A Polymorphic Residue That Attenuates Interferon Lambda 4 Activity in Hominid Lineages

Abstract

As antimicrobial signalling molecules, type III or lambda interferons (IFN{lambda}s) are critical for defence against infection by diverse pathogens. Counter-intuitively, expression of one member of the family, IFN{lambda}4, is associated with decreased clearance of hepatitis C virus (HCV) in the human population; by contrast, a natural in-frame nucleotide insertion that abrogates IFN{lambda}4 production improves viral clearance. To further understand how genetic variation between and within species affects IFN{lambda}4 function, we screened a panel of extant coding variants of human IFN{lambda}4 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 IFN{lambda}4 was found only in African Congo rainforest Pygmy hunter-gatherers. Remarkably, E154 was highly conserved as the ancestral residue in mammalian IFN{lambda}4s yet K154 is the dominant variant throughout evolution of the hominid genus Homo. Compared to chimpanzee IFN{lambda}4, 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 IFN{lambda}4 is consistent with differences in antiviral gene expression in vivo during HCV infection. Mechanistically, our data suggest that human-specific K154 likely affects IFN{lambda}4 activity by reducing secretion and potency. We postulate that evolution of an IFN{lambda}4 with attenuated activity in humans (K154) likely contributes to distinct host-specific responses to and outcomes of infection, such as HCV.