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1.
Lancet Infect Dis ; 15(11): 1283-91, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26257021

ABSTRACT

BACKGROUND: Revaccination with double-dose hepatitis B vaccine has been recommended in HIV-infected patients who do not respond to standard vaccination, but has not yet been assessed. We aimed to compare the safety and immunogenicity of a reinforced hepatitis B revaccination protocol with the standard revaccination schedule in HIV-infected patients not responding to primary vaccination. METHODS: We did this multicentre, open-label, randomised controlled trial, at 53 centres in France. HIV-infected adults (aged ≥18 years), with CD4 counts of 200 cells per µL or more and no response to a previous hepatitis B vaccination or a 20 µg booster dose, were randomly assigned (1:1), according to a computer-generated randomisation list with permuted blocks (block sizes of two to six), to receive either standard-dose (20 µg) or double-dose (40 µg) recombinant hepatitis B vaccine at weeks 0, 4, and 24. Randomisation was stratified by baseline CD4 count (200-349 vs ≥350 cells per µL). Patients and treating physicians were not masked to treatment allocation, but the randomisation list was concealed from the investigators who assigned participants to the vaccination groups. The primary endpoint was the proportion of responders, defined as patients with hepatitis B surface antibody (anti-HBs) titres of 10 mIU/mL or more, at week 28. We did analysis by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00670839. FINDINGS: Between May 19, 2008, and May 8, 2011, 178 participants were randomly assigned to the standard-dose group (n=90) or the double-dose group (n=88), of whom 176 (98%) participants were included in the primary efficacy analysis. At week 28, we recorded a response in 60 patients (67%, 95% CI 57-77) in the standard-dose group versus 64 patients (74%, 63-82) in the double-dose group (p=0·334). Except for more frequent local reactions in the double-dose group than the standard-dose group (13 [15%] vs four [4%] patients; p=0·020), there was no difference in safety between groups. INTERPRETATION: In adults with HIV-1 who have not responded to previous hepatitis B vaccination, double-dose revaccination did not achieve a higher response rate than did revaccination with standard single-dose regimen. However, the safety profile was similar between treatment groups. Our results should be assessed in future studies before double-dose vaccine can be considered for the standard of care of vaccine non-responders. FUNDING: French National Institute for Medical Research-French National Agency for Research on AIDS and Viral Hepatitis.


Subject(s)
HIV Infections/immunology , Hepatitis B Antibodies/blood , Hepatitis B Vaccines/administration & dosage , Hepatitis B Vaccines/immunology , Hepatitis B/prevention & control , Immunization, Secondary/methods , Adult , Aged , Female , France , Hepatitis B Vaccines/adverse effects , Humans , Immunization, Secondary/adverse effects , Male , Middle Aged , Single-Blind Method , Treatment Outcome , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/adverse effects , Vaccines, Synthetic/immunology , Young Adult
2.
Clin Res Hepatol Gastroenterol ; 39(4): 443-50, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25636238

ABSTRACT

BACKGROUND AND OBJECTIVE: To assess within the ANRS CO20-CUPIC cohort whether the viral load (VL) at week 2/week 6 for telaprevir/boceprevir-based triple therapy, respectively, was predictive of sustained virological response (SVR) in patients with hepatitis C virus (HCV) infection and to study the relevance of this measurement to early diagnose drug resistance. METHODS: Observational study of HCV genotype 1 patients with compensated cirrhosis (Child-Pugh A), non-responders to a prior course of interferon (IFN)-based therapy and who started triple therapy. Patients received either 12 weeks of telaprevir in combination with PEG-IFN/ribavirin (RBV), then 36 weeks of PEG-IFN/RBV, or 4 weeks of PEG-IFN/RBV, then 44 weeks of PEG-IFN/RBV and boceprevir. RESULTS: A total of 262 patients were analyzed. For telaprevir-treated patients, 28% had undetectable VL at W2 of whom 81% achieved SVR12 whereas 67% had undetectable VL at W4 of whom 67% achieved SVR12. For boceprevir-treated patients 20% had undetectable VL at W6 and 86% of them achieved SVR12 whereas 36% had undetectable VL at W8 among whom 73% achieved SVR12. Five telaprevir-treated patients had a VL increase between W2 and W4 after a decrease between D0 and W2. Four of them did not achieve SVR12. Similarly, six boceprevir-treated patients had a VL increase between W6 and W8 after a decrease between D0 and W6. Five did not reach SVR12. CONCLUSIONS: The assessment of HCV RNA level after two weeks of triple therapy in cirrhotic non-responder patients is a good predictor of SVR. This assessment was useful to do an early diagnosis of viral breakthrough.


Subject(s)
Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/drug therapy , Viral Load , Antiviral Agents/therapeutic use , Drug Therapy, Combination , Female , Hepacivirus/genetics , Hepacivirus/metabolism , Humans , Interferon-alpha/therapeutic use , Liver Cirrhosis/virology , Male , Middle Aged , Oligopeptides/therapeutic use , Polyethylene Glycols/therapeutic use , Proline/analogs & derivatives , Proline/therapeutic use , Prospective Studies , Protease Inhibitors/therapeutic use , RNA/metabolism , Recombinant Proteins/therapeutic use , Ribavirin/therapeutic use
3.
Apoptosis ; 13(9): 1100-10, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18670882

ABSTRACT

Apoptosis is increasingly implicated as an early line of defense against viral infections. Viruses have devised numerous strategies to delay apoptosis of infected cells. Many viruses encode cell death suppressors that target mitochondrial apoptotic signaling pathway, indicating the importance of this pathway in the anti-viral response. Human and primate cytomegaloviruses encode the viral mitochondria-localized inhibitor of apoptosis vMIA, but no overt homologue of vMIA was identified in any non-primate cytomegalovirus. Here we report that m38.5 protein encoded by murine cytomegalovirus, which is unrelated to vMIA in its amino acid sequence, delays death receptor ligation-induced cell death, and that m38.5 associates with Bax, recruits it to mitochondria, and blocks Bax-mediated but not Bak-mediated mitochondrial outer membrane permeabilization. Thus, primate and murine cytomegaloviruses have evolved non-homologous but functionally similar cell death suppressors selectively targeting the Bax-mediated branch of the mitochondrial apoptotic signaling pathway, indicating the importance of this branch in the response of diverse host organisms against cytomegalovirus infections.


Subject(s)
Mitochondrial Membranes/metabolism , Muromegalovirus/metabolism , Viral Proteins/metabolism , bcl-2-Associated X Protein/metabolism , Animals , Cell Death , HCT116 Cells , HeLa Cells , Humans , Mice , Permeability , Protein Binding , Protein Conformation , Protein Transport , RNA, Small Interfering/metabolism , Receptors, Death Domain/metabolism , bcl-2-Associated X Protein/chemistry , fas Receptor/metabolism
4.
Am J Physiol Endocrinol Metab ; 294(4): E794-801, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18378961

ABSTRACT

Loss of mechanical loading induces rapid bone loss resulting from reduced osteoblastogenesis and decreased bone formation. The signaling mechanisms involved in this deleterious effect on skeletal metabolism remain poorly understood. We have previously shown that hindlimb suspension in rats increases osteoblast apoptosis associated with decreased phosphatidylinositol 3-kinase (PI3K) signaling. In this study, we investigated whether transforming growth factor (TGF)-beta2 may prevent the altered signaling and osteoblast apoptosis induced by skeletal unloading in vivo. Hindlimb suspension-induced decreased bone volume was associated with reduced alpha(5)beta(1)-integrin protein levels and PI3K/Akt signaling in unloaded bone. Continuous administration of TGF-beta2 using osmotic minipumps prevented the decreased alpha(5)beta(1)-integrin expression and the reduced PI3K/Akt signaling in unloaded bone, resulting in the prevention of osteoblast apoptosis. We also show that TGF-beta2 prevented the decreased Bcl-2 levels induced by unloading, which suggests that TGF-beta2 targets Bcl-2 via PI3K/Akt to prevent osteoblast apoptosis in unloaded bone. Furthermore, we show that TGF-beta2 prevented the decrease in phosphorylated Bad, the inactive form of the proapoptotic protein Bad, induced by unloading. These results identify a protective role for TGF-beta2 in osteoblast apoptosis induced by mechanical unloading via the alpha(5)beta(1)/PI3K/Akt signaling cascade and downstream Bcl-2 and phospho-Bad survival proteins. We thus propose a novel role for TGF-beta2 in protection from unloading-induced apoptosis in vivo.


Subject(s)
Apoptosis/physiology , Hindlimb Suspension , Osteoblasts/metabolism , Signal Transduction/physiology , Transforming Growth Factor beta2/metabolism , Animals , Apoptosis/drug effects , Bone and Bones/drug effects , Bone and Bones/metabolism , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Osteoblasts/drug effects , Osteoblasts/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Wistar , Signal Transduction/drug effects , Transforming Growth Factor beta2/pharmacology , Up-Regulation/drug effects , Up-Regulation/physiology , bcl-Associated Death Protein/metabolism
5.
Bone ; 42(6): 1032-9, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18374639

ABSTRACT

Fibroblast growth factor receptor (FGFR) signaling plays an important role in skeletogenesis. The molecular mechanisms triggered by activated FGFR in bone forming cells are however not fully understood. In this study, we identify a role for phosphatidylinositol 3-kinase (PI3K) signaling in cell apoptosis induced by FGFR2 activation in osteoblasts. We show that FGFR2 activation leads to decrease PI3K protein levels, resulting in attenuation of PI3K signaling in human osteoblasts. Biochemical and molecular analyses revealed that the attenuated PI3K signaling induced by FGFR2 activation is due to increased Cbl-PI3K molecular interaction mediated by the Cbl Y731 residue, which results in increased PI3K ubiquitination and proteasome degradation. Biochemical and immunocytochemical analyses showed that FGFR2 and Cbl interact in raft micro-domains at the plasma membrane. FGFR2 activation increases FGFR2 and Cbl recruitment in micro-domains, resulting in increased molecular interactions. Consistently, functional analyses showed that the attenuation of PI3K/Akt signaling triggered by FGFR2 activation results in increased osteoblast apoptosis. These results identify a functional molecular mechanism by which activated FGFR2 recruits Cbl in raft micro-domains to trigger PI3K ubiquitination and proteasome degradation, and reveal a novel role for PI3K/Akt attenuation in the control of osteoblast survival by FGFR2 signaling.


Subject(s)
Membrane Microdomains/metabolism , Osteoblasts/physiology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-cbl/metabolism , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Signal Transduction/physiology , Apoptosis/physiology , Cell Line , Cell Survival , Humans , Mutation , Osteoblasts/cytology , Proto-Oncogene Proteins c-cbl/genetics , Receptor, Fibroblast Growth Factor, Type 2/genetics , Ubiquitin/metabolism
6.
Am J Pathol ; 169(4): 1303-11, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17003487

ABSTRACT

Genetic mutations of Twist, a basic helix-loop-helix transcription factor, induce premature fusion of cranial sutures in Saethre-Chotzen syndrome (SCS). We report here a previously undescribed mechanism involved in the altered osteoblastogenesis in SCS. Cranial osteoblasts from an SCS patient with a Twist mutation causing basic helix-loop-helix deletion exhibited decreased expression of E3 ubiquitin ligase Cbl compared with wild-type osteoblasts. This was associated with decreased ubiquitin-mediated degradation of phosphatidyl inositol 3 kinase (PI3K) and increased PI3K expression and PI3K/Akt signaling. Increased PI3K immunoreactivity was also found in osteoblasts in histological sections of affected cranial sutures from SCS patients. Transfection with Twist or Cbl abolished the increased PI3K/Akt signaling in Twist mutant osteoblasts. Forced overexpression of Cbl did not correct the altered expression of osteoblast differentiation markers in Twist mutant cells. In contrast, pharmacological inhibition of PI3K/Akt, but not ERK signaling, corrected the increased cell growth in Twist mutant osteoblasts. The results show that Twist haploinsufficiency results in decreased Cbl-mediated PI3K degradation in osteoblasts, causing PI3K accumulation and activation of PI3K/Akt-dependent osteoblast growth. This provides genetic and biochemical evidence for a role for Cbl-mediated PI3K signaling in the altered osteoblast phenotype induced by Twist haploinsufficiency in SCS.


Subject(s)
Acrocephalosyndactylia/enzymology , Nuclear Proteins/deficiency , Osteoblasts/cytology , Proto-Oncogene Proteins c-cbl/metabolism , Twist-Related Protein 1/deficiency , Acrocephalosyndactylia/genetics , Cell Proliferation , Cranial Sutures/enzymology , Down-Regulation , Humans , Nuclear Proteins/genetics , Osteoblasts/enzymology , Phosphatidylinositol 3-Kinases/analysis , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/analysis , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-cbl/genetics , Signal Transduction , Transfection , Twist-Related Protein 1/genetics , Ubiquitin/metabolism
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