Hepatitis C virus (HCV) infection is a global health problem with 130-170 million individuals infected worldwide and 3.2 million people infected in the USA. The majority of those infected develop chronic HCV infections, which are a leading cause of liver failure and hepatocellular carcinoma in the US. IFN-?-based treatment is currently the most effective therapy for HCV infection. Unfortunally, ~50% of HCV patients do not achieve sustained virological response (SVR;ie., viral clearance) during treatment. So, understanding the mechanisms by which IL28B genetic variation modulates clearance of HCV will help us better understand how the IFN lambda system controls viral infection. IL28B (IFN-lambda3) is a member of the recently discovered type III interferon (IFN) family and single nucleotide polymorphisms (SNPs) in the IL28B promoter have been recently shown to strongly associate with spontaneous and treatment-induced clearance of HCV. Among those SNPs, polymorphism rs12979860 C/T is the strongest predictor of SVR to IFN-?-based treatment in patients with HCV infection. During HCV infection, patients with SNP-C produce more IL28B and have much higher rates of viral clearance compared with patients harboring SNP-T. However, how genetic variations in IL28B gene contribute to different expression of IL28B and HCV clearance is unknown. We found that the expression of IL28B mRNA was significantly reduced in liver tissues of HCV patients and in hepatocytes harboring SNP-T compared with those carrying SNP-C. This differential expression of IL28B was also reflected at the promoter level. Most importantly, we found that a unique nuclear protein DNA binding complex strongly binds to SNP-T but not SNP-C in hepatocytes. Our preliminary data suggest that hepatocytes with SNP-T genotype fail to express high amounts of IL28B due to binding of an unknown transcription factor to IL28B promoter, contributing to the persistence of HCV infection. Since the underlying molecular mechanisms are largely unknown, we propose to determine the differential expression of IL28B in primary human hepatocytes and in liver tissues of HCV patients harboring different SNPs, and identify the unknown transcription factor responsible for the reduced expression of IL28B in hepatocytes carrying SNP-T. Our goals are to elucidate the molecular mechanisms by which IL28B is differentially regulated by genetic variation during HCV infection. This will help us understand how the IFN lambda system controls viral infections, which in turn may help improve antiviral therapies.

Public Health Relevance

Chronic HCV is the leading cause of hepatocellular carcinoma and the most common cause of liver failure in the US. So far, clearance of virus is considered the best strategy to prevent patients from liver cirrhosis and cancer, and genetic variations in IL28B gene are strongly associated with spontaneous and treatment-induced clearance of HCV. Our proposals to understand the mechanisms of IL28B genetic variation-mediated clearance of HCV will not only help us to better design a personalized therapy but also may provide us novel targets to treat this notorious disease.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI099780-02
Application #
8732600
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Koshy, Rajen
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103