Expression of interferon‐α subtypes in peripheral mononuclear cells from patients with chronic hepatitis C: a role for interferon‐α5

Abstract

Interferon (IFN)-alpha is a family of antiviral proteins encoded by different genes. The biological significance of the existence of various IFN-alpha subtypes is not clear. We have investigated the interferon system in chronic hepatitis C virus (HCV) infection, a disease that responds to interferon-alpha2 therapy in only a limited proportion of cases. We analysed the expression of interferon regulatory factor (IRF)-1, IRF-2, and IFN-alpha subtypes in nonstimulated and Sendai virus-stimulated peripheral blood mononuclear cells (PBMC) from HCV infected patients and healthy controls. We observed that the IRF-1 mRNA and IRF-1/IRF-2 ratios were increased in PBMC from hepatitis C patients with respect to normal subjects. Sendai virus stimulation of PBMC led to a significant increase in the levels of IRF-1, IRF-2 and IFN-alpha mRNAs and in the production of IFN-alpha protein with respect to basal values in healthy controls as well as in patients with HCV infection. In addition, we found that while natural HCV infection induced increased IFN-alpha5 expression in PBMC, in vitro infection of these cells with Sendai virus caused a raise in the expression of IFN-alpha8 in both patients and normal controls. In summary, our results indicate that virus-induced activation of the IFN system in human PBMC is associated with selective expression of individual IFN-alpha subtypes, IFN-alpha5 being the specific subtype induced in PBMC from patients with chronic HCV infection.

Hepatitis C Virus (HCV) Proteins Induce NADPH Oxidase 4 Expression in a Transforming Growth Factor β-Dependent Manner: a New Contributor to HCV-Induced Oxidative Stress

“…Interestingly, sequence analysis of the Nox4 promoter revealed putative binding sites for many of the important transcription factors in signaling pathways activated by HCV infection (SMAD3/4, NF-B, AP-1, Myc, Chop-cEBP, IRF-1, IRF-2, and PPAR␥) (Fig. 5A) (8,18,32,36,37,66). Further investigation of the Nox4 promoter is necessary to establish the precise mechanisms of transcriptional regulation of Nox4 by HCV.…”

Regulation of Hepatitis C Virus Replication by Interferon Regulatory Factor 1

“…A study with needle biopsy samples from chronic hepatitis C patients who had not been treated with IFN showed that IFN-␥ and IRF-1 mRNA were upregulated and correlated positively with the patients' alanine aminotransferase levels in blood (1). Another group reported that peripheral blood mononuclear cells from patients with hepatitis C showed increased expression of IRF-1 mRNA and higher IRF-1/IRF-2 ratios compared to normal subjects (23). A possible reason for the discrepancy in IRF-1 expression patterns between clinical samples and the replicon cell culture system may be the presence or absence of the immune system.…”

The Early Interferon Alpha Subtype Response in Infant Macaques Infected Orally With SIV

“…An exception is the use of Multiferon ™ . This is despite the fact that in human patients infected with Hepatitis C, IFN-α5 appears to be the most prominent IFN-α subtype expressed in the liver [4]. Based on the few, but striking results demonstrating differences in antiviral activity by various IFN-α subtypes, and considering the central role of type I interferons in the early immune defense and in directing T and B cell differentiation, a more comprehensive understanding of IFN-α subtypes in different disease settings is needed to determine whether distinct IFN-α subtype treatments might be beneficial in targeting distinct types of infections.…”