Biomedical subjects

Pascal Clayette

Publications and source records attributed to Pascal Clayette.

24 records · Page 2Linked to original sources

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

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↗

PubMed2003

The expression of P-glycoprotein and cellular kinases is modulated at the transcriptional level by infection and highly active antiretroviral therapy in a primate model of AIDS.

The beneficial effects of highly active antiretroviral therapy (HAART) in HIV-infected patients may be limited by inadequate compliance and viral resistance, but also by host cell factors, such as P-glycoprotein (P-gp) and intracellular kinases involved in the phosphorylation of nucleoside reverse transcriptase inhibitors. We investigated the effects of infection and HAART (zidovudine [AZT], lamivudine [3TC], and indinavir [IDV] on the expression of P-gp and cell kinases involved in the phosphorylation of AZT and 3TC in SHIV89.6P-infected cynomolgus macaques. Under unstimulated conditions, we observed a decrease in P-gp mRNA levels in the peripheral blood and lymph node mononuclear cells of infected macaques, which was accentuated by HAART. SHIV infection also resulted in the overexpression of thymidine kinase mRNA, which was abolished by HAART. In conclusion, retroviral infection and HAART modulate in vivo at the transcriptional level the expression of host cell factors that may affect the efficacy of HAART.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Regulated expression of sodium-dependent glutamate transporters and synthetase: a neuroprotective role for activated microglia and macrophages in HIV infection?

It is now widely accepted that neuronal damage in HIV infection results mainly from microglial activation and involves apoptosis, oxidative stress and glutamate-mediated neurotoxicity. Glutamate toxicity acts via 2 distinct pathways: an excitotoxic one in which glutamate receptors are hyperactivated, and an oxidative one in which cystine uptake is inhibited, resulting in glutathione depletion and oxidative stress. A number of studies show that astrocytes normally take up glutamate, keeping extracellular glutamate concentration low in the brain and preventing excitotoxicity. This action is inhibited in HIV infection, probably due to the effects of inflammatory mediators and viral proteins. Other in vitro studies as well as in vivo experiments in rodents following mechanical stimulation, show that activated microglia and brain macrophages express high affinity glutamate transporters. These data have been confirmed in chronic inflammation of the brain, particularly in SIV infection, where activated microglia and brain macrophages also express glutamine synthetase. Recent studies in humans with HIV infection show that activated microglia and brain macrophages express the glutamate transporter EAAT-1 and that expression varies according to the disease stage. This suggests that, besides their recognized neurotoxic properties in HIV infection, these cells also have a neuroprotective function, and may partly make up for the inhibited astrocytic function, at least temporarily. This hypothesis might explain the discrepancy between microglial activation which occurs early in the disease, and neuronal apoptosis and neuronal loss which is a late event. In this review article, we discuss the possible neuroprotective and neurotrophic roles of activated microglia and macrophages that may be generated by the expression of high affinity glutamate transporters and glutamine synthetase, 2 major effectors of glial glutamate metabolism, and the implications for HIV-induced neuronal dysfunction, the underlying cause of HIV dementia.

AIDS Dementia Complex↗

PubMed2003

Anti-human immunodeficiency virus activity of tau interferon in human macrophages: involvement of cellular factors and beta-chemokines.

Tau interferon (IFN-tau) is a noncytotoxic type I IFN responsible for maternal recognition of the fetus in ruminants. IFN-tau inhibits human immunodeficiency virus (HIV) replication more strongly than human IFN-alpha, particularly in human monocyte-derived macrophages. In this study performed in human macrophages, IFN-tau efficiently inhibited the early steps of the biological cycle of HIV, decreasing intracellular HIV RNA and inhibiting the initiation of the reverse transcription of viral RNA into proviral DNA. Two mechanisms induced by IFN-tau treatment in macrophages may account for this inhibition: (i) the synthesis of the cellular antiviral factors such as 2',5'-oligoadenylate synthetase/RNase L and MxA protein and (ii) an increased production of MIP-1alpha, MIP-1beta, and RANTES, which are natural ligands of CCR5, the principal coreceptor of HIV on macrophages. Our results suggest that IFN-tau induces the same antiviral pathways in macrophages as other type I IFNs but without associated toxicity.

Chemokines, CC↗

PubMed2002

A co-culture-based model of human blood-brain barrier: application to active transport of indinavir and in vivo-in vitro correlation.

The growing array of in vitro models of the blood-brain barrier (BBB) which have been used makes it difficult to draw firm conclusions concerning the BBB penetration of HIV-1 protease inhibitors. What is needed is a combined in vivo and in vitro study on biological models that mimic as closely as possible the normal human BBB, to establish whether and how indinavir crosses the BBB. We developed a new human BBB model using primary endothelial cells and astrocytes. The biological relevance of this model was checked with respect on the one hand, to the close relationship between the log of drug permeability coefficient normalized to molecular weight and the log of the 1-octanol/water partition coefficient, and on the other hand to the functional P-glycoprotein (P-gp) expression. We employed this model to perform transport studies with indinavir and showed that the rate of in vitro indinavir transport from the basal to apical compartment was higher than the rate of apical to basal transport. Pretreatment of the BBB model with the P-gp inhibitor, quinidine, significantly increased apical to basal transport. Intracellular indinavir accumulation was increased in BBB as a result of inhibition of active transport. These data were correlated with the indinavir-mediated P-gp ATPase modulation showing that indinavir specifically interacted with a binding site on P-gp. Moreover, the activation of P-gp ATPase by indinavir was inhibited by quinidine. In addition, the in vivo brain to plasma concentration ratio of indinavir into mice showed that indinavir concentration was up to five times higher in the brain of mdr1a(-/-) mice than in the brain of mdr1a(+/+) mice. All these results confirm the role of P-gp in preventing the passage of indinavir across BBB and thus its entry into the central nervous system (CNS). Our human BBB model represents a useful tool for the evaluation of drug penetration into the CNS.

ATP Binding Cassette Transporter, Subfamily B↗