Understanding the potential of hepatitis C virus internal ribosome entry site domains to modulate translation initiation via their structure and function

Translation initiation in the hepatitis C virus (HCV) occurs through a cap‐independent mechanism that involves an internal ribosome entry site (IRES) capable of interacting with and utilizing the eukaryotic translational machinery. In this review, we focus on the structural configuration of the different HCV IRES domains and the impact of IRES primary sequence variations on secondary structure conservation and function. In some cases, multiple mutations, even those scattered across different domains, led to restoration of the translational activity of the HCV IRES, although the individual occurrences of these mutations were found to be deleterious. We propose that such observation may be attributed to probable long‐range inter‐ and/or intra‐domain functional interactions. The precise functioning of the HCV IRES requires the specific interaction of its domains with ribosomal subunits and a subset of eukaryotic translation initiation factors (eIFs). The structural conformation, sequence preservation and variability, and translational machinery association with the HCV IRES regions are also thoroughly discussed, along with other factors that can affect and influence the formation of translation initiation complexes. WIREs RNA 2015, 6:211–224. doi: 10.1002/wrna.1268

• Publication year

  2014

• Venue

  Wiley Interdisciplinary Reviews - RNA

• Publication date

  2014-10-28

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1002/wrna.1268PMID 25352252PMCID 4361049
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• HCV IRES interacts with the 18S rRNA to activate the 40S ribosome for subsequent steps of translation initiation

  2013cited by this paper
• Once‐daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment‐naïve genotype 1 hepatitis C: The randomized PILLAR study

  2013cited by this paper
• Hepatitis-C-virus-like internal ribosome entry sites displace eIF3 to gain access to the 40S subunit

  2013cited by this paper
• Sofosbuvir for previously untreated chronic hepatitis C infection.

  2013cited by this paper
• Structure of the full-length HCV IRES in solution

  2013cited by this paper
• Two RNA-binding motifs in eIF3 direct HCV IRES-dependent translation

  2013cited by this paper
• Stimulation of Hepatitis C Virus RNA translation by microRNA-122 occurs under different conditions in vivo and in vitro.

  2012cited by this paper
• Structure of a hepatitis C virus RNA domain in complex with a translation inhibitor reveals a binding mode reminiscent of riboswitches

  2012cited by this paper
• HCV IRES manipulates the ribosome to promote the switch from translation initiation to elongation

  2012cited by this paper
• Crystal structure of the HCV IRES central domain reveals strategy for start-codon positioning.

  2011cited by this paper
• Introduction: A smouldering public-health crisis

  2011cited by this paper
• HCV IRES domain IIb affects the configuration of coding RNA in the 40S subunit's decoding groove.

  2011cited by this paper
• eIF2A mediates translation of hepatitis C viral mRNA under stress conditions

  2011cited by this paper
• Faculty Opinions recommendation of Crystal structure of the HCV IRES central domain reveals strategy for start-codon positioning.

  2011cited by this paper
• Regulation of PKR by HCV IRES RNA: importance of domain II and NS5A.

  2010cited by this paper
• Inhibitor-induced structural change in the HCV IRES domain IIa RNA

  2010cited by this paper
• Distinct regions of human eIF3 are sufficient for binding to the HCV IRES and the 40S ribosomal subunit.

  2010cited by this paper
• The HCV IRES pseudoknot positions the initiation codon on the 40S ribosomal subunit.

  2010cited by this paper
• GTP-independent tRNA Delivery to the Ribosomal P-site by a Novel Eukaryotic Translation Factor*

  2010cited by this paper
• Robust and generic RNA modeling using inferred constraints: a structure for the hepatitis C virus IRES pseudoknot domain.

  2010cited by this paper
• Discovery of a β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus.

  2010cited by this paper
• Translational insensitivity to potent activation of PKR by HCV IRES RNA.

  2009cited by this paper
• Conserved functional domains and a novel tertiary interaction near the pseudoknot drive translational activity of hepatitis C virus and hepatitis C virus-like internal ribosome entry sites

  2009cited by this paper
• The pathway of HCV mRNA recruitment to the human ribosome

  2009cited by this paper
• In vitro characterization of a miR-122-sensitive double-helical switch element in the 5′ region of hepatitis C virus RNA

  2009cited by this paper
• Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation.

  2009cited by this paper
• Human initiation factor eIF3 subunit b interacts with HCV IRES RNA through its N‐terminal RNA recognition motif

  2009cited by this paper
• Conformational inhibition of the hepatitis C virus internal ribosome entry site RNA.

  2009cited by this paper
• Analysis of natural variants of the hepatitis C virus internal ribosome entry site reveals that primary sequence plays a key role in cap-independent translation

  2008cited by this paper
• Positioning of subdomain IIId and apical loop of domain II of the hepatitis C IRES on the human 40S ribosome

  2008cited by this paper
• Eukaryotic translation initiation machinery can operate in a bacterial-like mode without eIF2

  2008cited by this paper
• eIF2‐dependent and eIF2‐independent modes of initiation on the CSFV IRES: a common role of domain II

  2008cited by this paper
• microRNA-122 stimulates translation of hepatitis C virus RNA

  2008cited by this paper
• Structure of hepatitis C virus IRES subdomain IIa.

  2008cited by this paper
• Role of the Hepatitis C Virus Core+1 Open Reading Frame and Core cis-Acting RNA Elements in Viral RNA Translation and Replication

  2008cited by this paper
• Mass spectrometry reveals modularity and a complete subunit interaction map of the eukaryotic translation factor eIF3

  2008cited by this paper
• HCV and CSFV IRES domain II mediate eIF2 release during 80S ribosome assembly

  2007cited by this paper
• Functional architecture of HCV IRES domain II stabilized by divalent metal ions in the crystal and in solution.

  2007cited by this paper
• Structural Characterization of the Human Eukaryotic Initiation Factor 3 Protein Complex by Mass Spectrometry*S

  2007cited by this paper
• Hepatitis C virus internal ribosome entry site initiates protein synthesis at the authentic initiation codon in yeast.

  2007cited by this paper
• Initiation factor-independent translation mediated by the hepatitis C virus internal ribosome entry site.

  2006cited by this paper
• SCH 503034, a Mechanism-Based Inhibitor of Hepatitis C Virus NS3 Protease, Suppresses Polyprotein Maturation and Enhances the Antiviral Activity of Alpha Interferon in Replicon Cells

  2006cited by this paper
• Proteins surrounding hairpin IIIe of the hepatitis C virus internal ribosome entry site on the human 40S ribosomal subunit

  2006cited by this paper
• Initiation of protein synthesis by hepatitis C virus is refractory to reduced eIF2.GTP.Met-tRNA(i)(Met) ternary complex availability.

  2006cited by this paper
• American Gastroenterological Association technical review on the management of hepatitis C.

  2006cited by this paper
• Preclinical Profile of VX-950, a Potent, Selective, and Orally Bioavailable Inhibitor of Hepatitis C Virus NS3-4A Serine Protease

  2006cited by this paper
• Structural Roles for Human Translation Factor eIF3 in Initiation of Protein Synthesis

  2005cited by this paper
• Pi release from eIF2, not GTP hydrolysis, is the step controlled by start-site selection during eukaryotic translation initiation.

  2005cited by this paper
• Mechanism of action of interferon and ribavirin in treatment of hepatitis C

  2005cited by this paper
• SAR by MS: discovery of a new class of RNA-binding small molecules for the hepatitis C virus: internal ribosome entry site IIA subdomain.

  2005cited by this paper
• Structure of the hepatitis C virus IRES bound to the human 80S ribosome: remodeling of the HCV IRES.

  2005cited by this paper
• Release of initiation factors from 48S complexes during ribosomal subunit joining and the link between establishment of codon-anticodon base-pairing and hydrolysis of eIF2-bound GTP.

  2004cited by this paper
• The pathway of HCV IRES-mediated translation initiation.

  2004cited by this paper
• Mutational and structural analysis of stem-loop IIIC of the hepatitis C virus and GB virus B internal ribosome entry sites.

  2004cited by this paper
• Inaugural Article: Coordinated assembly of human translation initiation complexes by the hepatitis C virus internal ribosome entry site RNA

  2004cited by this paper
• Structure of HCV IRES domain II determined by NMR

  2003cited by this paper
• The dynamic nature of the four-way junction of the hepatitis C virus IRES.

  2003cited by this paper
• Long-range RNA-RNA interaction between the 5' nontranslated region and the core-coding sequences of hepatitis C virus modulates the IRES-dependent translation.

  2003cited by this paper
• Domains on the hepatitis C virus internal ribosome entry site for 40s subunit binding.

  2002cited by this paper
• Crystal structure of an RNA tertiary domain essential to HCV IRES-mediated translation initiation

  2002cited by this paper
• A conserved RNA structure within the HCV IRES eIF3-binding site

  2002cited by this paper
• Mutational analysis of the apical region of domain II of the HCV IRES

  2002cited by this paper
• Initiation factor eIF5B catalyzes second GTP-dependent step in eukaryotic translation initiation

  2002cited by this paper
• Mechanism of ribosome recruitment by hepatitis C IRES RNA.

  2001cited by this paper
• The influence of downstream protein-coding sequence on internal ribosome entry on hepatitis C virus and other flavivirus RNAs.

  2001cited by this paper
• Mutational Analysis of the Different Bulge Regions of Hepatitis C Virus Domain II and Their Influence on Internal Ribosome Entry Site Translational Ability*

  2001cited by this paper
• Genetic Analysis of a Poliovirus/Hepatitis C Virus Chimera: New Structure for Domain II of the Internal Ribosomal Entry Site of Hepatitis C Virus

  2001cited by this paper
• The Ribosome Binding Site of Hepatitis C Virus mRNA

  2001cited by this paper
• Ribosomal Protein S5 Interacts with the Internal Ribosomal Entry Site of Hepatitis C Virus*

  2001cited by this paper
• Hepatitis C Virus IRES RNA-Induced Changes in the Conformation of the 40S Ribosomal Subunit

  2001cited by this paper
• The joining of ribosomal subunits in eukaryotes requires eIF5B

  2000cited by this paper
• A potential RNA drug target in the hepatitis C virus internal ribosomal entry site.

  2000cited by this paper
• Comparative Analysis of Translation Efficiencies of Hepatitis C Virus 5′ Untranslated Regions among Intraindividual Quasispecies Present in Chronic Infection: Opposite Behaviors Depending on Cell Type

  2000cited by this paper
• Core Protein-Coding Sequence, but Not Core Protein, Modulates the Efficiency of Cap-Independent Translation Directed by the Internal Ribosome Entry Site of Hepatitis C Virus

  2000cited by this paper
• X-Ray structures of the universal translation initiation factor IF2/eIF5B: conformational changes on GDP and GTP binding.

  2000cited by this paper
• Structures of two RNA domains essential for hepatitis C virus internal ribosome entry site function

  2000cited by this paper
• Hepatitis C Virus Internal Ribosome Entry Site (IRES) Stem Loop IIId Contains a Phylogenetically Conserved GGG Triplet Essential for Translation and IRES Folding

  2000cited by this paper
• An Enzymatic Footprinting Analysis of the Interaction of 40S Ribosomal Subunits with the Internal Ribosomal Entry Site of Hepatitis C Virus

  2000cited by this paper
• A single nucleotide insertion in the 5'-untranslated region of hepatitis C virus leads to enhanced cap-independent translation.

  1999cited by this paper
• The hepatitis C virus internal ribosome entry site adopts an ion-dependent tertiary fold.

  1999cited by this paper
• A Phylogenetically Conserved Stem-Loop Structure at the 5′ Border of the Internal Ribosome Entry Site of Hepatitis C Virus Is Required for Cap-Independent Viral Translation

  1999cited by this paper
• Mutational analysis of a conserved tetraloop in the 5′ untranslated region of hepatitis C virus identifies a novel RNA element essential for the internal ribosome entry site function

  1999cited by this paper
• Alterations to both the Primary and Predicted Secondary Structure of Stem-Loop IIIc of the Hepatitis C Virus 1b 5′ Untranslated Region (5′UTR) Lead to Mutants Severely Defective in Translation Which Cannot Be Complemented intrans by the Wild-Type 5′UTR Sequence

  1999cited by this paper
• Specific Interaction of Eukaryotic Translation Initiation Factor 3 with the 5′ Nontranslated Regions of Hepatitis C Virus and Classical Swine Fever Virus RNAs

  1998cited by this paper
• A prokaryotic-like mode of cytoplasmic eukaryotic ribosome binding to the initiation codon during internal translation initiation of hepatitis C and classical swine fever virus RNAs.

  1998cited by this paper
• Functional analysis of the interaction between HCV 5'UTR and putative subunits of eukaryotic translation initiation factor eIF3

  1998cited by this paper
• In vivo translational efficiency of different hepatitis C virus 5′‐UTRs

  1997cited by this paper
• Structural requirements for initiation of translation by internal ribosome entry within genome-length hepatitis C virus RNA.

  1996cited by this paper
• The influence of AUG codons in the hepatitis C virus 5' nontranslated region on translation and mapping of the translation initiation window.

  1996cited by this paper
• Internal initiation of translation of hepatitis C virus RNA: the ribosome entry site is at the authentic initiation codon.

  1996cited by this paper
• Stability of a stem-loop involving the initiator AUG controls the efficiency of internal initiation of translation on hepatitis C virus RNA.

  1996cited by this paper
• Unique features of internal initiation of hepatitis C virus RNA translation.

  1995cited by this paper
• Almost the entire 5′ non‐translated region of hepatitis C virus is required for cap‐independent translation

  1995cited by this paper
• An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region.

  1995cited by this paper
• A conserved helical element is essential for internal initiation of translation of hepatitis C virus RNA

  1994cited by this paper
• Translation of human hepatitis C virus RNA in cultured cells is mediated by an internal ribosome-binding mechanism

  1993cited by this paper
• Secondary structure of the 5' nontranslated regions of hepatitis C virus and pestivirus genomic RNAs.

  1992cited by this paper
• Internal ribosome entry site within hepatitis C virus RNA

  1992cited by this paper
• Structure and organization of the hepatitis C virus genome isolated from human carriers

  1991cited by this paper
• Genetic organization and diversity of the hepatitis C virus.

  1991cited by this paper

• Integrating rna structure and protein interactions to uncover the mechanisms of viral and cellular ires function

  2025cites this paper
• IRES-Mediated Translation: Expanding the Toolkits of RNA Therapy

  2025cites this paper
• Hijacking the unfolded protein response (UPR) pathway: Balancing viral infection and host cell survival

  2025cites this paper
• Emerging RNA-centric technologies to probe RNA-protein interactions: importance in decoding the life cycle of positive sense single strand RNA viruses and antiviral discovery

  2025cites this paper
• Development and characterization of a miRNA-responsive circular RNA expression system with cell type specificity

  2025cites this paper
• Host-like RNA Elements Regulate Virus Translation

  2024cites this paper
• Antibody designing against IIIabc junction (JIIIabc) of HCV IRES through affinity maturation; RNA-Antibody docking and interaction analysis

  2023cites this paper
• Characterization of host factors associated with the internal ribosomal entry sites of foot-and-mouth disease and classical swine fever viruses

  2022cites this paper
• Eukaryotic translation initiation factor eIF4G2 opens novel paths for protein synthesis in development, apoptosis and cell differentiation

  2022cites this paper
• Recent advances in RNA structurome

  2022cites this paper
• RNA-Protein Interactome at the Hepatitis E Virus Internal Ribosome Entry Site

  2022cites this paper
• Identification of cryptic putative IRESs within the ORF encoding the nonstructural proteins of the human rhinovirus 16 genome

  2021cites this paper
• Short and Sweet: Viral 5`-UTR as a Canonical and Non-Canonical Translation Initiation Switch

  2021cites this paper
• In the era of rapid mRNA-based vaccines: Why is there no effective hepatitis C virus vaccine yet?

  2021cites this paper
• DDX21, a Host Restriction Factor of FMDV IRES-Dependent Translation and Replication

  2021cites this paper
• Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

  2020cites this paper
• Physical and Functional Analysis of Viral RNA Genomes by SHAPE.

  2019cites this paper
• The search for a PKR code—differential regulation of protein kinase R activity by diverse RNA and protein regulators

  2019cites this paper
• miR-122 and Ago interactions with the HCV genome alter the structure of the viral 5′ terminus

  2019cites this paper
• Functionalized C-nucleosides as remarkable RNA binders: targeting of prokaryotic ribosomal A-site RNA.

  2019cites this paper
• Viral internal ribosomal entry sites: four classes for one goal

  2018cites this paper
• microRNA-122 amplifies hepatitis C virus translation by shaping the structure of the internal ribosomal entry site

  2018cites this paper
• Mutational Analysis of the Bovine Hepacivirus Internal Ribosome Entry Site

  2018cites this paper
• The Interplay between the RNA Decay and Translation Machinery in Eukaryotes.

  2018cites this paper
• Characterization of Hepatitis C Virus IRES Quasispecies – From the Individual to the Pool

  2018cites this paper
• Rewiring cellular networks by members of the Flaviviridae family

  2018cites this paper
• The Regulation of Translation in Alphavirus-Infected Cells

  2018cites this paper
• The Initiation Factors eIF2, eIF2A, eIF2D, eIF4A, and eIF4G Are Not Involved in Translation Driven by Hepatitis C Virus IRES in Human Cells

  2018cites this paper
• Viral RNA structure-based strategies to manipulate translation

  2018cites this paper
• Virus-host interactions in the early stages of the Equine Hepacivirus (EqHV) lifecycle

  2017cites this paper
• Regulation Mechanisms of Viral IRES-Driven Translation.

  2017cites this paper
• Extrémités 3’ de l’ARN du Virus de l’Hépatite C : structures et Rôles dans la réplication du génome

  2016cites this paper
• HCVIVdb: The hepatitis-C IRES variation database

  2016cites this paper
• Translation initiation by the hepatitis C virus IRES requires eIF1A and ribosomal complex remodeling

  2016cites this paper
• Stable Expression of Anti-CD52 Monoclonal Antibody Using a Bicistronic Vector System

  2016cites this paper
• The expanding universe of ribonucleoproteins: of novel RNA-binding proteins and unconventional interactions

  2016cites this paper