] group included both the CXCR4 (X4) samples and the dual and mixed CCR5/CXCR4 (R5/X4) samples. Compared with Trofile(TM) population PTTs, population GTTs showed a higher sensitivity (97%) and a higher negative predictive value (91%), but almost equal specificity and an equal positive predictive value. CONCLUSIONS: In line with recent reports from clinical trial data, our data support the use of population genotypic tropism testing as a tool for tropism determination before the start of maraviroc. [less ▲]

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See detailA pauci-symptomatic case of documented Hantavirus (Puumala) infection in a patient under anti-TNF treatment.
Moutschen, Pierre; Bourhaba, Maryam ULg; FRIPPIAT, Frédéric ULg et al

in Journal of Clinical Virology (2011), 50(3), 247-8

We describe the case of an 18-yr-old male under anti-TNF treatment for Crohn's disease for more than 8 months. He developed fever and biological inflammatory syndrome without absolutely no accompanying ... [more ▼]

We describe the case of an 18-yr-old male under anti-TNF treatment for Crohn's disease for more than 8 months. He developed fever and biological inflammatory syndrome without absolutely no accompanying sign or symptom or paraclinical abnormality despite extensive work-up performed in the context of his immunocompromised state. Symptoms disappeared after 10 days and a diagnosis of Puumala infection was made retrospectively on a serological basis. The case illustrates that anti-TNF treatment does not worsen the course of Puumala infection and could even be associated with a milder clinical picture. [less ▲]

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See detailDes interactions complexes entre les origines du VIH et sa pandemie, les activites coloniales en Afrique et la medecine coloniale Belge au Congo
DOUPAGNE, Gaëlle ULg; Toukouki, A.; Moutschen, Michel ULg

in Revue Médicale de Liège (2011), 66(9), 478-84

In this review article on the origin of HIV, we start from a historical fact which involved physicians from Liege working in Belgian Congo: the vaccination against polio of hundreds of thousands of ... [more ▼]

In this review article on the origin of HIV, we start from a historical fact which involved physicians from Liege working in Belgian Congo: the vaccination against polio of hundreds of thousands of Congolese between 1957 and 1960. We explain the genesis of an alternative hypothesis postulating that this campaign was at the origin of HIV pandemy. We show that the hypothesis is unfounded in view of genetic and epidemiological evidence on the one hand and after thorough examination of the activity reports of the Laboratoire Medical de Stanleyville on the other. In the second part of the article, we analyse the importance of other factors which might have contributed to the emergence of the pandemy. Some of these are clearly iatrogenic such as the prophylactic injections of pentamidine against trypanosomiasis, others are of demographic and sociological nature. All of them have a direct link with colonisation. [less ▲]

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See detailVaccinations in patients with immune-mediated inflammatory diseases.
Rahier, Jean-Francois; Moutschen, Michel ULg; Van Gompel, Alfons et al

in Rheumatology (2010), 49(10), 1815-27

Patients with immune-mediated inflammatory diseases (IMID) such as RA, IBD or psoriasis, are at increased risk of infection, partially because of the disease itself, but mostly because of treatment with ... [more ▼]

Patients with immune-mediated inflammatory diseases (IMID) such as RA, IBD or psoriasis, are at increased risk of infection, partially because of the disease itself, but mostly because of treatment with immunomodulatory or immunosuppressive drugs. In spite of their elevated risk for vaccine-preventable disease, vaccination coverage in IMID patients is surprisingly low. This review summarizes current literature data on vaccine safety and efficacy in IMID patients treated with immunosuppressive or immunomodulatory drugs and formulates best-practice recommendations on vaccination in this population. Especially in the current era of biological therapies, including TNF-blocking agents, special consideration should be given to vaccination strategies in IMID patients. Clinical evidence indicates that immunization of IMID patients does not increase clinical or laboratory parameters of disease activity. Live vaccines are contraindicated in immunocompromized individuals, but non-live vaccines can safely be given. Although the reduced quality of the immune response in patients under immunotherapy may have a negative impact on vaccination efficacy in this population, adequate humoral response to vaccination in IMID patients has been demonstrated for hepatitis B, influenza and pneumococcal vaccination. Vaccination status is best checked and updated before the start of immunomodulatory therapy: live vaccines are not contraindicated at that time and inactivated vaccines elicit an optimal immune response in immunocompetent individuals. [less ▲]

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See detailThymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes.
Geenen, Vincent ULg; Mottet, Marie ULg; Dardenne, Olivier ULg et al

in Current Opinion in Pharmacology (2010), 10

Before being able to react against infectious non-self antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins and this critical process takes place only ... [more ▼]

Before being able to react against infectious non-self antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins and this critical process takes place only in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programming central self-tolerance to pancreatic insulin-secreting islet β cells, leading to the breakdown of immune homeostasis with an enrichment of islet β-cell reactive effector T cells and a deficiency of β-cell specific natural regulatory T cells (nTregs) in the peripheral T-lymphocyte repertoire. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin family expressed during fetal life by the thymic epithelium under the control of the autoimmune regulator (AIRE) gene/protein. The very low degree of insulin gene transcription in normal murine and human thymus explains why the insulin protein is poorly tolerogenic as evidenced in many studies, including the failure of all clinical trials that have attempted immune tolerance to islet β cells via various methods of insulin administration. Based on the close homology and cross-tolerance between insulin, the primary T1D autoantigen, and IGF-2, the dominant self-antigen of the insulin family, a novel type of vaccination, so-called “negative/tolerogenic self-vaccination”, is currently being developed for prevention and cure of T1D. If this approach were found to be effective for reprogramming immunological tolerance in T1D, it could pave the way for the design of other self-vaccines against autoimmune endocrine diseases, as well as other organ-specific autoimmune diseases. [less ▲]

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See detailLong-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 phase iii trials.
Steigbigel, Roy T; Cooper, David A; Teppler, Hedy et al

in Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America (2010), 50(4), 605-12

BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus ... [more ▼]

BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone. [less ▲]

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See detailFibromyalgia and related conditions: Electromyogram profile during isometric muscle contraction
Maquet, Didier ULg; Croisier, Jean-Louis ULg; Dupont, Catherine ULg et al

in Joint Bone Spine (2010), 77

Objectives: To evaluate electromyogram (EMG) profiles in patients with three related conditions: fibromyalgia, chronic fatigue syndrome, and depression. Methods: We studied 44 healthy volunteers, 22 ... [more ▼]

Objectives: To evaluate electromyogram (EMG) profiles in patients with three related conditions: fibromyalgia, chronic fatigue syndrome, and depression. Methods: We studied 44 healthy volunteers, 22 patients with fibromyalgia, 11 patients with chronic fatigue syndrome, and 10 patients admitted for depression. The trapezius electromyogram was recorded during maximally sustained, bilateral, 90◦ abduction of the shoulders. EMG signal frequency and amplitude were measured throughout the test. Results: In the fibromyalgia group, isometric contraction duration was significantly shorter than in the other two patient groups (P < 0.001) and the EMG frequency and amplitude pattern indicated premature discontinuation of the muscle contraction. Findings in the chronic fatigue patients were similar to those in the healthy controls. The patients with depression had a distinctive EMG profile characterized by excessive initial motor-unit recruitment with a shift in the frequency spectrum. Conclusions: Fibromyalgia was associated with a specific EMG pattern indicating premature discontinuation of the muscle contraction. Therefore, maximal voluntary muscle contraction tests may be of limited value for assessing function in fibromyalgia patients. Chronic fatigue syndrome patients had similar EMG findings to those in the healthy controls. The EMG alterations in the patients with depression were consistent with manifestations of psychomotor retardation. [less ▲]

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See detailEpidemiology, assessment, and management of excess abdominal fat in persons with HIV infection.
Moyle, Graeme; Moutschen, Michel ULg; Martinez, Esteban et al

in AIDS Reviews (2010), 12(1), 3-14

Metabolic and morphologic abnormalities in persons with HIV remain common contributors to stigma and morbidity. Increased abdominal circumference and visceral adiposity were first recognized in the late ... [more ▼]

Metabolic and morphologic abnormalities in persons with HIV remain common contributors to stigma and morbidity. Increased abdominal circumference and visceral adiposity were first recognized in the late 1990s, soon after the advent of effective combination antiretroviral therapy. Visceral adiposity is commonly associated with metabolic abnormalities including low HDL-cholesterol, raised triglycerides, insulin resistance, and hypertension, a constellation of risk factors for cardiovascular disease and diabetes mellitus known as "the metabolic syndrome". Medline and conference abstracts were searched to identify clinical research on factors associated with visceral adiposity and randomized studies of management approaches. Data were critically reviewed by physicians familiar with the field. A range of host and lifestyle factors as well as antiretroviral drug choice were associated with increased visceral adiposity. Management approaches included treatment switching and metformin, both of which have shown benefit for insulin-resistant individuals with isolated fat accumulation. Testosterone supplements may also have benefits in a subset of individuals. Supra-physiological doses of recombinant human growth hormone and the growth hormone releasing hormone analog tesamorelin both significantly and selectively reduce visceral fat over 12-24 weeks; however, the benefits are only maintained if doping is continued. In summary, the prevention and management of visceral adiposity remains a substantial challenge in clinical practice. [less ▲]

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See detailHIV-1 V3 envelope deep sequencing for clinical plasma specimens failing in phenotypic tropism assays.
Vandenbroucke, Ina; Van Marck, Herwig; Mostmans, Wendy et al

in AIDS Research and Therapy (2010), 7

ABSTRACT : BACKGROUND : HIV-1 infected patients for whom standard gp160 phenotypic tropism testing failed are currently excluded from co-receptor antagonist treatment. To provide patients with maximal ... [more ▼]

ABSTRACT : BACKGROUND : HIV-1 infected patients for whom standard gp160 phenotypic tropism testing failed are currently excluded from co-receptor antagonist treatment. To provide patients with maximal treatment options, massively parallel sequencing of the envelope V3 domain, in combination with tropism prediction tools, was evaluated as an alternative tropism determination strategy. Plasma samples from twelve HIV-1 infected individuals with failing phenotyping results were available. The samples were submitted to massive parallel sequencing and to confirmatory recombinant phenotyping using a fraction of the gp120 domain. RESULTS : A cut-off for sequence reads interpretation of 5 to10 times the sequencing error rate (0.2%) was implemented. On average, each sample contained 7 different V3 haplotypes. V3 haplotypes were submitted to tropism prediction algorithms, and 4/14 samples returned with presence of a dual/mixed (D/M) tropic virus, respectively at 3%, 10%, 11%, and 95% of the viral quasispecies. V3 tropism prediction was confirmed by gp120 phenotyping, except for two out of 4 D/M predicted viruses (with 3 and 95%) which were phenotypically R5-tropic. In the first case, the result was discordant due to the limit of detection for the phenotyping technology, while in the latter case the prediction algorithms were not computing the viral tropism correctly. CONCLUSIONS : Although only demonstrated on a limited set of samples, the potential of the combined use of "deep sequencing + prediction algorithms" in cases where routine gp160 phenotype testing cannot be employed was illustrated. While good concordance was observed between gp120 phenotyping and prediction of R5-tropic virus, the results suggest that accurate prediction of X4-tropic virus would require further algorithm development. [less ▲]

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See detailMultidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.
Wu, Shuangding; Vossius, Sofie ULg; Rahmouni, Souad ULg et al

in Journal of Medicinal Chemistry (2009), 52(21), 6716-23

Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is ... [more ▼]

Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is upregulated in several cervix cancer cell lines as well as in carcinomas of the uterine cervix. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and exhibit antiproliferative effects on cervix cancer cells. Chemical library screening was used to identify hit compounds, which were further prioritized in profiling and kinetic experiments. SAR analysis was applied in the search for analogs with improved potency and selectivity, resulting in the discovery of novel inhibitors that are able to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR’s active site. This multidentate binding mode was confirmed by X-ray crystallography. The inhibitors decreased the proliferation of cervix cancer cells, while growth of primary normal keratinocytes was not affected. These compounds may be a starting point to develop drugs for the treatment of cervical cancer. [less ▲]

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