The Role of FGL2-FcgammaRIIB Inhibitory Pathway in Human Viral Hepatitis

Hepatitis C Virus (HCV) infection affects more than 200 million individuals worldwide. Only a fraction of infected individuals clear the virus, whereas the majority (70%) develops chronic infection. The current standard of care, pegylated interferon/ ribavirin (pegIFN/rib) is effective in only 50% of patients. Patients who fail anti-viral therapy gradually progress to end-stage liver disease and hepatocellular cancer; which can only be cured by a liver transplant. The reasons for treatment failure are unclear but involve both viral and host factors. One significant factor may be impaired T cell function. Chronic HCV infection is associated with functionally impaired or exhausted cytotoxic T lymphocytes (CTLs), with decreased anti-viral cytokine production, cytotoxicity and proliferative capacity. The investigators recently showed that many patients who fail treatment have elevated frequencies of CD4+CD25+Foxp3+regulatory T cells (Tregs) producing the novel fibrinogen-like-protein 2 (FGL2/fibroleukin) which appears to impair HCV specific immune responses. Binding of FGL2 to the FcγRIIB receptor leads to inhibition of dendritic cell (DC) maturation, B cell apoptosis and inhibition of development of effective CD4+and CD8+T and B cell anti-viral responses. In HCV, increased levels of secreted FGL2 may suppress anti-viral immune responses and promote disease progression.

Hypothesis: HCV suppresses innate and adaptive anti-viral immune responses through the FGL2-FcγRIIB inhibitory pathway. Inhibition of this pathway will restore effective virus-specific immunity and lead to successful viral eradication.

Significance: These studies will establish the importance of FGL2-FcγRIIB inhibitory pathway in the pathogenesis of HCV chronic infection and provide a novel therapeutic approach to improve virus eradication and long term patient outcomes.

Inclusion criteria

• Able and willing to give written informed consent
• Willing to follow the study protocol
• Between >18 and <70 years of age, both gender
• No history of active alcohol or drug abuse
• Adequate contraception for both gender
• Diagnosis of chronic HCV infection based on two positive serology tests.
• Pre- and post treatment viral load data must be available
• Naïve to antiviral treatment
• A pre treatment liver biopsy should be available for all patients

Exclusion criteria

• All other genotypes than genotype 1
• Less than 18 or greater than 70 years of age
• Pregnancy
• Co-infection with HBV (hepatitis B virus), HDV (Hepatitis Delta virus) or HIV co-infection
• Coexistence of liver disease of other etiology (autoimmune, alcohol)
• Evidence of hepatocellular carcinoma