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

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dc.contributor.advisorPfeiffer, Julie K.en
dc.creatorIbarra, Kristie Dawnen
dc.date.accessioned2011-02-01T19:35:17Z
dc.date.available2011-02-01T19:35:17Z
dc.date.issued2011-02-01
dc.description.abstractMany 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.en
dc.identifier.oclc719489268
dc.identifier.urihttps://hdl.handle.net/2152.5/853
dc.language.isoenen
dc.subjectAntiviral Agentsen
dc.subjectDrug Resistance, Viralen
dc.subjectRibavirinen
dc.subjectHepacivirusen
dc.titleHost-Based Mechanisms of Ribavirin Resistance: Implications In Treatment Response of Hepatatis C Virus Infectionen
dc.typeThesisen
dc.type.materialTexten
thesis.date.available2013-01-26
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineMolecular Microbiologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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