Hepatitis C virus (HCV) infects an estimated 3% of the world's population, and is a significant cause of liver disease. The interactions that occur between HCV proteins, cellular proteins and signal transduction machinery have a significant influence on virus replication, persistence, pathogenesis, and the outcome of antiviral therapy. Mutations in HCV proteins correlate with clinical responses to IFN therapy, and affect HCV replication in vivo and in vitro. HCV proteins also inhibit the antiviral actions of interferon (IFN). We have found that the HCV NS5A protein induces the pro-inflammatory CXC chemokine, interleukin 8 (IL-8), which is associated with inhibition of the IFN system. The in vivo significance of this finding is shown by elevated IL-8 levels in persons with chronic hepatitis C. In the HCV replicon system, we have also found that HCV replication is associated with increased production of IL-8 and attenuated IFN-induced transcriptional responses. Furthermore, exogenous IL-8 stimulates HCV protein production in HCV replicons. In this proposal, we hypothesize that HCV induced IL-8 inhibits the antiviral actions of IFN, promotes HCV replication, and contributes to HCV pathogenesis. To address this hypothesis, we propose 2 specific aims (SA) to determine the mechanisms of HCV induction of IL-8, and to determine the mechanisms of IL-8's anti-IFN activity. SA1 will focus on HCV induction of IL-8 via both transcriptional activation of the IL-8 promoter and stabilization of IL-8 mRNA. SA2 will focus on IL-8 mediated inhibition of the IFN-induced 2'-5' oligoadenylate synthetase/RNase L system, as well as cross-talk between IL-8 induced mitogen activated protein (MAP) kinases and IFN induced STAT-JAK pathways. The characterization of a new mechanism for modulation of the IFN system by a chemokine may be relevant to pathogenesis of chronic hepatitis C and many other viral and non-viral diseases. Moreover, IL-8 or its receptors may prove to be suitable targets for therapeutic intervention in chronic hepatitis C.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062187-02
Application #
6802021
Study Section
Special Emphasis Panel (ZRG1-GMA-3 (01))
Program Officer
Doo, Edward
Project Start
2003-09-15
Project End
2008-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$282,690
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Tang, Xi; Wagoner, Jessica; Negash, Amina et al. (2010) Functional characterization of core genes from patients with acute hepatitis C virus infection. J Infect Dis 201:912-22
Boriskin, Y S; Leneva, I A; Pecheur, E-I et al. (2008) Arbidol: a broad-spectrum antiviral compound that blocks viral fusion. Curr Med Chem 15:997-1005
Chung, Raymond T; Gale Jr, Michael; Polyak, Stephen J et al. (2008) Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop. Hepatology 47:306-20
Pecheur, Eve-Isabelle; Lavillette, Dimitri; Alcaras, Fanny et al. (2007) Biochemical mechanism of hepatitis C virus inhibition by the broad-spectrum antiviral arbidol. Biochemistry 46:6050-9
Wagoner, Jessica; Austin, Michael; Green, Jamison et al. (2007) Regulation of CXCL-8 (interleukin-8) induction by double-stranded RNA signaling pathways during hepatitis C virus infection. J Virol 81:309-18
Polyak, Stephen J; Morishima, Chihiro; Shuhart, Margaret C et al. (2007) Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin. Gastroenterology 132:1925-36
Koo, Bon Chang A; McPoland, Paula; Wagoner, Jessica P et al. (2006) Relationships between hepatitis C virus replication and CXCL-8 production in vitro. J Virol 80:7885-93
Green, Jamison; Khabar, Khalid S A; Koo, Bon Chang A et al. (2006) Stability of CXCL-8 and related AU-rich mRNAs in the context of hepatitis C virus replication in vitro. J Infect Dis 193:802-11
Boriskin, Yury S; Pecheur, Eve-Isabelle; Polyak, Stephen J (2006) Arbidol: a broad-spectrum antiviral that inhibits acute and chronic HCV infection. Virol J 3:56
Khabar, Khalid S A; Al-Haj, Latifa; Al-Zoghaibi, Fahad et al. (2004) Expressed gene clusters associated with cellular sensitivity and resistance towards anti-viral and anti-proliferative actions of interferon. J Mol Biol 342:833-46

Showing the most recent 10 out of 12 publications