Host-Based Mechanisms of Ribavirin Resistance: Implications In Treatment Response of Hepatatis C Virus Infection

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Title: Host-Based Mechanisms of Ribavirin Resistance: Implications In Treatment Response of Hepatatis C Virus Infection
Author: Ibarra, Kristie Dawn
Abstract: 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 .
URI: http : / /hdl .handle .net /2152 .5 /853
Date: 2011-02-01

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Host-Based Mechanisms of Ribavirin Resistance: Implications In Treatment Response of Hepatatis C Virus Infection. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /853 .

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