A Polymorphic Residue That Attenuates the Antiviral Potential of Interferon Lambda 4 in Hominid Lineages

As antimicrobial signalling molecules, type III or lambda interferons (IFNλs) are critical for defence against infection by diverse pathogens. Counter-intuitively, expression of one member of the family, IFNλ4, is associated with decreased clearance of hepatitis C virus (HCV) in the human population; by contrast, a natural in-frame nucleotide insertion that abrogates IFNλ4 production improves viral clearance. To further understand how genetic variation between and within species affects IFNλ4 function, we screened a panel of extant coding variants of human IFNλ4 and identified three variants that substantially affect antiviral activity (P70S, L79F and K154E). The most notable variant was K154E, which enhanced in vitro activity in a range of antiviral and interferon stimulated gene (ISG) assays. This more active E154 variant of IFNλ4 was found only in African Congo rainforest ‘Pygmy’ hunter-gatherers. Remarkably, E154 was highly conserved as the ancestral residue in mammalian IFNλ4s yet K154 is the dominant variant throughout evolution of the hominid genus Homo . Compared to chimpanzee IFNλ4, the human orthologue had reduced activity due to amino acid substitution of glutamic acid with lysine at position 154. Meta-analysis of published gene expression data from humans and chimpanzees showed that this difference in activity between K154 and E154 in IFNλ4 is consistent with differences in antiviral gene expression in vivo during HCV infection. Mechanistically, our data suggest that human-specific K154 likely affects IFNλ4 activity by reducing secretion and potency. We postulate that evolution of an IFNλ4 with attenuated activity in humans (K154) likely contributes to distinct host-specific responses to and outcomes of infection, such as HCV.