Hepatitis C Viral Pathogenesis

Investigator:

• Qiang Liu 

Overview:

Hepatitis C is a devastating infectious disease globally. Currently, there is no prophylactic or therapeutic vaccine available against hepatitis C. Therapy involving interferon and ribavirin is very costly, yet ineffective in about half of the patients. As such, there is an urgent need for a better understanding of the molecular mechanisms of hepatitis C pathogenesis.

Background:

The etiologic agent for hepatitis C, hepatitis C virus (HCV), is a positive, single-stranded RNA virus in the Flaviviridae family. While HCV infection can be cleared in some infected individuals, HCV infection becomes persistent in the majority of infected people.

Steatosis, or fatty liver, is a significant clinical manifestation of chronic HCV infections. The prevalence of steatosis in HCV patients is estimated at 2.5 fold higher than the general population. Hepatitis C patients who develop steatosis are much more likely to progress to fibrosis, cirrhosis and hepatocellular carcinoma. Therefore, prevention of steatosis may represent an important means to retard the progression of HCV-related severe liver diseases. Obviously, the elucidation of molecular mechanisms by which HCV causes steatosis is instrumental to the development of effective therapeutics for HCV-associated steatosis.

Translation of HCV protein is primarily mediated by an internal ribosomal entry site (IRES) within the 5'-untranslated region (UTR) of HCV genome. It has been demonstrated that differential translational efficiency is one of the determinants for the ultimate outcome of HCV infection as well as the responsiveness to interferon therapy. In addition, HCV IRES-mediated protein translation is a potential target for developing HCV-specific therapeutics.

VIDO-InterVac is a member of the National CIHR Training Program in Hepatitis C.

Objectives:

The objective of this project is to investigate the molecular mechanisms of HCV-associated pathogenesis. In particular, we are focusing our efforts on the following research objectives:

• Molecular mechanisms of HCV-associated steatosis.
• Molecular mechanisms of HCV protein translational control.

Progress:

HCV and steatosis:

Our recent research showed that HCV core protein can up-regulate fatty acid synthase (FAS) promoter activity. Sterol regulatory element-binding protein-1 (SREBP-1) is required for FAS activation by HCV core. We further showed that the core protein of HCV genotype 3a (HCV-3a) is a stronger inducer of FAS transcription than HCV-1b core. We also identified that the phenylalanine at position 164 of HCV-3a core plays a critical role.

Inaddition, we demonstrated that HCV non-structural protein-2 (NS2) can activate SREBP-1c transcription through liver X receptor element (LXRE) and sterol regulatory element (SRE) sequences on the SREBP-1c promoter.

HCV translational control:

We have established a novel experimental system by using the promoter and terminator sequences of RNA polymerase I, which allows generation of RNA molecules with authentic HCV 5'- and 3'-ends after plasmid DNA transfection. We plan to use this system to study the role of viral and cellular RNA binding proteins as well as signal transduction pathways in HCV protein translation.