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.

Figure 1

Odds ratio (OR) of treatment failure in hepatitis C virus (HCV) infection. OR of risk factors associated with treatment failure including the interferon λ3 (IFNλ3)-linked single nucleotide polymorphisms (rs8099917, rs12979860, rs12980275) in published genome-wide association studies. *Derived from Rauch et al.

Figure 2

Interferonλ3 (IFNλ3) risk allele frequency in specific populations infected with hepatitis C virus (HCV). Risk allele frequency in those who clear acute infection spontaneously and in those who have a successful treatment response (SVR) compared with individuals who develop persistent infection or who fail treatment (non-SVR).

Figure 3

Mean frequency of interferon λ3 (IFNλ3) protective allele in different ethnic groups. The protective allele is less common in African populations than in Asian populations, correlating with the known poor outcome from hepatitis C virus (HCV) infection in patients of African origin. Figure derived from data in Thomas et al.

Figure 4

The signalling pathway of type III interferons (IFNs) compared with type II and type I IFNs. IFNλ binds the IFNλR1 chain leading to a conformational change in the receptor. It recruits a second short receptor chain (IL10R2). JAK 1 and Tyk 2 transphosphorylate the receptor chains and form phosphorylated tyrosine peptides on the IFNλR1 receptor chain. STAT proteins bind and are phosphorylated. They can then form homo- or heterodimers and migrate to the nucleus to bind gene regulatory elements (gamma-activated sequences, GAS). In the case of type I and type III IFNs, they can also bind interferon regulatory factor 9 (IRF9) in the cytoplasm and then migrate to the nucleus to bind interferon stimulated regulatory elements (ISREs) to regulate gene transcription.

Figure 5

Model of the possible action of interferon λ (IFNλ) in chronic hepatitis C virus (HCV) infection. In chronic HCV infection, IFNα upregulates hepatic interferon-stimulated genes (ISGs) (represented by blue circle) but this fails to clear HCV. Addition of IFNλ may result in stimulation of different ISGs (represented by green circle) and therefore HCV clearance. The IFNλ polymorphism could impact on the expression of the right hepatic ISGs directly or through the stimulation of effector cell ISGs resulting in HCV clearance.