Interferon lambda 4 expression is suppressed by the host during viral infection

Interferon (IFN) lambdas are critical antiviral effectors in hepatic and mucosal infections. Although IFN lambda 1, IFN lambda 2, and IFN lambda 3 act antiviral, genetic association studies have shown that expression of the recently discovered IFNL4 is detrimental to hepatitis C virus (HCV) infection through a yet unknown mechanism. Intriguingly, human IFNL4 harbors a genetic variant that introduces a premature stop codon. We performed a molecular and biochemical characterization of IFN lambda 4 to determine its role and regulation of expression. We found that IFN lambda 4 exhibits similar antiviral activity to IFN lambda 3 without negatively affecting antiviral IFN activity or cell survival. We show that humans deploy several mechanisms to limit expression of functional IFN lambda 4 through noncoding splice variants and nonfunctional protein isoforms. Furthermore, protein-coding IFNL4 mRNA are not loaded onto polyribosomes and lack a strong polyadenylation signal, resulting in poor translation efficiency. This study provides mechanistic evidence that humans suppress IFN lambda 4 expression, suggesting that immune function is dependent on other IFNL family members.