SUMMARY
Type III or lambda interferons (IFNλs) form a critical barrier to infection by diverse pathogens. However in humans, production of IFNλ4 is associated with decreased clearance of hepatitis C virus (HCV). How an antiviral cytokine came to promote infection and whether this phenomenon occurs in other species is unknown. Here we show that, compared to chimpanzee IFNλ4, the human orthologue has reduced activity due to a single amino acid substitution (E154K). IFNλ4s with E154 restrict virus infection more potently and induce more robust antiviral gene expression. Remarkably, E154 is the ancestral residue in mammalian IFNλ4s but altered in representatives of the Homo genus. Nonetheless, the more active E154 form of IFNλ4 can be found in African Congo rainforest ‘Pygmy’ hunter-gatherers. We postulate that evolution of an IFNλ4 with attenuated activity in humans has been exploited by pathogens such as HCV, which could explain distinct host-specific outcomes of infection.