Comparative Sequence Analysis of the Core Protein and Its Frameshift Product, the F Protein, of Hepatitis C Virus Subtype 1b Strains Obtained from Patients with and without Hepatocellular Carcinoma

Ogata, Satoshi; Nagano-Fujii, Motoko; Ku, Yonson; Yoon, Seitetsu; Hotta, Hak

doi:10.1128/jcm.40.10.3625-3630.2002

Cited by 37 publications

(45 citation statements)

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“…In line with previously reported data, compartmentalization was observed consistently in tumoral hepatocytes. 25,27,29,30 Our results also showed that HCV replication is less efficient in tumoral hepatocytes and that HCC quasispecies are subjected to weak selective pressure, exhibiting stronger diversity and entropy than those derived from nontumoral tissues. Also, we demonstrated the compartmentalization of HCV core quasispecies between 2 cirrhotic nodules.…”

Section: Discussionsupporting

confidence: 50%

“…[22][23][24] The distribution of liver quasispecies may also differ when HCC and nontumoral cirrhotic liver are compared. [25][26][27][28][29][30] Finally, some articles have shown that peripheral blood mononuclear cells or hepatic lymph nodes can harbor minor or major variants not found in the serum. 31,32 However, in none of these studies was serum, different parts of the liver, and HCC from the same subjects examined.…”

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confidence: 99%

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Distinct hepatitis C virus core and F protein quasispecies in tumoral and nontumoral hepatocytes isolated via microdissection

et al. 2007

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Hepatitis C virus (HCV) genetic variability may be involved in liver carcinogenesis. We investigated HCV core and corresponding putative F protein genetic variability in hepatocellular carcinoma (HCC) and cirrhotic nodules. Hepatocyte clusters from 7 patients with HCC and HCV1b-related cirrhosis were isolated via microdissection of HCC tissues and 2 nontumoral cirrhotic nodules. The HCV core complementary DNA was cloned and sequenced from each liver compartment and from the serum of 2 patients. Nucleotide diversity and synonymous and nonsynonymous substitutions were analyzed within and between compartments via phylogenetic analysis and Mantel's test. Liver HCV RNA accumulation was lower in HCC. Increased quasispecies diversity and complexity was observed with HCC in 6 of 7 patients. Mantel's test demonstrated marked compartmentalization of quasispecies between HCC and cirrhotic nodules in all 7 patients and also between the 2 nontumoral nodules in 5 of them. Synonymousnonsynonymous substitution analysis indicated low selection against tumoral core quasispecies in all patients and a more selective pressure against F protein quasispecies in all compartments. In the 2 subjects analyzed, HCC and nontumoral hepatocyte quasispecies were only minor or undetected in serum. Conclusion: In tumoral hepatocytes, low-replicating hepatitis C quasispecies are compartmentalized and more diversified and are subjected to low selective pressure. Our study supports the importance of core genetic variability in hepatocellular carcinogenesis.

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Section: Discussionsupporting

confidence: 50%

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confidence: 99%

Distinct hepatitis C virus core and F protein quasispecies in tumoral and nontumoral hepatocytes isolated via microdissection

et al. 2007

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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: 99%

“…The length of the core11 protein appears to be genotype-specific, varying between 126 and 162 amino acids (162 aa for genotype 1a, 144 aa for 1b, 126 aa for 2a, and 126-155 amino acids for most of the sequences of other genotypes) (19). The core11 amino-acid sequence displays a lower level of conservation than the core protein (50,54,55), but is at least as well conserved as the E1 and NS2 HCV proteins encoded by the main ORF (55). Similar results were obtained in both conventional homology analysis, in which proteins encoded by diverse HCV RNA sequences are compared in pairs to determine the percentage of identical amino acids, and with a new package of data mining tools (Mutation Master) comparing individual sequences in a multiple alignment with a reference sequence (consensus sequence constructed to correct for the overrepresentation of certain genotypes) at each amino acid position.…”

Section: Conservation Of the Core11 Orf/protein Among Hcv Isolatesmentioning

confidence: 99%

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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“…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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Comparative Sequence Analysis of the Core Protein and Its Frameshift Product, the F Protein, of Hepatitis C Virus Subtype 1b Strains Obtained from Patients with and without Hepatocellular Carcinoma

Cited by 37 publications

References 34 publications

Distinct hepatitis C virus core and F protein quasispecies in tumoral and nontumoral hepatocytes isolated via microdissection

Distinct hepatitis C virus core and F protein quasispecies in tumoral and nontumoral hepatocytes isolated via microdissection

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

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