Résumé : L’HTLV-1 est l’agent étiologique de la TSP/HAM et de l’ATL. La TSP/HAM est une méningomyélite chronique d’évolution lente et progressive. La charge provirale HTLV-1 est corrélée à l’évolutivité de la maladie. La protéine virale Tax module la synthèse et la fonction de multiples protéines de la prolifération et de la survie des lymphocytes T infectés. L’expression virale n’est pas toujours détectable in vivo. Une modulation épigénétique par inhibiteurs d’HDAC a été proposée. Des travaux dans le modèle du BLV et in vitro dans l’infection à HTLV-1 ont conforté ce concept et conduit à un essai thérapeutique évaluant le VPA dans le traitement de la TSP/HAM, qui n’a pas montré d’impact sur la charge provirale. Nous nous sommes intéressés à l’effet du VPA sur les lymphocytes T CD4+ en culture, cibles du virus HTLV-1. L’expression du génome viral, surtout la balance entre les protéines Tax et HBZ a été étudiée avec ou sans VPA. Son expression serait corrélée à la charge provirale et à l’évolution de la TSP/HAM. Nous montrons qu’un tiers des cellules CD4+ infectées expriment Tax. Cette proportion augmente sous VPA. La détection de la protéine p19 est augmentée sous VPA. La stimulation par le VPA de la transcription sens du génome viral a été confirmée par quantification des messagers Tax et Gag alors que l’expression d’HBZ se trouve réprimée sous VPA. Les données cinétiques d’expression spontanée d’HBZ montrent l’existence d’un rétrocontrôle négatif exercé par HBZ sur l’expression de Tax et des gènes structuraux. Influer sur l’expression d’HBZ ouvre une voie nouvelle pour le traitement des maladies associées à HTLV-1.
HTLV-1 is the etiological agent of HAM/TSP and ATL. TSP/HAM is a chronic meningomyelitis with a course being slow and progressive. HTLV-1 proviral load correlates with disease progression. Tax protein modulates the synthesis and function of proteins involved in the regulation of infected T-lymphocytes proliferation and survival. Viral expression is not always detectable in vivo. An epigenetic modulation by the use of HDAC inhibitors has been proposed. A study in the BLV model and an in vitro study in a HTLV-1 infection have lead to a therapeutic assay in order to assess VPA in the treatment of HAM/TSP. This assay did not show any impact on the proviral load. We evaluated the impact of VPA treatment on viral genome expression in cultured lymphocytes, especially the balance between Tax and HBZ. A third of provirus-positive CD4+ T cells spontaneously became Tax-positive. The estimation rose up to two-thirds of Tax-positive infected cells when VPA was added. VPA enhanced Gag p19 protein release. VPA treatment enhanced and prolonged Tax mRNA expression, while it blocked HBZ expression. Our data are consistent with the hypothesis of a feed-back loop coordinating Tax and HBZ expression. Modulation of HBZ expression may impact the net outcome of VPA treatment on HTLV-1-infected cell proliferation and survival.

http://www.theses.fr/2011AGUY0403

Éditeur(s) : HAL CCSD
Résumé : International audience
Febrile illness is a common cause of attendance at emergency departments. The purpose of this study was to describe infectious aetiologies of fever in a tropical setting. We prospectively included 1443 febrile patients, all French Guiana residents, who presented at Cayenne Hospital emergency department. This report will propose an overview of aetiologies of febrile illness in French Guiana, and tropical diseases such as malaria and arbovirus infections are discussed. Almost 30% of fevers remained unexplained. Further prospective multicentre studies are warranted to improve the diagnosis of overlooked pathogens in French Guiana. Such studies would lead to conclusions of specific interest in the travel medicine field.
Transactions of the Royal Society of Tropical Medicine and Hygiene / Transactions of the Royal Society for Tropical Medicine and Hygiene

pasteur-00584097
https://hal-riip.archives-ouvertes.fr/pasteur-00584097
DOI : 10.1016/j.trstmh.2008.06.011
PUBMED : 18640694

Éditeur(s) : HAL CCSD Lippincott, Williams & Wilkins
Résumé : International audience
OBJECTIVES: The ANRS-112 INTERPRIM trial assessed whether fixed-cycles of antiretroviral treatment interruption (ART-STI) combined or not with pegylated interferon alpha-2b (peg-IFN) could lower viral load and achieve a healthier immune system in patients diagnosed during primary HIV-1-infection (PHI). DESIGN AND METHODS: Patients were randomized to receive either continuous ART (cART) during 72 weeks, or cART during 36 weeks followed by three ART-STIs, or the same ART-STIs associated with peg-IFN during the first 14 weeks and each interruption (ART-STI-IFN). Treatment was stopped at week 72. Final evaluation was based on plasma HIV-RNA level 6 months after the last treatment interruption. RESULTS: Eighty-seven percent of patients achieved undetectable HIV-RNA at week 32, with no deleterious impact of sequential treatment interruptions (STIs). Viral rebounds during interruptions were lower in the ART-STI-IFN than in the ART-STI group and during the second and third interruptions compared with the first one. However, HIV-RNA levels, CD4 T-cell counts and CD4 T/CD8 T ratios were similar between groups after the 6-month interruption, with a persistent effect on CD4 T cells and total cell-associated HIV-DNA levels. Predictive factors of virological outcome were HIV-RNA and HIV-DNA levels at PHI and HIV-DNA levels at treatment interruption. HIV-specific responses did not differ between strategies and were not associated with outcome. Forty-eight percent of patients experienced treatment resumption during long-term follow-up without difference between groups. CONCLUSION: When initiated during PHI, STIs associated or not with IFN did not result in a different outcome as compared to cART. All regimens showed a high response rate and a sustained immunological benefit after cessation.
ISSN: 0269-9370

hal-00875175
https://hal.archives-ouvertes.fr/hal-00875175
DOI : 10.1097/QAD.0b013e32835844d9
PUBMED : 22842994

Éditeur(s) : HAL CCSD Taylor & Francis (Routledge): STM, Behavioural Science and Public Health Titles
Résumé : International audience
The aim of this study was to determine factors associated with complete satisfaction with the care provided (satisfaction with physicians and satisfaction with services and organization) among HIV-infected patients followed up in the French ANRS CO8 APROCO-COPILOTE cohort. Analyses focused on cross-sectional data collected during the ninth year of cohort follow-up. Satisfaction with care, sociodemographic characteristics, and behavioral data were collected using self-administered questionnaires, while clinical data were derived from medical records. Complete satisfaction with care was defined as being 100% satisfied. Two logistic regression models were used to identify predictors of (1) complete satisfaction with physicians (n=404) and (2) complete satisfaction with services and organization (n=396). Sixteen percent of patients were completely satisfied with physicians, while 15.9% were completely satisfied with services and organization. Being older and reporting fewer discomforting antiretroviral therapy (ART) side effects were factors independently associated with complete satisfaction with both physicians and services and organization. Strong support from friends and absence of hepatitis C (HCV) co-infection were independently associated with complete satisfaction with physicians, while strong support from one's family and comfortable housing conditions were independently associated with complete satisfaction with services and organization. Even after nine years of follow-up, social vulnerabilities still strongly influence HIV-infected patients' interactions with the health care system. Day-to-day experience with the disease, including perceived treatment side effects, appears to play a key role in the quality of these interactions. More attention should be given to patient satisfaction, especially for socially vulnerable patients, in order to avoid potentially detrimental consequences such as poor adherence to ART.
AIDS Care

hal-00875619
https://hal.archives-ouvertes.fr/hal-00875619
DOI : 10.1080/09540121.2011.613909
PUBMED : 21999644

Éditeur(s) : HAL CCSD American Society for Microbiology
Résumé : International audience
Coronaviruses (CoVs) have shown neuroinvasive properties in human and animal secondary to replication in peripheral organ but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood brain barrier (BBB). Using the high hepatotropic mouse hepatitis virus (MHV) type 3, its attenuated variant 51.6-MHV3, showing low tropism for endothelial cells, and the low hepatotropic MHV-A59 strains from murine coronavirus group, we investigated the viral-induced dysfunctions of BBB in vivo and in brain microvascular endothelial cells (BMECs) in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was only observed in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of ZO-1, VE-cadherin and occludin but not claudin-5 in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective IFN-β production. Our findings highlight the importance of IFN-β production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain. IMPORTANCE: Coronaviruses (CoVs) infect several mammals including humans and are associated with respiratory, gastrointestinal and/or neurological diseases. Some evidences suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the SARS-CoV, causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS and multiple sclerosis patients respectively. These finding suggest that hematogenous spread CoVs may gain access to CNS at the BBB level. Herein we report for the first time that CoVs exhibit ability to cross the BBB according to strain virulence. BBB invasion by CoVs correlates with viral-induced disruption of tight junctions on BMECs, leading to BBB dysfunction and enhanced permeability. We provide evidence that production of IFN-β by BMECs during CoV infection may prevent BBB breakdown and brain viral invasion
ISSN: 0022-538X

hal-01187308
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187308
DOI : 10.1128/JVI.01501-15
PUBMED : 26202229

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Objective: To describe characteristics and outcomes of HIV-infected patients with Pneumocystis jirovecii pneumonia (PCP) over 2004–2011 in France, in particular in those previously enrolled (PE) in the French Hospital Database on HIV (FHDH). Methods: PE patients with an incident PCP were compared with patients with an inaugural PCP revealing HIV infection (reference). Adequate adherence to care was defined as a CD4 measurement at least every 6 months. Immune reconstitution (CD4$200/mm 3) and risk of death were studied using Kaplan-Meier estimates and multivariable Cox proportional hazards models. Results: In a context of a decreasing incidence of PCP, 1259 HIV-infected patients had a PCP diagnosis, and 593 (47%) were PE patients of whom 161 (27%) have had a prior history of AIDS-defining clinical illness (prior ADI). Median time since enrolment was 8 years for PE patients; 74% had received cART. Median proportion of time with adequate adherence to care was 85% (IQR, 66–96) for all FHDH enrollees, but only 45% (IQR, 1–81) for PE patients during the 2 years before PCP. Median CD4 cell count (38/mm 3) and HIV viral load (5.2 log10 copies/ml) at PCP diagnosis did not differ between PE patients and the reference group. Three year mortality rate of 25% was observed for PE prior ADI group, higher than in PE non-prior ADI group (8%) and the reference group (9%) (p,0.0001). In the PE prior ADI group, poor prognosis remained even after adjustment for virological control and immune reconstitution (HR, 2.4 [95%CI, 1.5–3.7]). Conclusion: Almost 50% of PCP diagnoses in HIV-infected patients occurred presently in patients already in care, mainly with a previous cART prescription but with waning adherence to care. Having repeated ADI is contributing to the risk of death beyond its impact on immune reconstitution and viral suppression: special efforts must be undertaken to maintain those patients in care.
ISSN: 1932-6203

Droits : http://creativecommons.org/licenses/by/
hal-01345090
http://hal.upmc.fr/hal-01345090
http://hal.upmc.fr/hal-01345090/document
http://hal.upmc.fr/hal-01345090/file/journal.pone.0094183.PDF
DOI : 10.1371/journal.pone.0094183

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Necroptosis is a programmed cell death pathway that has been shown to be of central pathophysiological relevance in multiple disorders (hepatitis, brain and cardiac ischemia, pancreatitis, viral infection and inflammatory diseases). Necroptosis is driven by two serine threonine kinases, RIPK1 (Receptor Interacting Protein Kinase 1) and RIPK3, and a pseudo-kinase MLKL (Mixed Lineage Kinase domain-Like) associated in a multi-protein complex called necrosome. In order to find new inhibitors for use in human therapy, a chemical library containing highly diverse chemical structures was screened using a cell-based assay. The compound 6E11, a natural product derivative, was characterized as a positive hit. Interestingly, this flavanone compound: inhibits necroptosis induced by death receptors ligands TNF-α (Tumor Necrosis Factor) or TRAIL (TNF-Related Apoptosis-Inducing Ligand); is an extremely selective inhibitor, among kinases, of human RIPK1 enzymatic activity with a nM Kd; has a non-ATP competitive mode of action and a novel putative binding site; is weakly cytotoxic towards human primary blood leukocytes or retinal pigment epithelial cells at effective concentrations; protects human aortic endothelial cells (HAEC) from cold hypoxia/reoxygenation injury more effectively than necrostatin-1 (Nec-1) and Nec-1s. Altogether, these data demonstrate that 6E11 is a novel potent small molecular inhibitor of RIPK1-driven necroptosis.
ISSN: 2045-2322

hal-01616456
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616456
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616456/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616456/file/s41598-017-12788-4.pdf
DOI : 10.1038/s41598-017-12788-4

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : International audience
The Société de pneumologie de langue française defines acute exacerbation of chronic obstructive pulmonary disease (AE COPD) as an increase in daily respiratory symptoms, basically duration ≥ 48h or need for treatment adjustment. Etiology of EA COPD are mainly infectious, viral (rhinovirus, influenzae or parainfluenzae virus, coronavirus, adenovirus and respiratory syncytial virus) or bacterial (Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis). Pollutant exposure can also lead to AE COPD, such as NO2, SO2, ozone or particulates (PM10 and PM2.5). In 30% the etiology remains unknown. Differential diagnoses of AE COPD include infectious pneumonia, pneumothorax, acute heart failure and pulmonary embolism. Presences of signs of severity impose hospitalization: signs of respiratory distress, shock, acute confusion but also fragile patients, insufficient home support or absence of response to initial treatment. AE COPD treatments consist on increase in bronchodilators, chest physiotherapy, and antibiotics if sputum is frankly purulent. Systemic corticosteroids should not be systematic.Recommended dose is 0.5 mg/kg on short course (7 days). During hospitalization, oxygen supplementation and thromboprophylaxis could be prescribed. The main interest in noninvasive ventilation is persistent hypercapnia despite optimal medical management. During ambulatory management or hospitalization, clinical assessment at 48-72h is mandatory. L’exacerbation aiguë de bronchopneumopathie chronique obstructive (EA BPCO) représente un événement important dans l’histoire naturelle de la BPCO, notamment en cas d’hospitalisation. Les EA BPCO interviennent dans la gravité et l’évolution de la BPCO ; et leur prévention est un des objectifs principal des traitements de fond.
La Société de pneumologie de langue française définie l’exacerbation aiguë de bronchopneumopathie chronique obstructive (EA BPCO) comme une majoration des symptômes respiratoires au-delà des variations quotidiennes, en pratique, d’une durée ≥ 48h ou justifiant une modification thérapeutique. L’étiologie de ces EA BPCO est principalement infectieuse, virale (rhinovirus, virus influenzae et parainfluenzae, coronavirus, adénovirus et virus respiratoire syncytial) ou bactérienne (principalement Haemophilus influenzae, Streptococcus pneumoniae et Moraxella catarrhalis). Elles peuvent également résulter de l’exposition à certains polluants comme le NO2, le SO2, l’ozone et la pollution particulaire (PM10 et PM2,5). L’étiologie reste indéterminée dans près de 30 % des cas. Les diagnostics différentiels des EA BPCO incluent les pneumopathies infectieuses, les pneumothorax, les poussées d’insuffisance cardiaque et les embolies pulmonaires. La présence de signes de gravité conditionnent l’hospitalisation : signes d’insuffisance respiratoire aiguë, de choc ou de défaillance neurologique, mais aussi en cas de patient fragile, d’absence de soutien familial à domicile ou d’absence de réponse au traitement initial. Le traitement d’une EA BPCO consiste en une majoration des bronchodilatateurs, une kinésithérapie respiratoire, une antibiothérapie en cas d’expectoration franchement purulente.La prescription de corticoïdes systémiques ne doit pas être systématique. La dose recommandée est de 0,5 mg/kg sur une courte période (7 jours). Lors d’une hospitalisation, une oxygénothérapie et une thromboprophylaxie peuvent être prescrite. La ventilation noninvasiveest principalement indiquée en cas de persistance d’une hypercapnie malgré un traitement médical optimal. Que le patient soit pris en charge en ambulatoire ou en hospitalisation, une réévaluation clinique à 48-72h est indispensable.
ISSN: 0755-4982

hal-01117949
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01117949
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01117949/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01117949/file/Prise%20en%20charge%20des%20exacerbations_accepted.pdf
DOI : 10.1016/j.jeurea.2015.02.002

Éditeur(s) : HAL CCSD
Résumé : Hepatitis C virus (HCV) is one of the leading causes of hepatocellular carcinoma. Therapeutic treatment against the virus has been recently improved by a tritherapy including pegylated interferon, ribavirin and antiviral protease. Nevertheless, the importance of side effects and the emergence of resistant mutants require the development of new antivirals. In this context, our team has recently discovered that Type III phosphatidylinositol 4-kinases (PI4KIIIα and PI4KIIIβ) are essential for the propagation of the virus in a human hepatic cell line at the entry and replication steps. To further characterize these potential therapeutic targets, we investigate the implication of these kinases during the HCV entry, using primary human hepatocytes, a model closer to the in vivo conditions. Two lines of research were developed: Verification of the importance of the kinase activity of PI4KIIIs during HCV entry in primary human hepatocytes, through a chemical approach; Validation of the involvement of these kinases and their enzymatic activity during viral entry through a genetic approach based on RNA interference and phenotype rescue. In parallel, we studied the expression of PI4KIIIα in liver diseases. Our results suggest the involvement of PI4KIIIα in HCV entry; the involvement of PI4KIIIIβ needs to be confirmed. The analysis of PI4KIIIα expression in hepatocellular carcinoma led us to propose this kinase as a new molecular marker, which could improve the already established prognosis models and could lead to the development of new therapeutic approaches.
Le virus de l’hépatite C (VHC) est l’un des principaux facteurs étiologiques du carcinome hépatocellulaire. Le traitement des hépatites virales C a été récemment amélioré grâce à une trithérapie (interféron, ribavirine et anti-protéase virale). Néanmoins l’importance des effets secondaires et l’émergence de mutants résistants nécessitent de découvrir de nouveaux antiviraux. Dans ce contexte, notre équipe a récemment découvert que les phosphatidylinositol 4-kinases de type III (PI4KIIIα et PI4KIIIβ) étaient indispensables à la propagation du virus dans une lignée hépatique humaine, et ce, à 2 étapes de son cycle biologique : l’entrée et la réplication. L’objectif du présent travail était de poursuivre la validation de ces nouvelles cibles thérapeutiques potentielles, en approfondissant nos connaissances sur la dépendance du virus à l’égard de ces kinases au cours de son entrée. Pour cela, nous avons utilisé le modèle des hépatocytes humains primaires, système in vitro plus proche du contexte physiologique que les modèles utilisés jusqu’à présent et qui étaient basés sur l’exploitation de lignées. Deux axes ont été développés : Vérification de l’importance de l’activité kinase des PI4KIIIs au cours de l’entrée du VHC dans les hépatocytes humains primaires, à travers une approche chimique ; Validation de l’implication de ces kinases et de leur activité enzymatique au cours de l’entrée virale grâce à une approche génétique basée sur l’ARN interférence et la restauration de phénotype. En parallèle, nous avons étudié l’expression de PI4KIIIα au cours de pathologies hépatiques. Nos résultats suggèrent une implication de PI4KIIIα au cours de l’entrée du VHC dans les hépatocytes humains primaires, mais restent à confirmer quant à l’implication de PI4KIIIβ. Par ailleurs, l’analyse de l’expression de PI4KIIIα dans le carcinome hépatocellulaire (CHC) conduit à proposer cette kinase comme un nouveau marqueur moléculaire, qui pourrait améliorer les modèles de pronostic déjà établis et pourrait conduire au développement de nouvelles approches thérapeutiques pour les patients atteints d’un CHC, quelque soit l’étiologie.
https://tel.archives-ouvertes.fr/tel-00950335

Droits : info:eu-repo/semantics/OpenAccess
NNT : 2013REN1B006
tel-00950335
https://tel.archives-ouvertes.fr/tel-00950335
https://tel.archives-ouvertes.fr/tel-00950335/document
https://tel.archives-ouvertes.fr/tel-00950335/file/ILBOUDOAdeodat.pdf

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
BACKGROUND AND AIMS: Infection by hepatitis C virus is a worldwide health problem. An inadequate Th2 cytokine response promotes the fibrosis-cirrhosis fate. Immune-modulating molecules favoring a Th2 profile, such as HLA-G molecules of the HLA class Ib family, may play a role in chronic hepatitis. HLA-G contributes to the escape of tumors, and their involvement in viral infections has been increasingly described. The aim of this work was to study the expression of HLA-G in the liver, its cellular source and its regulation in cases of chronic C hepatitis. METHODS: HLA-G cells in blocks of liver derived from patients infected with HCV were labeled by immunohistochemistry and enumerated. Double immunofluorescence allowed the identification of the cellular source. HLA-G secretion by a human mast cell line was quantified by ELISA after various stimulations. After treatment with IFN-α real-time PCR was performed to determine the kinetics of cytokine expression profiles, followed by heat map clustering analysis. RESULTS: The number of HLA-G + cells was significantly associated with the area of fibrosis. For the first time, we identify the HLA-G+ cells as being mast cells. HLA-G secretion was significantly induced in human mast cells stimulated by IL-10 or interferons of class I. The transcriptome of the secretome of this cell line stimulated by IFN-α revealed that i) the HLA-G gene is upregulated late, ii) T lymphocytes and NK cells are recruited. CONCLUSIONS: These findings suggest an autocrine loop in the genesis of HCV liver fibrosis, based on mast cells expressing HLA-G.
ISSN: 0168-8278

hal-00874106
https://hal.archives-ouvertes.fr/hal-00874106
https://hal.archives-ouvertes.fr/hal-00874106/document
https://hal.archives-ouvertes.fr/hal-00874106/file/Amiot-Expression-HLA-G-revised.pdf
DOI : 10.1016/j.jhep.2013.09.006