Interferon lambda 4 signals via the IFNλ receptor to regulate antiviral activity against HCV and coronaviruses

Abstract

The IFNL4 gene is a recently discovered type III interferon, which in a significant fraction of the human population harbours a frameshift mutation abolishing the IFNk4 ORF. The expression of IFNk4 is correlated with both poor spontaneous clearance of hepatitis C virus (HCV) and poor response to treatment with type I interferon. Here, we show that the IFNL4 gene encodes an active type III interferon, named IFNk4, which signals through the IFNkR1 and IL-10R2 receptor chains. Recombinant IFNk4 is antiviral against both HCV and coronaviruses at levels comparable to IFNk3. However, the secretion of IFNk4 is impaired compared to that of IFNk3, and this impairment is not due to a weak signal peptide, which was previously believed. We found that IFNk4 gets N-linked glycosylated and that this glycosylation is required for secretion. Nevertheless, this glycosylation is not required for activity. Together, these findings result in the paradox that IFNk4 is strongly antiviral but a disadvantage during HCV infection.

IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18

“…2a). These results confirmed previous observations that IFN-l4 is a novel member of the type III interferon family (Hamming et al, 2013;Prokunina-Olsson et al, 2013).…”

“…Two previous studies have reported that the dinucleotide variant ss469415590(DG) can induce the expression of the novel protein IFN-l4, which exhibits interferon-like activity by binding to type III interferon receptors (Hamming et al, 2013;Prokunina-Olsson et al, 2013 clearance of genotype 1b HCV in IFN-a based therapy. To our knowledge, for the first time these data reveal the role of IFN-l4 in the poor response to IFN-a therapy.…”

“…More interestingly, the DG genotype causes a frame shift mutation and leads to the expression of a new interferon-like protein IFN-l4. Results from a previous study have demonstrated that the antiviral functions of IFN-l4 are equivalent to those of other IFN-ls (Hamming et al, 2013). However, the mechanism by which IFN-l4 strongly inhibits viral replication but promotes HCV resistance to IFN-a therapy remains a paradox.…”

“…Rosetta (DE3) E. coli cells were transformed with the plasmids and grown at 37 C in Luria-Bertani medium containing 100 µg ampicillin ml À1 and 30 µg chloramphenicol ml À1 with continuous shaking until an OD 600 of 0.6-0.8 was achieved. Protein expression was induced by the addition of 1 mM isopropyl-b-D-thiogalactopyranoside, and the cultures were incubated for another 6 h at 37 C. IFN-l4 was refolded and purified as previously described (Dellgren et al, 2009;Hamming et al, 2013).…”

Reduction of MicroRNA 122 Expression in IFNL3 CT/TT Carriers and during Progression of Fibrosis in Patients with Chronic Hepatitis C

“…The expression of IFNL4 is associated with HCV persistence and a poorer response to PEG-IFN plus ribavirin (8). IFNL4 was suggested to regulate the antiviral activity against HCV (9). A strong decline of HCV viral RNA during the first weeks of treatment in patients with an IFNL3 rs12979860 CC genotype compared to the HCV viral RNA levels in patients with the CT or TT (CT/TT) genotype has been described (10).…”