IFN-lambda 4

Interferon-lambda 4 (IFN-λ4, gene IFNL4) is the most recently discovered human interferon, identified in 2013 through whole-genome analysis of spontaneous clearance of hepatitis C virus. Uniquely in human genetics, IFNL4 is polymorphic for its very existence: the rs368234815 ΔG allele creates a functional open reading frame and permits production of IFN-λ4 protein, whereas the common rs368234815 TT allele introduces a frameshift pseudogene, so most individuals of European and East Asian ancestry are genuine IFN-λ4 non-producers. Remarkably, producing IFN-λ4 is detrimental for hepatitis C: the ΔG allele correlates with impaired spontaneous clearance, poorer interferon treatment response and altered liver disease progression. Mechanistically, IFN-λ4 signals through the IFNLR1/IL10RB receptor with unusually strong and sustained STAT1/STAT2 activation that induces interferon-stimulated genes but simultaneously drives refractoriness of the type I interferon pathway. Beyond hepatitis C, ΔG carriage influences outcomes of other viral infections and has been associated with inflammatory and metabolic phenotypes.