Browsing by Subject "Ribavirin"
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Item Decreased microRNA-122 Levels with HCV Clearance in HIV-HCV Co-Infections(2013-01-22) Dubin, Perry H.; Yuan, Hejun; Devine, Robert K.; Jain, Mamta K.; Hynan, Kinda S.; Lee, William M.BACKGROUND AND AIMS: Micro RNA-122 (miR-122) is under investigation as a target for direct antiviral agents against the hepatitis C virus (HCV), and as a biomarker for both cancer and acute liver injury. Previous data suggest HCV mono-infection is associated with increased serum miR-122 levels. This study sought to determine outcomes in regard to miR-122 levels following clearance of HCV in human immunodeficiency virus (HIV) co-infected patients. METHODS: Nine HCV-HIV co-infected patients undergoing antiviral therapy were treated with interferon and ribavirin for 48 weeks between January 2009 and March 2011, and had serial miR-122 levels measured in triplicate from serum with mirVanaTM PARISTM kit according to the instructions from the manufacturer (Ambion, AM1556). Values were measured at baseline, 1 week, 4 weeks, end of treatment (EOT; 48 weeks), and at 24 weeks after treatment completion (SVR24). SAS V9.3 was used to analyze these data. Change from baseline (copies/μL) was calculated as Log10 (Baseline)-Log 10(time), where time was 1 week, 4weeks, EOT, and SVR24; a repeated measures ANOVA was used to compare the results over time for the patients. If the ANOVA was found significant, post hoc, pairwise comparisons were used to examine change from baseline across the four time points. RESULTS: Six of nine achieved SVR24, 1 was undetectable at EOT but relapsed, and 2 patients were non-responders. Among the 6 patients achieving SVR, all showed a decrease in miR-122 levels between 0.16 and 1.46 logs, between baseline and SVR24. The ANOVA confirmed a significant decrease in miR-122 levels from 1 week to SVR24 (p=0.0225). Significant pairwise comparisons for change from baseline were found at 1 week versus SVR24 (p=0.0063), 4 weeks versus SVR24 (p=0.0086), and EOT versus SVR24 (p=0.0458). CONCLUSION: Clearance of chronic HCV is associated with decreased miR-122 levels in HIV co-infected patients and was not improved in patients with continued infection who failed to respond to treatment.Item Host-Based Mechanisms of Ribavirin Resistance: Implications In Treatment Response of Hepatatis C Virus Infection(2011-02-01) Ibarra, Kristie Dawn; Pfeiffer, Julie K.Many individuals infected with hepatitis C virus (HCV) fail to respond to therapy, resulting in the development of chronic infection and increased risk for fibrosis, cirrhosis, and hepatocellular carcinoma. The current standard of care consists of pegylated interferon and ribavirin (RBV), a nucleoside analog. While RBV improves treatment outcome, and will likely be an important component of therapy with next-generation viral inhibitors, RBV’s mechanism is controversial. Most of RBV’s proposed mechanisms require RBV import into cells. Therefore, we examined whether host-based RBV resistance develops through reduced cellular uptake, analogous to chemotherapy resistance in some cancers. We examined the effect of host-based RBV resistance on a model RNA virus, poliovirus, HCV replication in cultured hepatoma liver cells, and whether RBV resistance develops in HCV patients. When liver cells permissive for poliovirus or HCV replication were exposed to RBV, resistance developed through reduced activity of the ENT1 nucleoside transporter, and antiviral efficacy was reduced. Importantly, RBV uptake significantly declined in HCV peripheral blood mononuclear cells (PBMCs) following four weeks of therapy. Furthermore, maintenance of RBV uptake correlated with rapid treatment response. Our results uncovered a novel form of antiviral drug resistance, suggesting that host-based RBV resistance develops in HCV patients undergoing therapy and that maintenance of RBV uptake may contribute to rapid viral clearance.Item Role of Ribavirin, an Anti-Viral Agent, In Eukaryotic Initiation Factor 4e (Eif4e) Subcellular Localization and Function(2008-05-13) Hsiung, Ying-Fan; Sternweis, Paul C.Expression of eukaryotic initiation factor 4E (eIF4E) is necessary for active cellular growth and catalysis of the rate-limiting step in cap-dependent protein synthesis3-5. Studies in the past decade have shown that eIF4E contributes to malignancy by selectively facilitating the translation of a specific set of mRNAs, those that generally encode key proteins involved in cellular growth, angiogenesis and survival6-9. Key questions remaining in the field are: (1) what is the mechanism by which eIF4E levels are increased in tumor cells? (2) What is the role of eIF4E in regulating the translation of gene products involved in various aspects of malignancy? Finally, (3) how can eIF4E be exploited as a therapeutic target for human cancer progression? Recently, Kentsis and colleagues10 demonstrated that ribavirin disrupts subcellular organization of eIF4E and suppresses eIF4E-mediated oncogenic transformation of murine cells and tumor growth of a mouse model of eIF4E-dependent human squamous cell carcinoma. These findings suggest a specific and novel mechanism by which ribavirin affects cellular distribution and function of eIF4E, a topic that will be explored in the current proposal. This investigation may facilitate understanding in the regulation of transcription and thus provide a potential strategy for interrupting oncogenic cascades.