Antibodies to a novel antigen in acute hepatitis C virus infections

Tobler, Leslie H.; Stramer, Susan L.; Chien, David; Lin, Sansan; Arcangel, Phillip; Phelps, Bruce H.; Cooper, Stewart; Busch, Michael P.

doi:10.1111/j.1423-0410.2006.00856.x

Cited by 6 publications

(6 citation statements)

References 35 publications

(52 reference statements)

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“…The serological test used throughout was the HCV 3.0 enzyme-immunoassay (EIA) (Ortho Clinical Diagnostics, Raritan, New Jersey) which includes recombinant proteins representing linear epitopes from the Core, NS3, NS4 and NS5 regions (Chien et al, 1999;Lin et al, 2005) and is used to screen approximately 80% of the blood supply in the United States (US) for antibodies to HCV. Three unlicensed EIAs containing antigenic proteins not present in HCV 3.0 EIA 1) MEFA 7.1-NS3/4a, 2) F and Core, and 3) E1/E2 proteins were also used for a subset of samples (Tobler et al, 2007). MEFA 7.1 contains the linear epitopes used in licensed EIAs, including the latest EIA-3.0, in combination with genotype 1-3 specific epitopes.…”

Section: Serological Assaysmentioning

confidence: 99%

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High levels of subgenomic HCV plasma RNA in immunosilent infections

et al. 2007

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A genetic analysis of hepatitis C virus (HCV) in rare blood donors who remained HCV seronegative despite long-term high-level viremia revealed the chronic presence of HCV genomes with large in frame deletions in their structural genes. Full-length HCV genomes were only detected as minority variants. In one immunodeficiency virus (HIV) co-infected donor the truncated HCV genome transiently decreased in frequency concomitant with delayed seroconversion and re-emerged following partial seroreversion. The long-term production of heavily truncated HCV genomes in vivo suggests that these viruses retained the necessary elements for RNA replication while the deleted structural functions necessary for their spread in vivo was provided in trans by wild-type helper virus in co-infected cells. The absence of immunological pressure and a high viral load may therefore promote the emergence of truncated HCV subgenomic replicons in vivo.

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Section: Serological Assaysmentioning

confidence: 99%

“…Subjects TN9, TN78 and TN168 have previously been reported as sero-silent infections using HCV EIA 3.0 with normal plasma alanine aminotransferase (ALT) (Peoples et al, 2000;Stramer et al, 2004). Samples from subject TN9 and TN78 were also tested by three unlicensed EIA and were also seronegative (Tobler et al, 2007).…”

Section: Subjectsmentioning

confidence: 99%

High levels of subgenomic HCV plasma RNA in immunosilent infections

et al. 2007

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“…Importantly, recent work from our laboratory verified the expression of the two coreϩ1/ARFP isoforms in the context of replicons derived from the genotype 2a HCV isolate JFH1 and revealed differences in the expression kinetics of the coreϩ1/ARFP isoforms during infection (17). Importantly, the detection of coreϩ1/ARFP-specific antibodies (18)(19)(20)(21)(22)(23)(24)(25) and T-cell responses in HCV-infected patients (26)(27)(28)(29) reported by several laboratories worldwide suggest that this protein is also expressed in vivo. However, coreϩ1/ARFP is not required for JFH1 HCV (genotype 2a) replication in cultured cells (30) and for HCV genotype 1a replication in vivo in chimpanzees (31).…”

mentioning

confidence: 57%

Hepatitis C Virus core+1/ARF Protein Modulates the Cyclin D1/pRb Pathway and Promotes Carcinogenesis

Moustafa

Karakasiliotis

Mavromara

2018

J Virol

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Viruses often encompass overlapping reading frames and unconventional translation mechanisms in order to maximize the output from a minimum genome and to orchestrate their timely gene expression. Hepatitis C virus (HCV) possesses such an unconventional open reading frame (ORF) within the core-coding region, encoding an additional protein, initially designated ARFP, F, or core+1. Two predominant isoforms of core+1/ARFP have been reported, core+1/L, initiating from codon 26, and core+1/S, initiating from codons 85/87 of the polyprotein coding region. The biological significance of core+1/ARFP expression remains elusive. The aim of the present study was to gain insight into the functional and pathological properties of core+1/ARFP through its interaction with the host cell, combining and approaches. Our data provide strong evidence that the core+1/ARFP of HCV-1a stimulates cell proliferation in Huh7-based cell lines expressing either core+1/S or core+1/L isoforms and in transgenic liver disease mouse models expressing core+1/S protein in a liver-specific manner. Both isoforms of core+1/ARFP increase the levels of cyclin D1 and phosphorylated Rb, thus promoting the cell cycle. In addition, core+1/S was found to enhance liver regeneration and oncogenesis in transgenic mice. The induction of the cell cycle together with increased mRNA levels of cell proliferation-related oncogenes in cells expressing the core+1/ARFP proteins argue for an oncogenic potential of these proteins and an important role in HCV-associated pathogenesis. This study sheds light on the biological importance of a unique HCV protein. We show here that core+1/ARFP of HCV-1a interacts with the host machinery, leading to acceleration of the cell cycle and enhancement of liver carcinogenesis. This pathological mechanism(s) may complement the action of other viral proteins with oncogenic properties, leading to the development of hepatocellular carcinoma. In addition, given that immunological responses to core+1/ARFP have been correlated with liver disease severity in chronic HCV patients, we expect that the present work will assist in clarifying the pathophysiological relevance of this protein as a biomarker of disease progression.

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“…Concerning the biological relevance of core+1 protein, specific antibodies [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ] and T-cell responses [ 32 , 33 , 34 ] have been detected in HCV-infected individuals. Moreover, studies conducted by us revealed a high prevalence of core+1 antibodies in HCV patients with advanced cirrhosis [ 35 ] and hepatocellular carcinoma (HCC) [ 36 ], suggesting that core+1 antibodies in HCV infection may present a marker for the progression of liver disease and the development of liver cancer.…”

Section: Introductionmentioning

confidence: 99%

A Novel Cis-Acting RNA Structural Element Embedded in the Core Coding Region of the Hepatitis C Virus Genome Directs Internal Translation Initiation of the Overlapping Core+1 ORF

Vassilaki

Frakolaki

Kalliampakou

et al. 2020

IJMS

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Hepatitis C virus (HCV) genome translation is initiated via an internal ribosome entry site (IRES) embedded in the 5′-untranslated region (5′UTR). We have earlier shown that the conserved RNA stem-loops (SL) SL47 and SL87 of the HCV core-encoding region are important for viral genome translation in cell culture and in vivo. Moreover, we have reported that an open reading frame overlapping the core gene in the +1 frame (core+1 ORF) encodes alternative translation products, including a protein initiated at the internal AUG codons 85/87 of this frame (nt 597–599 and 603–605), downstream of SL87, which is designated core+1/Short (core+1/S). Here, we provide evidence for SL47 and SL87 possessing a novel cis-acting element that directs the internal translation initiation of core+1/S. Firstly, using a bicistronic dual luciferase reporter system and RNA-transfection experiments, we found that nucleotides 344–596 of the HCV genotype-1a and -2a genomes support translation initiation at the core+1 frame AUG codons 85/87, when present in the sense but not the opposite orientation. Secondly, site-directed mutagenesis combined with an analysis of ribosome–HCV RNA association elucidated that SL47 and SL87 are essential for this alternative translation mechanism. Finally, experiments using cells transfected with JFH1 replicons or infected with virus-like particles showed that core+1/S expression is independent from the 5′UTR IRES and does not utilize the polyprotein initiation codon, but it requires intact SL47 and SL87 structures. Thus, SL47 and SL87, apart from their role in viral polyprotein translation, are necessary elements for mediating the internal translation initiation of the alternative core+1/S ORF.

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Antibodies to a novel antigen in acute hepatitis C virus infections

Cited by 6 publications

References 35 publications

High levels of subgenomic HCV plasma RNA in immunosilent infections

High levels of subgenomic HCV plasma RNA in immunosilent infections

Hepatitis C Virus core+1/ARF Protein Modulates the Cyclin D1/pRb Pathway and Promotes Carcinogenesis

A Novel Cis-Acting RNA Structural Element Embedded in the Core Coding Region of the Hepatitis C Virus Genome Directs Internal Translation Initiation of the Overlapping Core+1 ORF

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