Interferon lambdas: the next cytokine storm

Abstract

For two decades the scientific community has sought to understand why some people clear hepatitis C virus (HCV) and others do not. Recently, several large genome-wide association studies have identified single nucleotide polymorphisms (SNPs) linked to interferon lambda 3 (IFNλ3) that are associated with the spontaneous resolution and successful treatment of HCV infection. These observations are generating intense research activity; the hope is that IFNλ3 genetic variants may serve as important predictive biomarkers of treatment outcome and offer new insights into the biological pathways involved in viral control. A pharmacogenomic treatment approach for HCV can now be envisaged, with the incorporation of host genetic variants into a predictive treatment algorithm with other factors. The SNPs associated with the clinical outcome of HCV infection are located some distance from the IFNλ3 gene itself, and causal genetic variants have yet to be clearly defined. Locating these causal variants, mapping in detail the IFNλ3 signalling pathways and determining the downstream genetic signature so induced will clarify the role of IFNλ3 in the pathogenesis of HCV. Clinical studies assessing safety and efficacy in the treatment of HCV with exogenous IFNλ3 are currently underway. Early results suggest that IFNλ3 treatment inhibits HCV replication and is associated with a limited side effect profile. However, hepatotoxicity in both healthy volunteers and HCV-infected patients has been described. This review discusses the genetic studies that link IFNλ3 to both the spontaneous resolution and treatment-induced clearance of HCV and the potential impact of this in clinical practice, the biology of IFNλ3 as currently understood and how this may impact on HCV infection, and describes the early studies that assess the role of this cytokine in the treatment of patients with HCV.

Characterization of the Interleukin-28B Gene rs12979860 C/T Polymorphism in Turkish Chronic Hepatitis C Patients and Healthy Individuals

“…GWAS results have indicated that the IL28B rs12979860 (C>T) polymorphism plays an important role in the response for CHC to the treatment and spontaneous clearance of the virus (13,14,17,18,30). While spontaneous viral clearance occurs only in 15-50% of HCV-infected patients, chronic infection develops in the majority (31).…”

Aspects of interferons (IFNs) interfering with HCV-G1 response

“…Formation of ISGF3 complex occurs by the activation of STATs 1 and 2 enabling the fusion of IRF9. The chief entrance for IFN-λ stimulation is considered to be the ISGF3 complex which consecutively causes the activation of STAT 3 and STAT 5 [21].…”

Primary Cutaneous Lymphomas and Interferon Treatment

“…There are three types of INFs: Type I; consisting primarily of IFN-α and IFN-β (formerly known as leukocyte interferon and ibroblast interferon), type II; consisting of IFN-γ (formerly known as immune interferon) and type III; consisiting of IFN-λ which was identi ied during the recent years and classi ied as a new group. Type I IFNs are produced by many cell types, type II IFN (IFN-γ) is produced by T lymphocytes and NK cells, promote cellular immune responses and type III IFN-λ receptors are highly expressed on hepatocytes [40] (Table 2).…”