Investigation into the role of novel interferon lambdas in the treatment of viral disease, primarily hepatitis C

• Main Author: Lowe, Rhiannon May
• Other Authors: Thursz, Mark ; Morley, Peter
• Published: Imperial College London 2012
• Subjects: 610
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.568015

Interferon lambdas (IFNλs), termed IFN-λ1, IFN-λ2 and IFN-λ3, or IL-29, IL-28A and IL-28B are a recently identified family of cytokines with antiviral activity. IL-28A/B and IL-29 bind to a novel heterodimeric receptor complex formed between IL-28 receptor (IL-28R) and IL-10 receptor (IL-10R2). Type I IFNs are used therapeutically in the treatment of chronic hepatitis B and C; however only ~30% of patients with hepatitis B virus will be successfully treated and only ~60% of patients with chronic HCV. New interventions are therefore required to address this unmet medical need and this thesis aimed to evaluate the potential use of IFNλs in treating viral infection. A range of in vitro antiviral assays were developed to determine which viruses were inhibited by IFNλs. Results showed IL-28A and IL-29 have antiviral effects with HCV 1a and 1b replicons and HBV. No antiviral effect was demonstrated against dengue, RSV or HIV. Gene expression stimulated by IFNλ was compared with IFNα; and the effects of IFNλ against HCV were investigated. The types of genes induced, and the kinetics of gene induction were similar between the type I and type III IFNs in the HCV replicon cell line. With the parental cell line, the interferon signalling pathway was the most greatly affected by IFNα, IL-28A and IL-29, but IL-29 strongly regulated the antigen presenting pathway compared with IFNα. IL-28R distribution was determined to investigate the tissue and cellular distribution of IFNλ responsive cells. IL-28R was expressed in epithelial tissues, lymphoid tissue, spleen, liver, kidney and thymus, with majority of IL-28R expression on macrophages and dendritic cells. The differences between type I and type III IFNs need to be further investigated but these differences identified provide a rationale for exploring the use of type III IFNs as an alternative to IFNα in the treatment of viral diseases.