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Dominique Dormont

Publications and source records attributed to Dominique Dormont.

At least 37 records · Page 2Linked to original sources
PubMed2004

[Neurotoxicity and neuroprotection, two aspects of microglial activation in human immunodeficiency virus (HIV) infection].

Microglial cells and macrophages are the only cells within the central nervous system, in which productive HIV infection has been unquestionably demonstrated. Those cells play a key role in the origin of the neuronal dysfunction underlying HIV-related cognitive disorders. The neurotoxicity of the cells is both direct, related to HIV proteins, and indirect, through the release by activated macrophages and microglial cells (AMM) of multiple neurotoxic factors. The mechanisms of neuronal damage, the final irreversible stage of which is neuronal apoptosis, are only partly understood but appear to involve oxidative stress and glutamate-receptor mediated toxicity. On the other hand, recent experimental in vitro and in vivo studies, and neuropathological studies in HIV infected patients at different stages of the disease, tend to show that AMM express excitatory amino acid transporters (EAAT) suggesting that in addition to their neurotoxic properties, they also have a neuroprotective role by clearing extra-cellular glutamate and producing antioxidant glutathione. This neuroprotective role could counteract, at least in the early stages of the disease, the neurotoxicity of AMM explaining the discrepancy between the conspicuous microglial activation at that stage and the absence of cognitive disorder, neuronal loss and neuronal apoptosis. It could also explain the regression of the cognitive disorders in some patients who received highly active antiretroviral treatment.

Animals↗
PubMed2004

Knock-down of the 37-kDa/67-kDa laminin receptor in mouse brain by transgenic expression of specific antisense LRP RNA.

The 37-kDa/67-kDa laminin receptor (LRP/LR) plays a major role in the propagation of PrPSc, the abnormal form of the prion protein. In order to ablate the expression of LRP/LR in mouse brain we generated transgenic mice ectopically expressing antisense LRP RNA in the brain under control of the neuron-specific enolase (NSE) promoter. Hemizygous transgenic mice TgN(NSEasLRP)2 showed a significant reduction of LRP/LR protein levels in hippocampal and cerebellar brain regions. These mice might act as powerful tools to investigate the role of the laminin receptor in scrapie pathogenesis.

Animals↗
PubMed2004

Up-regulation of glutamate concentration in the putamen and in the prefrontal cortex of asymptomatic SIVmac251-infected macaques without major brain involvement.

We quantified putamen and prefrontal cortex metabolites in macaques with simian immunodeficiency virus infection and searched for virological and histological correlates. Fourteen asymptomatic macaques infected since 8-78 months (median: 38) were compared with eight uninfected ones. Absolute concentrations of acetate, alanine, aspartate, choline, creatine, GABA, glutamate, glutamine, lactate, myo-inositol, N-acetylaspartate, taurine and valine were determined by ex vivo proton magnetic resonance spectroscopy. Glutamate concentration in the CSF was determined by HPLC. Gliosis was assessed by glial fibrillary acidic protein and CD68 immunohistochemistry. Glutamate concentration was slightly increased in the prefrontal cortex (19%, p = 0.0152, t-test) and putamen (13%, p = 0.0354, t-test) of the infected macaques, and was unaffected in the CSF. Myo-inositol concentration was increased in the prefrontal cortex only (27%, p = 0.0136). The concentrations of glutamate and myo-inositol in the prefrontal cortex were higher in the animals with marked or intense microgliosis (p = 0.0114). The other studied metabolites, including N-acetylaspartate, were not altered. Glutamate concentration may thus increase in the cerebral parenchyma in asymptomatic animals, but is not accompanied by a detectable decrease in N-acetylaspartate concentration (neuronal dysfunction). Thus, there are probably compensatory mechanisms that may limit glutamate increase and/or counterbalance its effects.

Animals↗
PubMed2004

Expression of excitatory amino acid transporter-1 (EAAT-1) in brain macrophages and microglia of patients with prion diseases.

The mechanisms of neuronal apoptosis in prion diseases are unclear. Experimental studies suggest that it may result from 2 associated mechanisms: glutamate-mediated excitotoxicity and oxidative stress. Recent studies showed that activated macrophages/microglia (AMM) express excitatory amino acid transporters (EAATs) in HIV infection, suggesting that they may play a neuroprotective role by clearing extra-cellular glutamate and producing anti-oxidant glutathione. In order to test this hypothesis in prion diseases, samples from cerebral cortex, striatum, thalamus, and cerebellum from 14 patients with Creutzfeldt-Jakob disease (8 sporadic, 2 familial, 2 iatrogenic, and 2 variant), and 4 with fatal familial insomnia (3 homozygous Met/Met at codon 129 of the PRNP gene, 1 heterozygous Met/Val), and 3 controls were immunostained for EAAT-1, GFAP, HLA-DR, CD68, IL-1, caspase 3, and PrP. In prion diseases, EAAT-1 immunopositivity was found in affected areas. Only AMM, interstitial, perivascular, perineuronal (sometimes around apoptotic neurons), or close to reactive astrocytes, expressed EAAT-1. Astrocyte EAAT-1 expression was scarcely detectable in controls and was not detected in prion disease cases. The proportion of AMM expressing EAAT-1 did not correlate with the severity of neuronal apoptosis, spongiosis, astrocytosis, microgliosis, or PrP deposition, but only with disease duration. Occasional EAAT-1 expressing AMM were found in patients with short survival, whereas diffuse EAAT-1 expression by AMM was observed in cases with long survival (24 to 33 months) that most often were heterozygous for Met/Val at codon 129 of the PRNP gene. Our findings suggest that AMM may develop a partial neuroprotective function in long-lasting prion diseases, although it does not seem to efficiently prevent neurological and neuropathological deterioration. Whether this neuroprotective function of microglia is the cause or the effect of longer survival needs to be clarified.

Adult↗
PubMed2004

Relapse after more than 20 years of follow-up for epithelial ovarian carcinoma.

BACKGROUND: Very late relapse of ovarian cancer is unusual and may present with atypical symptoms. CASES: We diagnosed 3 cases of relapse occurring after more than 20 years of follow-up. In the first case, the first recurrence was diagnosed by an appendicitis syndrome. With the second recurrence, small pelvic nodules were detected by fluorodeoxyglucose scintigraphy, whereas other imaging method results were negative. In the second case, a nodule in the axilla revealed the recurrence, and imaging methods confirmed multiple metastasis. In the third case, the patient presented with paroxysmal abdominal pain, and fluorodeoxyglucose scintigraphy showed a tiny lesion. CONCLUSION: Late relapses of ovarian cancer raise the issue of regrowth of dormant cells or the development of a new primary cancer. The absence of family history and BRCA gene mutations in these 3 patients favor late recurrence. Fluorodeoxyglucose scintigraphy was useful for diagnosis, particularly of small lesions not visible by classic imaging methods.

Abdominal Pain↗
PubMed2004

Cationic phosphorus-containing dendrimers reduce prion replication both in cell culture and in mice infected with scrapie.

Over the last 30 years, many drugs have been tested both in cell culture and in vivo for their ability to prevent the generation of prions and the development of transmissible spongiform encephalopathies. Among the compounds tested, dendrimers are defined by their branched and repeating molecular structure. The anti-prion activity of new cationic phosphorus-containing dendrimers (P-dendrimers) with tertiary amine end-groups was tested. These molecules had a strong anti-prion activity, decreasing both PrP(Sc) and infectivity in scrapie-infected cells at non-cytotoxic doses. They can bind PrP and decrease the amount of pre-existing PrP(Sc) from several prion strains, including the BSE strain. More importantly, when tested in a murine scrapie model, the dendrimers were able to decrease PrP(Sc) accumulation in the spleen by more than 80 %. These molecules have a high bio-availability and therefore exhibit relevant potential for prion therapeutics for at least post-exposure prophylaxis.

Animals↗
PubMed2004

Differential expression levels of MRP1, MRP4, and MRP5 in response to human immunodeficiency virus infection in human macrophages.

Multidrug resistance proteins (MRPs) have been reported to be involved in the efflux of some anti-human immunodeficiency virus (HIV) drugs. We show here that MRP1, MRP4, and MRP5 are expressed at the mRNA level in human monocyte-derived macrophages. HIV infection caused increased transcription of these MRPs; however, temporal differences in stimulation are reported.

Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)↗
PubMed2004

ATP binding cassette multidrug transporters limit the anti-HIV activity of zidovudine and indinavir in infected human macrophages.

OBJECTIVES: To investigate whether P-glycoprotein (P-gp) and multidrug resistance proteins (MRPs), which limit the bioavailability of HIV protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), modulate the anti-HIV activity of NRTIs, non-NRTIs and PIs in vitro. DESIGN: We used primary cultures of major HIV target cells: human monocyte-derived macrophages (MDMs) and lymphocytes. METHODS: P-gp and MRP expression in response to long-term zidovudine (3'-azido-3'-deoxythymidine; AZT) or indinavir treatment was quantified by RT-PCR. MDM and lymphocytes were infected in vitro with HIV-1/Ba-L and HIV-1-LAI, respectively, and treated with antiretroviral drugs. We evaluated the activity of these drugs in combination with PSC833, a P-gp inhibitor, and/or probenecid, an MRP1 inhibitor. Intracellular AZT triphosphate derivative (AZT-TP) was quantified by HPLC-MSMS. P-gp ATPase activity was measured with inside-out native membrane vesicles enriched in P-gp. RESULTS: Levels of MDR1, mrp4 and mrp5 mRNA were high following AZT treatment. In infected MDM, PSC833 and probenecid increased the anti-HIV activity of AZT and indinavir. AZT (5 nM) decreased HIV replication by 34% alone and by 72% in combination with P-gp/MRP inhibitors. Indinavir (10 nM) gave 14% inhibition alone and 81% in combination. The increase in anti-HIV activity of AZT was correlated with an increase in intracellular AZT-TP concentration. However, unlike PIs, neither AZT nor its metabolites interacted with P-gp. CONCLUSION: AZT increases the expression of multidrug transporters, thereby decreasing its pharmacological activity. The cellular efflux of AZT probably involves MRP4 or MRP5. In contrast, increases in indinavir anti-HIV activity require the inhibition of both P-gp and MRP1.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2003

A biased Valpha24+ T-cell repertoire leads to circulating NKT-cell defects in a multiple sclerosis patient at the onset of his disease.

As natural killer T (NKT) cells have been implicated in the regulation of multiple sclerosis (MS), we investigated expression of the Valpha24JalphaQ canonical rearrangement in MS patients during relapses. We observed major changes in the entire blood Valpha24(+) T-cell repertoire. Seven of the eight patients showed a marked decrease in Valpha24(+) transcript number and a decrease in the diversity of the Valpha24(+) T-cell repertoire, with the exception of a few expanded clones. These perturbations, exacerbated in patient MS (A), led to circulating NKT cell defects.

Amino Acid Sequence↗
PubMed2003

Inhibition of HIV-1 replication by cell-penetrating peptides binding Rev.

New therapeutic agents able to block HIV-1 replication are eagerly sought after to increase the possibilities of treatment of resistant viral strains. In this report, we describe a rational strategy to identify small peptide sequences owning the dual property of penetrating within lymphocytes and of binding to a protein target. Such sequences were identified for two important HIV-1 regulatory proteins, Tat and Rev. Their association to a stabilizing domain consisting of human small ubiquitin-related modifier-1 (SUMO-1) allowed the generation of small proteins named SUMO-1 heptapeptide protein transduction domain for binding Tat (SHPT) and SUMO-1 heptapeptide protein transduction domain for binding Rev (SHPR), which are stable and efficiently penetrate within primary lymphocytes. Analysis of the antiviral activity of these proteins showed that one SHPR is active in both primary lymphocytes and macrophages, whereas one SHPT is active only in the latter cells. These proteins may represent prototypes of new therapeutic agents targeting the crucial functions exerted by both viral regulatory factors.

Anti-HIV Agents↗
PubMed2003

Mucosal administration of three recombinant Mycobacterium bovis BCG-SIVmac251 strains to cynomolgus macaques induces rectal IgAs and boosts systemic cellular immune responses that are primed by intradermal vaccination.

The widely administered Mycobacterium bovis BCG is an attractive live vector for the development of AIDS vaccines. We explored immune responses induced in cynomolgus macaques to rBCG-SIV(3), a mixture of three recombinant BCG strains expressing the SIVmac251 nef, gag and env genes. After a single intradermal (ID) inoculation, circulating blood cells from rBCG-SIV(3)-vaccinated monkeys exhibited CTL responses targeted against the three antigens and interferon-gamma (IFNgamma) secretion was observed. A rectal or oral boosting dose of rBCG-SIV(3) elicited anti-SIV IgAs in the rectum of vaccinated monkeys and increased IFNgamma secretion by circulating blood cells. Despite a good response against the vector, rBCG-SIV(3) administration did not induce IgG antibody responses or lymphoproliferation against the SIV antigens in blood. This could be due to the lack of in vivo persistence of the recombinant BCG strains that were used. Rectal challenge with fully pathogenic SIVmac251-infected all animals. However, after viral challenge, anti-SIV cellular and antibody responses were higher in rBCG-SIV(3) monkeys than in controls indicating that the vaccine induced anti-SIV CD4(+) T-cell memory.

Adjuvants, Immunologic↗
PubMed2003

Isolation of drugs active against mammalian prions using a yeast-based screening assay.

We have developed a rapid, yeast-based, two-step assay to screen for antiprion drugs. The method allowed us to identify several compounds effective against budding yeast prions responsible for the [PSI+] and [URE3] phenotypes. These inhibitors include the kastellpaolitines, a new class of compounds, and two previously known molecules, phenanthridine and 6-aminophenanthridine. Two potent promoters of mammalian prion clearance in vitro, quinacrine and chlorpromazine, which share structural similarities with the kastellpaolitines, were also active in the assay. The compounds isolated here were also active in promoting mammalian prion clearance. These results validate the present method as an efficient high-throughput screening approach to identify new prion inhibitors and furthermore suggest that biochemical pathways controlling prion formation and/or maintenance are conserved from yeast to humans.

Animals↗
PubMed2003

Are 5'-O-carbamate-2',3'-dideoxythiacytidine new anti-HIV and anti-HBV nucleoside drugs or prodrugs?

In contrast to 5'-O-carbonate 3TC derivatives (23, 24), which are clearly 3TC prodrugs, the corresponding 3TC carbamates (15-21 and 25), found to be very stable compounds with respect to enzymatic hydrolysis (cellular lysates and culture cell media) and still active on both HIV-1 and HBV infected cells, may not be 3TC prodrugs. The antiviral properties as well as the mechanism of action of 3TC analogues have been studied and evaluated.

Anti-HIV Agents↗
PubMed2003

HIV type 1 diversity in France, 1999-2001: molecular characterization of non-B HIV type 1 subtypes and potential impact on susceptibility to antiretroviral drugs.

Non-B HIV-1 samples collected in France between 1999 and 2001 were sequenced in the env, reverse transcriptase (RT), and protease genes (1) to characterize further the non-B strains circulating in the country, (2) to assess the importance of recombination, and (3) to describe the polymorphism of RT and protease genes and appreciate a possible impact on susceptibility to antiretroviral (ARV) drugs. The results show that, within a background of CRF02_AG predominance, there is a high genetic diversity of non-B isolates, including intersubtype recombinants. There is an extensive polymorphism of protease and RT genes compared with B consensus sequences; we have so far no data indicating that these non-B isolates may have reduced sensitivity to ARV drugs.

Adult↗
PubMed2003

Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes.

Within the brain, quinolinic acid (QUIN) is an important neurotoxin, especially in AIDS dementia complex (ADC). Its production by monocytic lineage cells is increased in the context of inflammation. However, it is not known whether QUIN promotes inflammation. Astrocytes are important in immunoregulation within the brain and so we chose to examine the effects of QUIN on the astrocyte. Using purified primary human fetal astrocyte cultures, we determined chemokine production using ELISA assays and RT-PCR and chemokine receptor expression using immunocytochemistry and RT-PCR with QUIN in comparison to TNFalpha, IL-1beta, and IFNgamma. We found that QUIN induces astrocytes to produce large quantities of MCP-1 (CCL2) and lesser amounts of RANTES (CCL5) and IL-8 (CXCL8). QUIN also increases SDF-1alpha (CXCL12), HuMIG (CXCL9), and fractalkine (CX(3)CL1) mRNA expression. Moreover, QUIN leads to upregulation of the chemokine receptor expression of CXCR4, CCR5, and CCR3 in human fetal astrocytes. Most of these effects were comparable to those induced by TNFalpha, IL-1beta, and IFNgamma. The present work represents the first evidence that QUIN induces chemokine and chemokine receptor expression in astrocytes and is at least as potent as classical mediators such as inflammatory cytokines. These results suggest that QUIN may be critical in the amplification of brain inflammation, particularly in ADC.

Astrocytes↗
PubMed2003

Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNF alpha and IFN gamma in CXCR4 and CCR5 modulation.

Chemokines are key mediators of the selective migration of leukocytes that occurs in neurodegenerative diseases and related inflammatory processes. Astrocytes, the most abundant cell type in the CNS, have an active role in brain inflammation. To ascertain the role of astrocytes during neuropathological processes, we have investigated in two models of primary cells (human fetal and simian adult astrocytes) the repertoire of chemokines and their receptors expressed in response to inflammatory stimuli. We demonstrated that, in the absence of any stimulation, human fetal and simian adult astrocytes express mRNA for receptors APJ, BOB/GPR15, Bonzo/CXCR6, CCR2, CCR3, CCR5, CCR8, ChemR23, CXCR3/GPR9, CXCR4, GPR1, and V28/CX3CR1. Moreover, TNFalpha and IL-1beta significantly increase BOB/GPR15, CCR2, and V28/CX3CR1 mRNA levels in both models. Furthermore, TNFalpha and IFNgamma act synergistically to induce expression of the major coreceptors for HIV infection, CXCR4 and CCR5, at both the mRNA and protein levels in human and simian astrocytes, whereas CCR3 expression was not affected by cytokine treatment. Finally, TNFalpha/IFNgamma was the most significant cytokine combination in leading to a pronounced upregulation in a comparable, time-dependent manner of the production of chemokines IP-10/CXCL10, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IL-8/CXCL8. In summary, these data suggest that astrocytes serve as an important source of chemokines under the dependence of a complex cytokine regulation, and TNFalpha and IFNgamma are important modulators of chemokines and chemokine receptor expression in human as well as simian astrocytes. Finally, with the conditions we used, there was no difference between species or age of tissue.

Animals↗
PubMed2003

The same TCR (N)Dbeta(N)Jbeta junctional region is associated with several different vbeta13 subtypes in a multiple sclerosis patient at the onset of the disease.

In multiple sclerosis (MS), the T-cell receptors (TCRS) of autoreactive T lymphocytes recognize various myelin components or derivatives including peptides of the myelin basic protein (MBP). Using the exhaustive immunoscope approach we showed that the T-cell repertoires of MS patients differ from those of healthy controls, with expansion of Vbeta13 cell clones in cerebrospinal fluid (CSF) and in peripheral blood lymphocytes (PBLs). Sequencing of the beta13(+) chains of T cells recovered from the CSF revealed high interindividual diversity, and no particular Vbeta13(+) rearrangements were shown to be myelin-autoreactive. Within the overall Vbeta13 repertoire in the CSF of patient MS3 at the onset of the disease, most of the overrepresented (N)Dbeta(N)Jbeta junctional regions were found to be associated with two or three different Vbeta13 segments. These rearrangements were most common in the PBLs of patient MS3. No such associations were detected in the Vbeta5 multigene family that was used as a control. Thus, Vbeta13 T cells infiltrating the CSF from patient MS3 may have been selected on the basis of both the Vbeta13 segments and the (N)Dbeta(N)Jbeta junctional CDR3 sequence.

Adult↗