Interferon lambda 4 impacts broadly on hepatitis C virus diversity.
Ansari A., Aranday-Cortes E., Ip CLC., da Silva Filipe A., Hin LS., Bamford C., Bonsall D., Trebes A., Piazza P., Sreenu V., Cowton V., Hudson E., Bowden R., Patel A., Foster G., Irving W., Agarwal K., Thomson E., Simmonds P., Klenerman P., Holmes C., Barnes E., Spencer CCA., McLauchlan J., Pedergnana V., STOP-HCV Consortium None.
Type III interferons (IFN-λ) are part of the innate immune response to hepatitis C virus (HCV) infection however the specific role of IFN-λ4 and the nature of the viral adaption to this pressure have not been defined. Here we use paired genome-wide human and viral genetic data in 485 patients infected with HCV genotype 3a to explore the role of IFN-λ4 on HCV evolution during chronic infection. We show that genetic variations within the host IFNL4 locus have a broad and systematic impact on HCV amino acid diversity. We also demonstrate that this impact is larger in patients producing a more active form of IFN-λ4 protein compared to the less active form. A similar observation was noted for viral load. We conclude that IFN-λ4 protein is a likely causal agent driving widespread HCV amino acid changes and associated with viral load and possibly other clinical and biological outcomes of HCV infection.