A Novel Substrate-Based HIV-1 Protease Inhibitor Drug Resistance Mechanism

BACKGROUND: HIV protease inhibitor (PI) therapy results in the rapid selection of drug resistant viral variants harbouring one or two substitutions in the viral protease. To combat PI resistance development, two approaches have been developed. The first is to increase the level of PI in the plasma of the patient, and the second is to develop novel PI with high potency against the known PI-resistant HIV protease variants. Both approaches share the requirement for a considerable increase in the number of protease mutations to lead to clinical resistance, thereby increasing the genetic barrier. We investigated whether HIV could yet again find a way to become less susceptible to these novel inhibitors. METHODS AND FINDINGS: We have performed in vitro selection experiments using a novel PI with an increased genetic barrier (RO033-4649) and demonstrated selection of three viruses 4- to 8-fold resistant to all PI compared to wild type. These PI-resistant viruses did not have a single substitution in the viral protease. Full genomic sequencing revealed the presence of NC/p1 cleavage site substitutions in the viral Gag polyprotein (K436E and/or I437T/V) in all three resistant viruses. These changes, when introduced in a reference strain, conferred PI resistance. The mechanism leading to PI resistance is enhancement of the processing efficiency of the altered substrate by wild-type protease. Analysis of genotypic and phenotypic resistance profiles of 28,000 clinical isolates demonstrated the presence of these NC/p1 cleavage site mutations in some clinical samples (codon 431 substitutions in 13%, codon 436 substitutions in 8%, and codon 437 substitutions in 10%). Moreover, these cleavage site substitutions were highly significantly associated with reduced susceptibility to PI in clinical isolates lacking primary protease mutations. Furthermore, we used data from a clinical trial (NARVAL, ANRS 088) to demonstrate that these NC/p1 cleavage site changes are associated with virological failure during PI therapy. CONCLUSIONS: HIV can use an alternative mechanism to become resistant to PI by changing the substrate instead of the protease. Further studies are required to determine to what extent cleavage site mutations may explain virological failure during PI therapy

Hemodialysis Removes Uremic Toxins That Alter the Biological Actions of Endothelial Cells

Chronic kidney disease is linked to systemic inflammation and to an increased risk of ischemic heart disease and atherosclerosis. Endothelial dysfunction associates with hypertension and vascular disease in the presence of chronic kidney disease but the mechanisms that regulate the activation of the endothelium at the early stages of the disease, before systemic inflammation is established remain obscure. In the present study we investigated the effect of serum derived from patients with chronic kidney disease either before or after hemodialysis on the activation of human endothelial cells in vitro, as an attempt to define the overall effect of uremic toxins at the early stages of endothelial dysfunction. Our results argue that uremic toxins alter the biological actions of endothelial cells and the remodelling of the extracellular matrix before signs of systemic inflammatory responses are observed. This study further elucidates the early events of endothelial dysfunction during toxic uremia conditions allowing more complete understanding of the molecular events as well as their sequence during progressive renal failure

Atlas de l'Empire napoléonien, 1799-1815. Vers une nouvelle civilisation européenne.

International audienceLes quelque 100 cartes et infographies aident à comprendre une période charnière de l’histoire de France et de l’Europe, depuis la construction de l’Empire jusqu’à son effondrement.• Une analyse fine et contrastée du projet politique de Napoléon, officiellement inspiré des Lumières mais bâti sur la conquête et le contrôle autoritaire des populations.• Les dynamiques démographiques, sociales, économiques et culturelles : un état des lieux des grands bouleversements de l’époque.• Un héritage pérenne : création du Code civil, développement des voies de communication, réformes de l’administration, modernisation des villes, essor de Paris en capitale impériale…Plus de deux siècles après la chute de l’Empire, cet atlas dresse le juste portrait d’une époque, au plus près des populations

Etude mathématique des modèles réduits mise à la terre

(J. de la Recherche Scientifique de l'Université de Lomé, 1999, 3(2): 193-200

Barrier properties of polyamide 12/montmorillonite nanocomposites: Effect of clay structure and mixing conditions

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Multilayers polyethylene film for crop protection in harsh climatic conditions.

In this work the performance and durability of a new generation of greenhouse covers, in which the cover is composed of five layers, are investigated. A sand wind ageing was performed under different exposure conditions. Surface morphology and chemical, physical, and thermal characteristics were investigated by using optical microscopy, FTIR, and tensile test techniques. In addition, the mechanical integrity of the five-layer film was assessed. The analysis indicated that the sand wind treatments have a significant influence only on the performance of the film. An attempt has been done to compare the properties of the five-layer film with the monolayer and trilayer films with or without air bubble under similar conditions.Theresults revealed that the five-layer film proved to be a promising greenhouse covering film

Transport Mechanisms of Small Molecules through Polyamide 12/Montmorillonite Nanocomposites

International audienceThe aim of this work is to study the transport of small molecules through the hybrid systems polyamide 12 (PA12)/organo-modified montmorillonite (Cloisite 30B, C30B) prepared by melt blending, using two blending conditions. The transport mechanisms were investigated by using three probe molecules: nitrogen, water, and toluene. While a barrier effect appears clearly with nitrogen, this effect changes with the amount of fillers for water and disappears for toluene. The reduction of permeability for nitrogen is mainly due to the increase of tortuosity. For water and toluene, the permeation kinetics reveals many concomitant phenomena responsible for the permeation behavior. Despite the tortuosity effect, the toluene permeability of nanocomposites increases with C30B fraction. The water and toluene molecules interact differently with fillers according to their hydrophilic/hydrophobic character. Moreover, the plasticization effect of water and toluene in the matrix, involving a concentration-dependent diffusion coefficient, is correctly described by the law D = D0eγC. On the basis of Nielsen's tortuosity concept, we suggest a new approach for relative permeability modeling, not only based on the geometrical parameters (aspect ratio, orientation, recovery) but also including phenomenological parameters deduced from structural characterization and permeation kinetics