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Single-nucleotide polymorphisms <jats:italic>rs12979860<\/jats:italic> and <jats:italic>rs8099917<\/jats:italic> within the <jats:italic>IFNL<\/jats:italic> gene locus predict hepatitis C virus (HCV) clearance, as well as inflammation and fibrosis progression in viral and non-viral liver disease. The underlying mechanism, however, is not defined. Here we show that the <jats:italic>rs12979860<\/jats:italic> CC genotype correlates with increased hepatic metallothionein expression through increased systemic zinc levels. Zinc interferes with IFN-\u03bb3 binding to IFNL receptor 1 (IFNLR1), resulting in decreased antiviral activity and increased viral replication (HCV, influenza) <jats:italic>in vitro<\/jats:italic>. HCV patients with high zinc levels have low hepatocyte antiviral and inflammatory gene expression and high viral loads, confirming the inhibitory role of zinc <jats:italic>in vivo<\/jats:italic>. We provide the first evidence that zinc can act as a potent and specific inhibitor of IFN-\u03bb3 signalling and highlight its potential as a target of therapeutic intervention for IFN-\u03bb3-mediated chronic disease.<\/jats:p>","DOI":"10.1038\/ncomms15245","type":"journal-article","created":{"date-parts":[[2017,5,17]],"date-time":"2017-05-17T10:41:25Z","timestamp":1495017685000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Zinc is a potent and specific inhibitor of IFN-\u03bb3 signalling"],"prefix":"10.1038","volume":"8","author":[{"given":"Scott A.","family":"Read","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate S.","family":"O\u2019Connor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Suppiah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantelle L. 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