Guest guest Posted April 11, 2011 Report Share Posted April 11, 2011 J Virol. 2011 Apr 6. [Epub ahead of print] Hepatitis C virus NS3/4A protease quasispecies complexity and catalytic efficiency influence responsiveness to peginterferon plus ribavirin treatment in HCV/HIV-co-infected patients. Aparicio E, Franco S, Parera M, Andrés C, Tural C, Clotet B, MartÃnez MA. Fundació irsiCaixa, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Hospital Universitari Germans Trias i Pujol, Fundació de la Lluita contra la Sida Badalona, Spain. Abstract The role of the HCV NS3/4A protease in ablating the signaling pathway involved in the production of interferon (IFN)-α/β suggests a relationship between NS3/4A proteolytic activity and a patient's response to IFN-based therapy. To identify viral factors associated with the HCV treatment response, we analyzed the pre-treatment NS3/4A protease gene quasispecies composition of 56 HCV genotype 1/HIV-1 co-infected patients treated in our clinic with pegIFN plus ribavirin (RBV). The catalytic efficiency of the dominant quasispecies (i.e. the most abundant) from each quasispecies was also assayed for Cardif cleavage and correlated with treatment outcome. A total of 1745 clones were isolated and sequenced. Significantly less nucleotide quasispecies heterogeneity and lower 's entropy values were detected within the responder group (p < 0.05). A correlation was also found between the efficiency of NS3/4A protease Cardif cleavage and therapy outcome. Proteases from sustained responder patients were more efficient at processing Cardif (mean ± SEM, 0.8960 ± 0.05568; n=19) than proteases from non-responders (mean ± SEM, 0.7269 ± 0.05306; n=37; p < 0.05). Finally, the amino acid p-distance was significantly less in patients with an IL28B risk allele (p < 0.01), suggesting that IL28B risk allele carriers exert a lower positive selection pressure on the NS3/4A protease. NS3/4A protease efficiency in cleaving Cardif may be associated with the pegIFN-RBV treatment response, as shown in our cohort of HIV/HCV-co-infected patients. Greater NS3/4A nucleotide heterogeneity and higher 's entropy values in non-responders suggest that less HCV quasispecies complexity may favor a better response to pegIFN-RBV. PMID: 21471227 [PubMed - as supplied by publisher] ----------------------------------------------------- Hepatology. 2011 Apr 4. doi: 10.1002/hep.24340. [Epub ahead of print] Downregulation of PTEN and IRS-1 by HCV 3a core protein triggers the formation of large lipid droplets in hepatocytes. Clément S, Peyrou M, -Pareja A, Bourgoin L, Ramadori P, Suter D, Vinciguerra M, Guilloux K, Pascarella S, Rubbia-Brandt L, Negro F, Foti M. Divisions of Clinical Pathology, University of Geneva, Geneva, Switzerland. Abstract The hepatitis C virus (HCV) perturbs the host lipid metabolism, often resulting in hepatic steatosis. In non-alcoholic fatty liver disease, the intrahepatic downregulation of PTEN is a critical mechanism leading to steatosis and its progression towards fibrosis and hepatocellular carcinoma. However, whether HCV infection triggers the formation of large lipid droplets through PTEN-dependent mechanisms is unknown. We assessed PTEN expression in the liver of patients infected with HCV genotype 1 or 3, with or without steatosis. The role of PTEN in HCV-induced lipid droplet biogenesis was further investigated in vitro using hepatoma cells transduced with the HCV core protein of genotype 1b or 3a. Our data indicate that PTEN expression is downregulated at the post-transcriptional level in steatotic patients infected with genotype 3a. Similarly, the in vitro expression of the HCV genotype 3a core protein (but not 1b), typically leading to the appearance of large lipid droplets, downregulates PTEN expression by a mechanism involving a microRNA-dependent blockade of PTEN mRNA translation. PTEN downregulation promoted in turns a decrease of IRS-1 expression. Interestingly, either PTEN or IRS-1 overexpression prevented the development of large lipid droplets, indicating that both PTEN and IRS-1 downregulation are required to affect lipid droplet biogenesis. However, IRS-1 knock-down per se did not alter lipid droplet morphology, suggesting that other PTEN-dependent mechanisms are involved in this process. In conclusion, PTEN and IRS-1 downregulation are critical events leading to the HCV genotype 3a-induced large lipid droplets formation in hepatocytes. (HEPATOLOGY 2011.). Copyright © 2011 American Association for the Study of Liver Diseases. PMID: 21465511 [PubMed - as supplied by publisher] --------------------------------------------------- Gastroenterology. 2011 Mar 30. [Epub ahead of print] Malnutrion Impairs Interferon Signaling through mTOR and FoxO pathways in Patients with Chronic Hepatitis C. Honda M, Takehana K, Sakai A, Tagata Y, Shirasaki T, Nishitani S, Muramatsu T, Yamashita T, Nakamoto Y, Mizukoshi E, Sakai Y, Yamashita T, Nakamura M, Shimakami T, Yi M, Lemon SM, Suzuki T, Wakita T, Kaneko S; Hokuriku Liver Study Group. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan. Abstract BACKGROUND & AIMS: Patients with advanced chronic hepatitis C (CH-C) are often malnourished, but the effects of malnutrition on interferon (IFN) signaling and response to treatment have not been determined. We assessed the importance of the nutritional state of the liver on IFN signaling and treatment response. METHODS: We studied data from 168 patients with CH-C who were treated with the combination of Peg-IFN and ribavirin. Plasma concentrations of amino acids were measured by mass spectrometry. Liver gene expression profiles were obtained from 91 patients. Huh-7 cells were used to evaluate the IFN signaling pathway, mammalian target of rapamycin complex1 (mTORC1), and forkhead box O (Foxo). Antiviral signaling induced by branched-chain amino acids (BCAAs) was determined using the in vitro HCV replication system. RESULTS: Multivariate logistic regression analysis showed that Fischer's ratio was significantly associated with non-responders, independent of IL28B polymorphisms or the histologic stage of the liver. Fischer's ratio was inversely correlated with expression of BCAA transaminase 1, and was affected by hepatic mTORC1 signaling. IFN stimulation was substantially impaired in Huh-7 cells grown in medium low in amino acid concentration, through repressed mTORC1 signaling and increased Socs3 expression, which was regulated by Foxo3a. BCAA could restore impaired IFN signaling and inhibit hepatitis C virus replication under conditions of malnutrition. CONCLUSIONS: Malnutrition impaired IFN signaling, by inhibiting mTORC1 and activating Socs3 signaling through Foxo3a. Increasing BCAAs to upregulate IFN signaling might be used as a new therapeutic approach for patients with advanced CH-C. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved. PMID: 21458454 [PubMed - as supplied by publisher] --------------------------------------------------------- Am J Gastroenterol. 2011 Apr 5. [Epub ahead of print] A New Combination of Blood Test and Fibroscan for Accurate Non-Invasive Diagnosis of Liver Fibrosis Stages in Chronic Hepatitis C. Boursier J, de Ledinghen V, Zarski JP, Rousselet MC, Sturm N, Foucher J, Leroy V, Fouchard-Hubert I, Bertrais S, Gallois Y, Oberti F, Dib N, Calès P. 1] Service d'Hépato-Gastroentérologie, CHU, Angers, France [2] Laboratoire HIFIH, UPRES 3859, IFR 132, Université, Angers, France [3] PRES UNAM, France. Abstract OBJECTIVES: Precise evaluation of the level of liver fibrosis is recommended in patients with chronic hepatitis C (CHC). Blood fibrosis tests and Fibroscan are now widely used for the non-invasive diagnosis of liver fibrosis. Detailed fibrosis stage classifications have been developed to provide an estimation of the liver fibrosis stage from the results of these non-invasive tests. Our aim was to develop a new and more accurate fibrosis stage classification by using new scores combining non-invasive fibrosis tests. METHODS: In all, 729 patients with CHC (exploratory set: 349; validation set: 380) had liver biopsy for Metavir fibrosis (F) staging, and 6 fibrosis tests: Fibroscan, Fibrotest, FibroMeter, Hepascore, FIB-4, APRI. RESULTS: Exploratory set: Fibroscan and FibroMeter were the independent predictors of different diagnostic targets of liver fibrosis. New fibrosis indexes combining FibroMeter and Fibroscan were thus developed for the diagnosis of clinically significant fibrosis (CSF-index) or severe fibrosis (SF-index). The association of CSF- and SF-indexes provided a new fibrosis stage classification (CSF/SF classification): F0/1, F1/2, F2±1, F2/3, F3±1, F4. Validation set: CSF/SF classification had a high diagnostic accuracy (85.8% well-classified patients), significantly higher than the diagnostic accuracies of FibroMeter (69.7%, P<0.001), Fibroscan (63.3%, P<0.001), or Fibrotest (43.9%, P<0.001) classifications. CONCLUSIONS: The association of new fibrosis indexes combining FibroMeter and Fibroscan provides a new fibrosis stage classification. This classification is significantly more accurate than Fibrotest, FibroMeter, or Fibroscan classifications, and improves the accuracy of the non-invasive diagnosis of liver fibrosis stages to 86% without any liver biopsy.Am J Gastroenterol advance online publication, 5 April 2011; doi:10.1038/ajg.2011.100. PMID: 21468012 [PubMed - as supplied by publisher] Quote Link to comment Share on other sites More sharing options...
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