Institute National Des Science Et Of La Recherche Medicale

Toulouse, France

Institute National Des Science Et Of La Recherche Medicale

Toulouse, France
SEARCH FILTERS
Time filter
Source Type

Cuzin L.,University Hospital | Trabelsi S.,University Pierre and Marie Curie | Delobel P.,University Hospital | Delobel P.,Institute National Des Science Et Of La Recherche Medicale | And 10 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2012

Objective: To address the ability of a 24-week Maraviroc (MVC) intensification of a stable antiretroviral therapy (cART) to significantly increase the CD4 cell count slope. Methods: Patients were eligible if they had CD4 <350 cells/mm3, a CD4 slope <50 cells/mm3 per year, and sustained plasma HIV-RNA <50 copies/mL over the last 2 years, while receiving a stable cART. Patients harboring pure X4-using viruses by a phenotypic tropism assay were excluded. MVC was added to cART for 24 weeks, at the recommended dosage per drug-drug interactions. The primary endpoint was a significant positive difference in CD4 slopes (with MVC-pre-MVC, paired t test). Results: Sixty patients (55 men), with median age 51 years, baseline CD4 238 cells/mm3, and slope before intensification +14.1 cells/mm 3 per year were included. CD4 nadir was <50/mm3 in 47% of the population. The full set of patients (N = 57) completed week 24, and the on-treatment patients (N = 48) did not discontinue MVC. The median CD4 slope difference from baseline was +22.6 cells/mm3 per year (P = 0.08) in full set and +22.6 cells/mm3 per year (P = 0.04) in on-treatment. Slope evolution was not different according to baseline tropism, CD4 nadir, or ongoing cART regimen. No drug-related severe adverse events were recorded during intensification. MVC plasma concentrations were significantly different depending on drug-drug interaction with ongoing cART regimen and tended to be correlated with CD4 cells increase. Conclusion: In this study, MVC intensification of stable cART over 24 weeks was able to enhance CD4 cell slopes in patients with prior insufficient immune restoration despite long-term virological control. Copyright © 2012 by Lippincott Williams & Wilkins.


De Toni-Costes F.,Institute National Des Science Et Of La Recherche Medicale | De Toni-Costes F.,University Paul Sabatier | Despeaux M.,Institute National Des Science Et Of La Recherche Medicale | Despeaux M.,University Paul Sabatier | And 11 more authors.
PLoS ONE | Year: 2010

Background: Cell survival mediated by integrin engagement has been implicated in cell adhesion-mediated drug resistance. We have recently demonstrated that the activation of glycogen synthase kinase 3 β (GSK3β) is a new pathway supporting the chemoresistance of leukemic cells adhered to fibronectin. Methodology and Principal Findings: We show here that in conditions of serum starvation, the fibronectin receptor α5β1 integrin, but not α4β1, induced activation of GSK3β through Ser-9 dephosphorylation in adherent U937 cells. The GSK3β dependent survival pathway occurred in adherent leukemic cells from patients but not in the HL-60 and KG1 cell lines. In adhesion, activated GSK3β was found in the cytosol/plasma membrane compartment and was co-immunoprecipitated with a5 integrin, the phosphatase PP2A and the scaffolding protein RACK1. PP2A and its regulatory subunit B′ regulated the Ser-9 phosphorylation of GSK3β. In adherent leukemic cells, α5β1 integrin but not α4β1 upregulated the resistance to TNF-α-induced apoptosis. Both extrinsic and intrinsic apoptotic pathways were under the control of α5β1 and GSK3β. Conclusions and Significance: Our data show that, upon serum starvation, α5β1 integrin engagement could regulate specific pro-survival functions through the activation of GSK3β. © 2010 De Toni-Costes et al.


PubMed | Institute National Des Science Et Of La Recherche Medicale
Type: Journal Article | Journal: PloS one | Year: 2010

Cell survival mediated by integrin engagement has been implicated in cell adhesion-mediated drug resistance. We have recently demonstrated that the activation of glycogen synthase kinase 3 beta (GSK3beta) is a new pathway supporting the chemoresistance of leukemic cells adhered to fibronectin.We show here that in conditions of serum starvation, the fibronectin receptor alpha(5)beta(1) integrin, but not alpha(4)beta(1), induced activation of GSK3beta through Ser-9 dephosphorylation in adherent U937 cells. The GSK3beta-dependent survival pathway occurred in adherent leukemic cells from patients but not in the HL-60 and KG1 cell lines. In adhesion, activated GSK3beta was found in the cytosol/plasma membrane compartment and was co-immunoprecipitated with alpha(5) integrin, the phosphatase PP2A and the scaffolding protein RACK1. PP2A and its regulatory subunit B regulated the Ser-9 phosphorylation of GSK3beta. In adherent leukemic cells, alpha(5)beta(1) integrin but not alpha(4)beta(1) upregulated the resistance to TNFalpha-induced apoptosis. Both extrinsic and intrinsic apoptotic pathways were under the control of alpha(5)beta(1) and GSK3beta.Our data show that, upon serum starvation, alpha(5)beta(1) integrin engagement could regulate specific pro-survival functions through the activation of GSK3beta.

Loading Institute National Des Science Et Of La Recherche Medicale collaborators
Loading Institute National Des Science Et Of La Recherche Medicale collaborators