A polymorphic residue that attenuates the antiviral potential of interferon lambda 4 in hominid lineages
Natural genetic variation and its influence on the outcome of viral infection is a topical area given the wealth of genetic data now available. However, understanding how clinical phenotype is affected by genetic variation at the molecular level is often lacking yet critical for any insight into immunity and disease. It is known that variants in the antiviral ‘interferon lambda 4’ (IFNL4) gene significantly influence outcome of hepatitis C virus (HCV) infection in humans. Counter-intuitively, those producing IFNL4 have greater risk of establishing chronic HCV infection, compared to individuals with an inactive variant, although the underlying mechanisms remain poorly understood. From a comprehensive screen of all natural human variants, we show that the most common form of IFNλ4 is less able to protect human cells from pathogenic virus infection than the equivalent protein from our closest living relative the chimpanzee. This is as a result of a single amino acid substitution that impedes its release from cells and reduces antiviral gene expression. Our observed differences in activity correlated with divergent host responses in HCV-infected livers from humans and chimpanzees. We suggest that human IFNL4 evolution places humans at a disadvantage when infected with pathogens such as HCV.
