Interferons α, β, γ each inhibit hepatitis C virus replication at the level of internal ribosome entry site‐mediated translation

Abstract

Interferon (IFN)-alpha is the standard therapy for the treatment of chronic hepatitis C, but the mechanisms underlying its antiviral action are not well understood. In this report, we demonstrated that IFN-alpha, -beta and -gamma inhibit replication of the hepatitis C virus (HCV) in a cell culture model at concentrations between 10 and 100 IU/ml. We demonstrated that the antiviral actions each of each these IFNs are targeted to the highly conserved 5' untranslated region of the HCV genome, and that they directly inhibit translation from a chimeric clone between full-length HCV genome and green fluorescent protein (GFP). This effect is not limited to HCV internal ribosome entry site (IRES), since these IFNs also inhibit translation of the encephalomyocardititis virus (EMCV) chimeric mRNA in which GFP is expressed by IRES-dependent mechanisms (pCITE-GFP). These IFNs had minimal effects on the expression of mRNAs from clones in which translation is not IRES dependent. We conclude that IFN-alpha, -beta and -gamma inhibit replication of sub-genomic HCV RNA in a cell culture model by directly inhibiting two internal translation initiation sites of HCV- and EMCV-IRES sequences present in the dicistronic HCV sub-genomic RNA. Results of this in vitro study suggest that selective inhibition of IRES-mediated translation of viral polyprotein is a general mechanism by which IFNs inhibits HCV replication.

RETRACTED ARTICLE: Small interfering RNA targeted to stem-loop II of the 5' untranslated region effectively inhibits expression of six HCV genotypes

“…In the majority of patient infected the virus either does not respond to therapy or relapses when the therapy is discontinued [6-8]. Studies from our laboratories and others suggest that interferon inhibits hepatitis C virus replication by blocking it at the level of IRES mediated translation [9]. Therefore, the development of innovative approach to inhibit IRES may offer an alternative therapy for chronic hepatitis C patients that are non-responders to interferon.…”

RETRACTED: Selection of cyclic peptide aptamers to HCV IRES RNA using mRNA display

“…Translation initiation from the HCV IRES does not require the eIF4F complex: the IRES is recognized directly by the 40S ribosomal subunit and eIF3, recruits eIF2/GTP/Met-tRNA, and the resulting 48S complex assembles at the initiation codon (9,10). It is noteworthy that the pathway of IFN inhibition of viral replication occurs via an IRES-dependent mechanism (11). Both the IRES structure and the mechanism of HCV translation initiation (e.g., 12, 13) have been the subject of intense research in recent years as a therapeutic target (14)(15)(16)(17).…”

The up-regulation of type I interferon receptor gene plays a key role in hepatocellular carcinoma cells in the synergistic antiproliferative effect by 5-fluorouracil and interferon-α

“…The human type I IFN family is composed of at least 14 structurally related IFN-· subtypes and single IFN-ß and IFN-ˆsubtypes. Type I IFNs have various biological activities, including antiviral, anti-proliferative, immunomodulatory (10)(11)(12), and antiangiogenic effects (13,14), mediated by the type I IFN receptor. This receptor is composed of two functional transmembrane subunits, type I IFN receptor subunit 1 (IFNAR1) and subunit 2 (IFNAR2), cooperating to form a high-affinity receptor for all type I IFNs (15,16).…”