Publications (13)53.89 Total impact
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Article: Consistent high concentration of the viral microRNA BART17 in plasma samples from nasopharyngeal carcinoma patients - evidence of non-exosomal transport.
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ABSTRACT: BACKGROUND: Because latent Epstein Barr (EBV)-infection is a specific characteristic of malignant nasopharyngeal carcinoma (NPC), various molecules of viral origin are obvious candidate biomarkers in this disease. In a previous study, we could show in a few clinical samples that it was possible to detect a category of EBV microRNAs called miR-BARTs in the plasma of at least a fraction of NPC patients. The first aim of the present study was to investigate the status of circulating miR-BART17-5p (one of the miR-BARTs hereafter called miR-BART17) and EBV DNA in a larger series of NPC plasma samples. The second aim was to determine whether or not circulating miR-BART17 was carried by plasma exosomes. Patients and methods: Plasma samples were collected from 26 NPC patients and 10 control donors, including 9 patients with non-NPC Head and Neck squamous cell carcinoma and one healthy EBV carrier. Concentrations of miR-BART17 and two cellular microRNAs (hsa-miR-16 and -146a) were assessed by real-time quantitative PCR with spike-in normalization and absolute quantification. In addition, for 2 patients, exosome distributions of miR-BART17 and miR-16 were investigated following plasma lipoprotein fractionation by isopycnic density gradient ultrcentrifugation. RESULTS: The miR-BART17 was significantly more abundant in plasma samples from NPC patients compared to non-NPC donors. Above a threshold of 506 copies/mL, detection of miR-BART17 was highly specific for NPC patients (ROC curve analysis: AUC=0.87 with true positive rate = 0.77, false positive rate = 0.10). In this relatively small series, the concentration of plasma miR-BART17 and the plasma EBV DNA load were not correlated. When plasma samples were fractionated, miR-BART17 co-purified with a protein-rich fraction but not with exosomes. CONCLUSIONS: Detection of high concentrations of plasma miR-BART17 is consistent in NPC patients. This parameter is, at least in part, independent of the viral DNA load. Circulating miR-BART17 does not co-purify with exosomes.Virology Journal 04/2013; 10(1):119. · 2.34 Impact Factor -
Article: Mother-to-child transmission of HIV-1 drug resistance in a French cohort
Retrovirology 04/2012; 5:1-1. · 6.47 Impact Factor -
Article: Extra-cellular release and blood diffusion of BART viral micro-RNAs produced by EBV-infected nasopharyngeal carcinoma cells.
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ABSTRACT: Nasopharyngeal carcinoma (NPC) is a human epithelial malignancy consistently associated with the Epstein-Barr virus. The viral genome is contained in the nuclei of all malignant cells with abundant transcription of a family of viral microRNAs called BART miRNAs. MicroRNAs are well known intra-cellular regulatory elements of gene expression. In addition, they are often exported in the extra-cellular space and sometimes transferred in recipient cells distinct from the producer cells. Extra-cellular transport of the microRNAs is facilitated by various processes including association with protective proteins and packaging in secreted nanovesicles called exosomes. Presence of microRNAS produced by malignant cells has been reported in the blood and saliva of tumor-bearing patients, especially patients diagnosed with glioblastoma or ovarian carcinoma. In this context, it was decided to investigate extra-cellular release of BART miRNAs by NPC cells and their possible detection in the blood of NPC patients. To address this question, we investigated by quantitative RT-PCR the status of 5 microRNAs from the BART family in exosomes released by NPC cells in vitro as well as in plasma samples from NPC xenografted nude mice and NPC patients. We report that the BART miRNAs are released in the extra-cellular space by NPC cells being associated, at least to a large extent, with secreted exosomes. They are detected with a good selectivity in plasma samples from NPC xenografted nude mice as well as NPC patients. Viral BART miRNAs are secreted by NPC cells in vitro and in vivo. They have enough stability to diffuse from the tumor site to the peripheral blood. This study provides a basis to explore their potential as a source of novel tumor biomarkers and their possible role in communications between malignant and non-malignant cells.Virology Journal 10/2010; 7:271. · 2.34 Impact Factor -
Article: Evaluation of the genotypic prediction of HIV-1 coreceptor use versus a phenotypic assay and correlation with the virological response to maraviroc: the ANRS GenoTropism study.
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ABSTRACT: Genotypic algorithms for prediction of HIV-1 coreceptor usage need to be evaluated in a clinical setting. We aimed at studying (i) the correlation of genotypic prediction of coreceptor use in comparison with a phenotypic assay and (ii) the relationship between genotypic prediction of coreceptor use at baseline and the virological response (VR) to a therapy including maraviroc (MVC). Antiretroviral-experienced patients were included in the MVC Expanded Access Program if they had an R5 screening result with Trofile (Monogram Biosciences). V3 loop sequences were determined at screening, and coreceptor use was predicted using 13 genotypic algorithms or combinations of algorithms. Genotypic predictions were compared to Trofile; dual or mixed (D/M) variants were considered as X4 variants. Both genotypic and phenotypic results were obtained for 189 patients at screening, with 54 isolates scored as X4 or D/M and 135 scored as R5 with Trofile. The highest sensitivity (59.3%) for detection of X4 was obtained with the Geno2pheno algorithm, with a false-positive rate set up at 10% (Geno2pheno10). In the 112 patients receiving MVC, a plasma viral RNA load of <50 copies/ml was obtained in 68% of cases at month 6. In multivariate analysis, the prediction of the X4 genotype at baseline with the Geno2pheno10 algorithm including baseline viral load and CD4 nadir was independently associated with a worse VR at months 1 and 3. The baseline weighted genotypic sensitivity score was associated with VR at month 6. There were strong arguments in favor of using genotypic coreceptor use assays for determining which patients would respond to CCR5 antagonist.Antimicrobial Agents and Chemotherapy 08/2010; 54(8):3335-40. · 4.84 Impact Factor -
Article: HIV-1-infected patients from the French National Observatory experiencing virological failure while receiving enfuvirtide.
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ABSTRACT: We studied gp41 mutations associated with failing enfuvirtide salvage therapy. This multicentre study involved patients with HIV-1 plasma viral load (pVL) > 5000 copies/mL after at least 3 months of uninterrupted enfuvirtide therapy and with plasma samples available at inclusion (T0), at initial enfuvirtide failure (T1) and at last follow-up visit during continued failing enfuvirtide therapy (T2). The HR-1 and HR-2 domains of the gp41 gene were sequenced at T0, T1 and T2. Ninety-nine patients were enrolled. At baseline, the median pVL and CD4 cell count were 5.1 log copies/mL and 72 cells/mm(3), respectively. Based on the ANRS Resistance Group algorithm, the proportion of patients harbouring viruses with enfuvirtide resistance mutations increased significantly between T0 and T1. In the HR-1 domain, the V38A/M, Q40H, N42T, N43D and L45M mutations wereselected (P < 0.02). In the HR-2 domain, no mutations were significantly selected during the follow-up. None of the mutations was associated with a CD4 cell count increment. Mutations selected during failing enfuvirtide salvage therapy are mainly located in the HR-1 domain of the gp41 gene, between codons 38 and 45. No mutations were associated with an increase in the CD4 cell count.Journal of Antimicrobial Chemotherapy 06/2008; 62(3):451-5. · 5.07 Impact Factor -
Article: Immunological responses and long-term treatment interruption after human immunodeficiency virus type 1 (HIV-1) lipopeptide immunization of HIV-1-infected patients: the LIPTHERA study.
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ABSTRACT: We studied the time course of immunological and virological markers after highly active antiretroviral therapy (HAART) interruption in chronically human immunodeficiency virus type 1 (HIV-1)-infected patients immunized with an HIV lipopeptide preparation. In a prospective open pilot study, 24 HIV-1-infected HAART-treated patients with undetectable plasma viral loads (pVLs) and CD4(+) T-cell counts above 350/mm(3) were immunized at weeks 0, 3, and 6 with a candidate vaccine consisting of six HIV lipopeptides. At week 24, patients with pVLs of <1.7 log(10) copies/ml were invited to stop taking HAART. Antiretroviral therapy was resumed if the pVL rose above 4.47 log(10) copies/ml and/or if the CD4(+) cell count fell below 250/mm(3). Immunological and virologic parameters were studied before and after HAART interruption. The median baseline and nadir CD4(+) cell counts were 482 (interquartile range [IQR], 195 to 826) and 313 (IQR, 1 to 481)/mm(3), respectively. New specific CD8(+) cell responses to HIV-1 epitopes were detected after immunization in 13 (57%) of 23 assessable patients. Twenty-one patients were evaluated 96 weeks after HAART interruption. The median time to pVL rebound was 4 weeks (IQR, 2 to 6), and the median peak pVL was 4.26 (IQR, 3 to 5) log(10) copies/ml. Thirteen of these 21 patients resumed HAART a median of 60 weeks after immunization (IQR, 9.2 to 68.4 weeks), when the median pVL was 4.8 (IQR, 2.9 to 5.7) log(10) copies/ml and the median CD4(+) cell count was 551 (IQR, 156 to 778)/mm(3). Eight patients were still off therapy at 96 weeks, with a median pVL of 4 (IQR, 1.7 to 4.6) log(10) copies/ml and a median CD4(+) cell count of 412 (IQR, 299 to 832)/mm(3). No clinical disease progression had occurred. Despite the lack of a control arm, these findings warrant a randomized study of therapeutic vaccination with HIV lipopeptides followed by long-term HAART interruption in AIDS-free chronically infected patients.Clinical and vaccine immunology: CVI 03/2008; 15(3):562-8. · 2.37 Impact Factor -
Article: Virologic and immunologic efficacy of the tenofovir/didanosine/lamivudine regimen.
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ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.JAIDS Journal of Acquired Immune Deficiency Syndromes 08/2006; 42(3):389-90. · 4.43 Impact Factor -
Article: Prevalence of complete resistance to at least two classes of antiretroviral drugs in treated HIV-1-infected patients: a French nationwide study.
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ABSTRACT: The objective of the study was to estimate the prevalence of HIV-1 resistance to all drugs belonging to two or more antiretroviral drug (ARV) classes in treated patients in France. All genotyping assays performed in June 2001 and in November 2002 by the ANRS resistance laboratory network were analyzed by the ANRS algorithm. The 17 and 21 centers of the ANRS network participating in the study in 2001 and 2002, respectively, genotyped the viruses in plasma of 456 and 529 patients, respectively. In 2002, the proportions of patients harboring viruses fully resistant to one, two, and three ARV classes were 5.1%, 8.1%, and 2.5%, respectively. These results were similar to those obtained in 2001. In 2002, among the 56 patients with viruses completely resistant to at least two ARV classes, 98%, 96%, and 29% of patients had viruses with complete class resistance to NRTIs, NNRTIs, and PIs, respectively. Complete resistance to PIs was less frequent than full resistance to the other two ARV classes, and ritonavir-boosted amprenavir and lopinavir/r remained potentially active in respectively 71.4% and 42.9% of these 56 patients. In 2001 and 2002, respectively 30% of the 65 patients and 24% of the 56 patients with viruses completely resistant to at least two ARV classes were at an advanced stage of HIV disease, with CD4(+) cell counts below 200/microl and viral loads above 30 000 copies/ml. In France, the prevalence of HIV-1 viruses completely resistant to two or more ARV classes remained stable between 2001 and 2002. Resistance to RT inhibitors was more frequent than resistance to PIs in patients with viruses completely resistant to two or three classes of ARV.Journal of Medical Virology 09/2005; 76(4):441-6. · 2.82 Impact Factor -
Article: Virological and pharmacological parameters predicting the response to lopinavir-ritonavir in heavily protease inhibitor-experienced patients.
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ABSTRACT: The genotypic inhibitory quotient (GIQ) has been proposed as a way to integrate drug exposure and genotypic resistance to protease inhibitors and can be useful to enhance the predictivity of virologic response for boosted protease inhibitors. The aim of this study was to evaluate the predictivity of the GIQ in 116 protease inhibitor-experienced patients treated with lopinavir-ritonavir. The overall decrease in human immunodeficiency virus type 1 (HIV-1) RNA from baseline to month 6 was a median of -1.50 log(10) copies/ml and 40% of patients had plasma HIV-1 RNA below 400 copies/ml at month 6. The overall median lopinavir study-state C(min) concentration was 5,856 ng/ml. Using univariate linear regression analyses, both lopinavir GIQ and the number of baseline lopinavir mutations were highly associated with virologic response through 6 months. In the multivariate analysis, only lopinavir GIQ, baseline HIV RNA, and the number of prior protease inhibitors were significantly associated with response. When the analysis was limited to patients with more highly mutant viruses (three or more lopinavir mutations), only lopinavir GIQ remained significantly associated with virologic response. This study suggests that GIQ could be a better predictor of the virologic response than virological (genotype) or pharmacological (minimal plasma concentration) approaches used separately, especially among patients with at least three protease inhibitor resistance mutations. Therapeutic drug monitoring for patients treated by lopinavir-ritonavir would likely be most useful in patients with substantially resistant viruses.Antimicrobial Agents and Chemotherapy 06/2005; 49(5):1720-6. · 4.84 Impact Factor -
Article: French National Sentinel Survey of Antiretroviral Drug Resistance in Patients With HIV-1 Primary Infection and in Antiretroviral-Naive Chronically Infected Patients in 2001-2002
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ABSTRACT: Objective: To survey the frequency of genotypic antiretroviral resistance and the spread of non-B subtypes in patients with primary HIV-1 infection (2001-2002) and in treatment-naive chronically HIV-1-infected patients (2001). Methods: Plasma samples from 303 patients with acute HIV-1 infection (Primo study) and 363 treatment-naive patients with chronic HIV-1 infection (Odyssee study) were tested for genotypic resistance. Resistance mutations were identified from the International AIDS Society Resistance Testing-USA panel and resistant viruses were defined according to the French Agence Nationale de Recherches sur le SIDA (ANRS) resistance algorithm. Results: In the Primo study, 14% of the patients had viruses with resistance mutations and 12% of patients had viruses with mutations conferring resistance to least 1 antiretroviral drug. Thirty patients had viruses with mutations to at least 1 antiretroviral drug in a single pharmacologic class. Six patients were infected by viruses resistant to 2 or 3 classes of drugs. In the Odyssee study, the prevalence of reverse transcript (RT) associated and major protease inhibitor-associated mutations was 6.1% (95% CI: 3.6-8.6). Six patients had viruses resistant to at least 1 antiretroviral drug and 3 patients had viruses resistant to 2 classes of antiretroviral drugs. Twenty-four percent of acutely infected patients harbored non-B subtype strains (19% in 1999-2000) and 33.2% of chronically infected patients (10% in 1998; P < 0.0001). Conclusion: In France, the frequency of HIV-1 resistance in untreated patients was not significantly higher in 2001-2002 than in previous surveys while the prevalence of non-B subtypes is increasing.JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2005; 38(5):545-552. · 4.43 Impact Factor -
Article: Genotypic determinants of the virological response to tenofovir disoproxil fumarate in nucleoside reverse transcriptase inhibitor-experienced patients.
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ABSTRACT: To assess the genotypic determinants of the virological response to tenofovir disoproxil fumarate (TDF) in a multicentre cohort of antiretroviral (ARV)-experienced patients receiving TDF as a part of a salvage therapy. HIV-1 genotype was assessed at baseline in a subgroup of 161 patients of the French expanded access program receiving a stable TDF-including regimen for 3 months or more. Reverse transcriptase mutations associated with the viral load decrease at month 3 with a P-value <0.15 were retained for the construction of a mutation score. The score was then validated using a multivariate analysis and bootstrap resampling method. The strongest association with decrease in viral load was observed with a set of seven mutations (TDF mutation score) that consisted of M41L, E44D, D67N, T69D/N/S, L74V, L210W and T215Y/F RT mutations. The RT K65R mutation and the insertions at codon 69 were not included in the analysis due to low prevalences. A TDF mutation score of < or = 2 predicted the absence of resistance to TDF and > or = 6 mutations predicted resistance to TDF with corresponding reductions in viral load of -1.3 +/- 1.1, and +0.1 +/- 0.7 log10 copies/ml, respectively. In patients with a TDF mutation score of 3-5, the decrease in viral load was -0.8 +/- 1.0 log10 copies/ml and was considered possibly resistant. In the multivariate analysis, a TDF mutation score > or = 6, previous use of amprenavir, indinavir and lopinavir, and co-prescription of didanosine were associated with a worse virological response. The bootstrap analysis showed the robustness of the TDF mutation score. In ARV-experienced patients receiving TDF-containing regimens, a score derived from seven reverse transcriptase mutations was shown to be independently predictive of the virological response.Antiviral therapy 07/2004; 9(3):315-23. · 3.16 Impact Factor -
Article: Peptide insertions in reverse transcriptase pol gene of human immunodeficiency virus type 1 as a rare cause of persistent antiretroviral therapeutic failure.
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ABSTRACT: Peptide insertions in codons 67-71 of the reverse transcriptase (RT) pol gene were detected in 11 (2.7%) of 414 genotypic analyses performed in a hospital cohort of 2900 outpatients with human immunodeficiency virus type 1 (HIV-1) infection. The duration of antiretroviral treatment (bi- or tri-therapy) before the detection of insertions ranged from 12 to 60 months. Dipeptide insertions were detected in ten patients, of which the most frequent was serine-serine. A monopeptide insertion was diagnosed once. The amino-acid composition patterns of insertions varied with time in five of the 11 patients. Peptide insertions were always associated with various patterns of pre-existing or appearing resistance mutations in the RT pol gene to different antiretroviral drugs. Genotypic-guided treatment resulted in virological and immunological improvement in two patients. In contrast, the remaining patients did not respond to any of the various antiretroviral regimens prescribed. Furthermore, various patterns of resistance mutations developed to the prescribed antiretroviral drugs, with AIDS-related conditions leading to death in two patients. It was concluded that peptide insertion in this region of the HIV-1 RT pol gene constitutes a rare cause of persistent therapeutic failure, and that management of such patients remains challenging despite successive genotypic analyses aimed at detecting mutations conferring antiretroviral drug resistance.Clinical Microbiology and Infection 03/2004; 10(2):127-36. · 4.54 Impact Factor -
Article: Stable prevalence of genotypic drug resistance mutations but increase in non-B virus among patients with primary HIV-1 infection in France.
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ABSTRACT: To evaluate the frequency of drug-resistant HIV-1 viral strains from patients presenting with primary infection in 1999-2000 and to survey the molecular epidemiology of these viruses circulating in France. Resistance mutations were detected by sequencing the reverse transcriptase and the protease genes in plasma samples from 249 individuals. Phylogenetic analysis was performed on the reverse transcriptase genes. Ten per cent of patients [26/249; 95% confidence interval (CI) 7-15%] presented with virus mutations associated with resistance to at least one antiretroviral drug. The distribution of the resistance mutations was as follows: to nucleoside reverse transcriptase inhibitors in 19 (8%; 95% CI 5-12%) and to non-nucleoside reverse transcriptase inhibitors in 10 (4%; 95% CI 2-7%). Primary resistance mutations to protease inhibitors were detected in 14 (6%; 95% CI 3-9%). Twelve patients (5%; 95% CI 3-8%) presented with virus harbouring mutations associated with resistance to two or three classes of antiretroviral drugs. The median HIV RNA in plasma at enrollment was lower in patients with one or more drug resistance mutations than in patients with no mutations (5.05 log versus 5.47 log, P = 0.05). Phylogenetic analysis revealed that 19% (14-24%) of patients harboured HIV-1 non-B subtype strains; this proportion remained high when Caucasian patients only were considered (14%). This study, performed within the French network on HIV-1 primary infection survey, revealed no change in the frequency of resistant viral strains over time, but showed an increasing prevalence of non-B subtypes overall and among Caucasian individuals.AIDS 01/2004; 17(18):2635-43. · 6.24 Impact Factor
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Institutions
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2008
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Hôpital "Bichat - Claude-Bernard" – Hôpitaux Universitaires Paris Nord Val de Seine
Paris, Ile-de-France, France
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2004
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Centre Hospitalier Universitaire de Bordeaux
Bordeaux, Aquitaine, France
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