Approximately 3% of the global population is chronically infected by the Hepatitis C Virus (HCV). The only approved treatment for chronic HCV infection, pegylated interferon-alpha (IFN-alpha) plus ribavirin clears the virus in less than half of genotype 1 infected patients. The precise molecular mechanisms of HCV resistance to IFN-alpha are unclear, therefore we sought to uncover HCV resistance mechanisms utilizing a stable human hepatoma cell line containing sub-genomic HCV that is resistant to interferon. Characterization of this resistant cell line revealed that a truncated IFNAR1gives rise to the IFN-alpha resistant phenotype. These in vitro findings were then confirmed in human explant liver samples obtained from patients with and without HCV infection. Next we employed a novel strategy utilizing constructs containing the TAD of STAT1 or STAT2 fused to IRF9 in an attempt to circumvent Jak-STAT cellular defects in the resistant cell line. The STAT2 TAD fusion product showed antiviral and immunoregulatory activity in the resistant cell line and caused minimal toxicity. A second novel strategy utilized a STAT1-CC double cysteine substituted construct that showed potent antiviral and immunoregulatory properties in the resistant cell line. In conclusion, IFNAR1 may play a role in IFN resistance in vivo and Jak-STAT pathway components can be engineered to overcome HCV resistance to IFN / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_24758 |
| Date | January 2010 |
| Contributors | Poat, Bret Erik (Author), Engel, Astrid (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Rights | Access requires a license to the Dissertations and Theses (ProQuest) database., Copyright is in accordance with U.S. Copyright law |
Page generated in 0.0015 seconds