Abstract
The cytokine interleukin-28B (IL-28B) has potential antiviral properties and regulatory roles in adaptive cellular immunity. A genome-wide association study identified a single nucleotide polymorphism near the IL-28B gene that strongly predicts response to hepatitis C treatment with interferon and ribavirin. In this study, we produced human serum albumin (HSA) fused to interleukin-28B (HSA-IL28B) in an attempt to determine the effects of albumin fusion on anti-Hepatitis C virus (HCV) activity and protein stability. HSA-IL28B was expressed at high levels in the yeast expression system we used and was easily purified. The biological activities of IL-28B were only retained when HSA was fused at the N-terminus. Compared with the native IL-28B, HSA-IL28B showed improved protein stability. HSA-IL28B inhibited HCV infection through the membrane receptors IL28R1and IL10R2. Additionally, we demonstrated that HSA-IL28B was able to induce interferon-stimulated genes, phosphorylate intracellular STAT1, and act in restricted cell types. Our findings highlight the potential clinical applications of the fusion protein during virus infection and for immune regulation.
Highlights
Interferons (IFNs) are cytokines produced naturally, or upon pathogen challenge
Direct antiviral agents (DAAs) targeting Hepatitis C virus (HCV) NS3/ 4A protease were recently approved by the Food and Drug Administration, existing and adaptive mutations conferring drug resistance have forced the development of more novel anti-HCV therapeutics
These results demonstrated that human serum albumin (HSA)-IL28B fusion protein is more resistant to degradation by proteases than native IL28B protein
Summary
Interferons (IFNs) are cytokines produced naturally, or upon pathogen challenge. Currently, three types of IFNs (types I, II and III) have been characterized, with type I IFN widely used to treat hepatitis C, leukemia, lymphomas, and recurrent melanoma. A pegylated IL-29 has been developed and is being used in phase 2 clinical trials This particular molecule has shown some promising outcomes compared with pegylated IFN-a, with better tolerance and lower adverse effects observed for pegylated IL-29. Based on these results, we believe that type III IFNs can be applied as novel treatments for chronic hepatitis C. It has been successfully used to generate fusion proteins with hormones (insulin, human growth hormone) [12,13] and cytokines (interferon-a, interferon-b, IL-2) [14] This has resulted in reduced immunogenicity and modulation of pharmacokinetic properties, improving the therapeutic efficacy of these molecules. We expressed and purified IL-28B that was fused to HSA (HSA-IL28B), and evaluated its efficacy against HCV
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