IL-28B (IFN-[lamda]3) and IFN-[alpha] synergistically inhibit HCV replication

• Published in: Journal of viral hepatitis 2013-04, Vol.20 (4), p.281
• Main Authors: Shindo, H, Maekawa, S, Komase, K, Miura, M, Kadokura, M, Sueki, R, Komatsu, N, Shindo, K, Amemiya, F, Nakayama, Y, Inoue, T, Sakamoto, M, Yamashita, A, Moriishi, K, Enomoto, N
• Format: Article
• Language: English
• Subjects: Gene expression; Hepatitis; Interferon
• ISSN: 1352-0504; 1365-2893
• DOI: 10.1111/j.1365-2893.2012.01649.x

Summary Genetic variation in the IL-28B (interleukin-28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C treated with peginterferon-[alpha] and ribavirin. However, the mechanisms by which polymorphisms in the IL-28B gene region affect host antiviral responses are not well understood. Using the HCV 1b and 2a replicon system, we compared the effects of IFN-[lamda]s and IFN-[alpha] on HCV RNA replication. The anti-HCV effect of IFN-[lamda]3 and IFN-[alpha] in combination was also assessed. Changes in gene expression induced by IFN-[lamda]3 and IFN-[alpha] were compared using cDNA microarray analysis. IFN-[lamda]s at concentrations of 1 ng/mL or more exhibited concentration- and time-dependent HCV inhibition. In combination, IFN-[lamda]3 and IFN-[alpha] had a synergistic anti-HCV effect; however, no synergistic enhancement was observed for interferon-stimulated response element (ISRE) activity or upregulation of interferon-stimulated genes (ISGs). With respect to the time course of ISG upregulation, the peak of IFN-[lamda]3-induced gene expression occurred later and lasted longer than that induced by IFN-[alpha]. In addition, although the genes upregulated by IFN-[alpha] and IFN-[lamda]3 were similar to microarray analysis, interferon-stimulated gene expression appeared early and was prolonged by combined administration of these two IFNs. In conclusion, IFN-[alpha] and IFN-[lamda]3 in combination showed synergistic anti-HCV activity in vitro. Differences in time-dependent upregulation of these genes might contribute to the synergistic antiviral activity. [PUBLICATION ABSTRACT]