A Relationship between the Evolution of Hepatitis C Virus Variants, Liver Damage, and Hepatocellular Carcinoma in Patients with Hepatitis C Viremia

Hayashi, Jun; Furusyo, Norihiro; Ariyama, Iwao; Sawayama, Yasunori; Etoh, Yoshitaka; Kashiwagi, Seizaburo

doi:10.1086/315431

Cited by 73 publications

(41 citation statements)

References 35 publications

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“…In addition, phylogenetic analysis with the core11 amino-acid sequence has shown that the core11 variants obtained from HCC samples differ from those in nontumor cells, consistent with the selection of core11 variants with modified functional properties in HCV-induced HCC. Previous studies also reported the accumulation of characteristic mutations in specific regions of the HCV core/core11 RNA sequence in patients with HCC, these mutations being associated with an increase in the production of alternative forms of core/core11 proteins in cell-free systems in several cases (46)(47)(48)(49)(50)(51).…”

Section: Evidence For Core11 Protein Production During Natural Hcv Inmentioning

confidence: 93%

The HCV ARFP/F/core+1 protein: Production and functional analysis of an unconventional viral product

Vassilaki

Mavromara

2009

IUBMB Life

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Hepatitis C virus (HCV) is an enveloped positive‐strand RNA virus of the Flaviviridae family. It has a genome of about 9,600 nucleotides encoding a large polyprotein (about 3,000 amino acids) that is processed by cellular and viral proteases into at least 10 structural and nonstructural viral proteins. A novel HCV protein has also been identified by our laboratory and others. This protein—known as ARFP (alternative reading frame protein), F (for frameshift) or core+1 (to indicate the position) protein ‐ is synthesized by an open reading frame overlapping the core gene at nucleotide +1 (core+1 ORF). However, almost 10 years after its discovery, we still know little of the biological role of the ARFP/F/core+1 protein. Abolishing core+1 protein production has no affect on HCV replication in cell culture or uPA‐SCID mice, suggesting that core+1 protein is probably not important for the HCV reproductive cycle. However, the detection of specific anti‐core+1 antibodies and T‐cell responses in HCV‐infected patients, as reported by many independent laboratories, provides strong evidence that this protein is produced in vivo. Furthermore, analyses of the HCV sequences isolated from patients with hepatocellular carcinoma and in vitro studies have provided strong preliminary evidence to suggest that core+1 protein plays a role in advanced liver disease and liver cancer. The available in vitro data also suggest that certain core function proteins may depend on production of the core+1 protein. We describe here the discovery of the various forms of the core+1 protein and what is currently known about the mechanisms of their production and their biochemical and functional properties. We also provide a detailed summary of the results of patient‐based research. © 2009 IUBMB IUBMB Life, 61(7): 739–752, 2009

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Section: Evidence For Core11 Protein Production During Natural Hcv Inmentioning

confidence: 93%

The HCV ARFP/F/core+1 protein: Production and functional analysis of an unconventional viral product

Vassilaki

Mavromara

2009

IUBMB Life

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“…These studies suggest a link between coreϩ1/ARFP and development of liver cancer (22)(23)(24)(25)(26)(27). Conversely, coreϩ1/ARFP has no obvious effect on virus replication following electroporation of Huh7-Lunet cells with fulllength JFH1 wild-type and mutated viral RNAs or in mice xenografted with human liver tissue (28).…”

mentioning

confidence: 99%

Expression of the Novel Hepatitis C Virus Core+1/ARF Protein in the Context of JFH1-Based Replicons

Kotta‐Loizou

Karakasiliotis

Vassilaki

et al. 2015

J Virol

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Hepatitis C virus (HCV) infection is a major cause of non-A, non-B hepatitis, which frequently leads to chronic liver disease and hepatocellular carcinoma (1); no vaccine is available, while the recent broadly effective therapy is highly expensive (2, 3). The single-stranded positive-sense RNA genome of HCV (9.6 kb) encodes a polyprotein precursor of about 3,000 amino acids flanked by conserved untranslated regions (UTRs) (4, 5). The UTRs are required for RNA translation and replication, and an internal ribosome entry site (IRES) within the 5= UTR controls translation initiation (6). The polyprotein is processed by cellular and viral proteases to yield at least 10 structural and nonstructural proteins (C, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (4, 5).Previous studies from our laboratory and others have shown that HCV possesses a second functional open reading frame (ORF) within the core region of the polyprotein encoding an additional protein designated coreϩ1/alternative reading frame protein (ARFP) (7-9). This alternate ORF is present in all six HCV genotypes (9) but has been studied only in subtypes 1a and 1b. At first, a 17-kDa protein (p17), initially named ARFP (alternative reading frame protein), F (frameshift), or coreϩ1 (to indicate its position), was shown to be synthesized in rabbit reticulocyte lysate (RRL) from the initiating codon of the polyprotein sequence of a genotype 1a HCV type 1 (HCV-1) strain by a ϩ1 frameshift occurring in an A-rich core-encoding region (codons 8 to 11) (7-10). However, the expression of this form of coreϩ1/ARFP (known as F) is limited to the HCV-1 isolate, which is unique in carrying a stretch of 10 consecutive adenine nucleotides within codons 8 to 11 (7,11,12), and its expression in transfected cells is dependent on cytoplasmic transcription (11). Interestingly, other coreϩ1/ARFP forms are expressed independently of the A-rich sequence by an alternative translation mechanism(s). Internal translation initiation at methionine codons 85/87 of HCV-1a and HCV-1b, resulting in a shorter form of coreϩ1/ARFP, has been observed in transfected hepatoma cells (13-15). Furthermore, codon 26 of HCV-1a (12) and HCV-1b (15) was also found to function as an internal translation initiation site in mammalian cells. Additionally, a ϩ1 frameshift at codon 42 of HCV-1b, followed by a rephrasing into the core ORF at stop codon 144, was observed in Escherichia coli (16).The detection of specific anti-coreϩ1/ARFP antibodies and T-cell responses in HCV-infected patients (especially with hepatocellular carcinoma), as reported by many independent laboratories, provides strong evidence that coreϩ1/ARFP is produced during natural infection (7-9, 17-21). These studies suggest a link between coreϩ1/ARFP and development of liver cancer (22-27). Conversely, coreϩ1/ARFP has no obvious effect on virus replication following electroporation of Huh7-Lunet cells with fulllength JFH1 wild-type and mutated viral RNAs or in mice xenografted with human liver tissue (28). Those studies were based on a ...

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“…HCV exists in its host as a collection of variants termed quasispecies (18), whose evolution correlates with viral persistence (6,7,16,34), long-term outcome of HCV disease (13), and response to interferon treatment (9,24). Studies of HCVinfected agammaglobulinemic patients (11) and adults coinfected with HIV-1 (17,25,26,31) have suggested that relative immunocompetence modulates HCV quasispecies diversity.…”

Section: Fig 1 Clinical Parameters Measured In Coinfected Childrenmentioning

confidence: 99%

Differing Patterns of Liver Disease Progression and Hepatitis C Virus (HCV) Quasispecies Evolution in Children Vertically Coinfected with HCV and Human Immunodeficiency Virus Type 1

Canobio¹,

Guilbert²,

Troesch³

et al. 2004

J Clin Microbiol

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Hepatitis C virus (HCV) quasispeciation was studied in two children vertically coinfected with HCV and human immunodeficiency virus type 1 (HIV-1). HCV quasispecies diversification and liver injury were more significant in patient C1, who was immunocompetent with anti-HIV therapy, than in patient C2, who was immunosuppressed, in consistency with modulation of HCV quasispeciation and liver injury by immunocompetence in coinfected children.To characterize the evolution of hepatitis C virus (HCV) disease and the influence of human immunodeficiency virus type 1 (HIV-1) and antiretroviral therapy (ART) (17), longitudinal sequence analysis of E2 envelope gene hypervariable region 1 (HVR1) was undertaken for two male Caucasian children (C1 and C2), who acquired HCV and HIV-1 infection by mother-to-child transmission.Patient C1, born in 1996, was treated from birth with zidovudine, which was complemented with lamivudine when HIV-1 cocultures became positive at 6 weeks of age. Early HIV-1 viremia correlated with a rise in CD8 cell counts, a sharp decline in CD4 counts, and an inversion of the CD4:CD8 ratio, consistent with acute HIV-1 infection ( Fig. 1A and B) (3). HIV-1 viral load decreased and stabilized at the end of the first year of life, while CD4 counts remained within the normal range. At 1.16 years of age, combination ART (lamivudinestavudine-ritonavir) was introduced, resulting in a further decline in HIV-1 viral load and a rise in CD4 counts (Fig. 1). Levels of alanine (ALT) and aspartate (AST) aminotransferases peaked 36 days later, followed by a decline over the following weeks without a change in treatment (Fig. 1C). Infection with HCV-1b (21) at 1.77 years of age was confirmed by PCR. Stored plasma samples were used retrospectively to measure HCV RNA levels, which were not influenced by ART (Fig. 1B). Between the ages of 3 and 6, HIV-1 levels declined but remained detectable, HCV viral load was stable, ALT and AST levels remained at twice normal or less, and CD4 counts declined but remained within the normal range ( Fig. 1) (3). A liver biopsy performed at 5.83 years of age showed chronic hepatitis characterized by distorted lobular architecture together with mild, diffuse lobular inflammation with occasional nodular lymphoid infiltrate and prominent macro-and microvesicular steatosis. Portal tracts were expanded with mononuclear cell infiltrates, and interface hepatitis was present in the majority. Mild periportal and sinusoidal fibrosis was observed.At 4.5 months later, changes in ART brought the HIV-1 viral load to Ͻ50 copies/ml and raised CD4 counts. Common clinical complications related to pediatric HIV infection were not seen. HCV RNA was extracted from plasma and was amplified using previously described primers and conditions (8,9). Strict PCR precautions were adopted. A total of 115 independent subclones were sequenced. Multiple alignments were performed using Clustal X version 1.81 (30). Overall, accumulation of nucleotide substitutions was observed within HVR1 (nucleotides 1482 to 1562), while f...

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A Relationship between the Evolution of Hepatitis C Virus Variants, Liver Damage, and Hepatocellular Carcinoma in Patients with Hepatitis C Viremia

Cited by 73 publications

References 35 publications

The HCV ARFP/F/core+1 protein: Production and functional analysis of an unconventional viral product

The HCV ARFP/F/core+1 protein: Production and functional analysis of an unconventional viral product

Expression of the Novel Hepatitis C Virus Core+1/ARF Protein in the Context of JFH1-Based Replicons

Differing Patterns of Liver Disease Progression and Hepatitis C Virus (HCV) Quasispecies Evolution in Children Vertically Coinfected with HCV and Human Immunodeficiency Virus Type 1

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