Inhibiteurs de Nef du VIH-1 : applications et développements pour une guérison efficace.

Résumé La thérapie anti-rétrovirale peut contrôler la réplication du virus de l'immunodéficience humaine de type 1 (VIH-1) chez les individus vivant avec le VIH. Par contre, ces traitements ne constituent pas une guérison et aucune approche pour une guérison du VIH-1 n'a encore montré de succès lors des études cliniques. Les approches de guérison sont souvent contrées in vivo par des barrières développées par le VIH-1. L'inhibition pharmacologique de la protéine accessoire Nef du VIH-1 représente une approche ambitieuse et prometteuse pour développer une nouvelle stratégie de guérison. Des petites molécules inhibitrices de Nef peuvent inverser les défauts reliés à l'infection par le VIH dans la signalisation des récepteurs des cellules T et les kinases, l'apoptose, l'autophagie et surtout, la présentation d'antigène. Ensemble, ces activités démontrent la grande capacité des inhibiteurs de Nef à être appliqués comme agents thérapeutiques dans un traitement contre le VIH-1. Dans cette revue, nous présentons les motifs pour lesquels Nef constitue une cible thérapeutique et nous soulignons les progrès effectués dans l'identification et le développement d'inhibiteurs de Nef.

Inhibitors of HIV-1 Nef: applications and developments for a practical cure.

Antiretroviral therapy can control human immunodeficiency virus type 1 (HIV-1) replication in people living with HIV; however, these treatments are not curative and no practical approach for an HIV-1 cure has yet shown success in clinical trials. Counteracting the multiple barriers HIV-1 presents against a practical cure is a direct means to functionalize these curative approaches in vivo. Pharmacological inhibition of the HIV-1 accessory protein, Nef, represents a particularly promising and ambitious approach, with Nef inhibitors holding the potential to reverse HIV-1-related defects in T cell receptor and kinase signaling, apoptosis, autophagy and most importantly, antigen presentation. Together, the capacity for Nef inhibitors to restore these activities underscores their potential as supportive agents in a practical HIV-1 cure. In this review, we outline a rationale for pharmacologically targeting Nef and review the progress made in the identification and development of Nef inhibitors.

Deployment of fingertip forces in tactile exploration.

The purpose of this study was to examine how contact forces normal to the skin surface and shear forces tangential to the skin surface are deployed during tactile exploration of a smooth surface in search of a tactile target. Six naive subjects participated in two experiments. In the first experiment, the subjects were asked to explore a series of unseen smooth plastic surfaces by using the index finger to search for either a raised or recessed target. The raised targets were squares with a height of 280 micro m above the background surface and that varied in side lengths from 0.2 mm to 8.0 mm. A second series of smooth plastic surfaces consisted of small recessed squares (side lengths: 2.0, 3.0, 4.0 and 8.0 mm) that were etched to a depth of 620 micro m. Although made of an identical material, the plastic substrate had a lower coefficient of friction against the skin because only the recessed square had been subjected to the electrolytic etching process. The surfaces were mounted on a six-axes force and torque sensor connected to a laboratory computer. From the three axes of linear force, the computer was able to calculate the instantaneous position of the index finger and the instantaneous tangential force throughout the exploratory period. When exploring for the raised squares, the subjects maintained a relatively constant, average normal force of about 0.49 N with an average exploration speed of 8.6 cm/s. In contrast, all subjects used a significantly higher average normal force (0.64 N) and slightly slower mean exploration speed (7.67 cm/s) when searching for the small recessed squares. This appeared to be an attempt to maximize the amount of skin penetrating the recessed squares to improve the probability of target detection. In a second experiment, subjects were requested to search for an identical set of raised squares but with the fingertip having been coated with sucrose to impede the scanning movement by increasing the friction. Overall, the subjects maintained the same constant normal force that they used on the uncoated surface. However, they increased the tangential force significantly. The similarity of the search strategy employed by all subjects supports the hypothesis that shear forces on the skin provide a significant stimulus to mechanoreceptors in the skin during tactile exploration. Taken together, these data suggest that, in active tactile exploration with the fingertip, the tangential finger speed, the normal contact force, and the tangential shear force are adjusted optimally depending on the surface friction and whether the target is a raised asperity or a recessed indentation.