ID: 101: Investigating the role of interferon λ4 in hepatitis C virus infection.

IFNL4 , a recently discovered member of the interferon λ family (IFN λ s or type III IFNs), is a pseudogene in a significant fraction of the human population. A single nucleotide polymorphism located in IFNL4 , which determines the ability to express IFN λ 4, has been correlated with poor spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infections. We show that IFN λ 4 is an active type III IFN that induces a typical subset of ISGs, signals through the classical type III IFN receptor complex and is antiviral against HCV and coronaviruses. However, its secretion is impaired and this impairment is caused by a yet unknown molecular determinant, but appears to be partially caused by a weak signal peptide and inefficient N-linked glycosylation. This glycosylation is not required for antiviral activity and secretion of IFN λ 4, but seems to improve its processing. The impaired secretion of IFN λ 4 appears to be a recently acquired feature of primates. A single amino acid substitution in IFN λ 4 changing a proline at position 70 to a serine (P70S) alters its activity. We demonstrate that the IFN λ 4-S70 variant has a significantly lower antiviral activity compared to IFN λ 4-P70. Our subsequent genetic study on a cohort of patients infected with HCV shows that individuals, who encode IFN λ 4-S70, display lower hepatic ISG expression, better treatment response rates and better spontaneous clearance rates than patients encoding IFN λ 4-P70. This study provides important evidence supporting a role for active IFN λ 4 as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance. [ABSTRACT FROM AUTHOR]