Heterogeneity of hepatitis B virus C-gene sequences: Implications for amplification and sequencing

Miska, Stefan; Günther, Stephan; Vassilev, M.; Meisel, Helga; Pape, Gerd R.; Will, Hans

doi:10.1016/s0168-8278(05)80009-1

Cited by 20 publications

(8 citation statements)

References 28 publications

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“…elsewhere (1,5,14,15,16,17,21,22,29,33,43,50,61,64,65,66). Finally, it should be noted that previous reports also suggest that core protein mutations could have an immune escape nature (5,16,27).…”

Section: Vol 76 2002 Host Factor Independence Of Hbv Core Mutant I9mentioning

confidence: 88%

“…Naturally occurring mutations in HBV have been hypothesized to play a role in the pathology of HBV-related diseases and in the persistence of HBV infection (23, 27, 59, 60, 68, 69). As a major T-cell target (13, 42), the core protein accumulates frequent mutations in chronic carrier patients with active liver disease (1,5,8,14,15,16,27).Within the core protein, the most frequent mutation occurs at amino acid 97 (1,5,14,15,16,17,21,22,27,29,33,40,41,43,48,50,61,64,65,70). The codon 97 mutation changes the wild-type amino acid from a phenylalanine to a leucine in the ayw subtype (F97L) or from an isoleucine to a leucine in the adr subtype (I97L).…”

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confidence: 99%

“…Within the core protein, the most frequent mutation occurs at amino acid 97 (1,5,14,15,16,17,21,22,27,29,33,40,41,43,48,50,61,64,65,70). The codon 97 mutation changes the wild-type amino acid from a phenylalanine to a leucine in the ayw subtype (F97L) or from an isoleucine to a leucine in the adr subtype (I97L).…”

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confidence: 99%

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Replication Advantage and Host Factor-Independent Phenotypes Attributable to a Common Naturally Occurring Capsid Mutation (I97L) in Human Hepatitis B Virus

Suk

Lin

Newman

et al. 2002

J Virol

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Mutations of human hepatitis B virus (HBV) occur frequently within the capsid (core) protein in natural infections. The most frequent mutation of the core protein in HBV from Southeast Asia occurs at amino acid 97, changing an isoleucine (I) to a leucine (L). In our systematic study of virus-host interactions, we have examined the replication efficiency of a site-directed mutant, I97L, and its parental wild-type HBV in several different hepatoma cell lines. Interestingly, we found that this capsid variant replicated in human Huh7 hepatoma cells approximately 4.8-fold better than its parental wild-type HBV. A similar phenomenon was observed in another hepatoma cell line, J3. In addition, the level of encapsidated RNA pregenome in mutant I97L was about 5.7-fold higher than that of the wild-type HBV in Huh7 cells. Unlike Huh7 cells, no significant difference in viral DNA replication between the same I97L mutant and its parental wild-type HBV was observed in HepG2, a human hepatoblastoma cell line. This finding of a profound replication advantage for mutant I97L in Huh7 and J3 cells but not in HepG2 cells may have important implications for the emergence of this mutant in chronic HBV carriers. We speculate here that the mutation confers a host factor-independent growth advantage for the survival of HBV variants in gradually dedifferentiating hepatocytes and thus helps prolong viral persistence.Human hepatitis B virus (HBV) can cause acute and chronic hepatitis in humans, with the latter often resulting in cirrhosis and hepatocellular carcinoma (6,11,55,56). HBV is an enveloped virus, which consists of an outer lipoprotein envelope and an inner nucleocapsid containing a 3.2-kb partially doublestranded DNA genome. The nucleocapsid, formed by a 183-amino-acid core antigen, assembles in the cytoplasm with a 3.2-kb pregenomic RNA and the viral polymerase. The encapsidated pregenomic RNA is then retrotranscribed into viral DNA (20,53).Because the polymerase of HBV lacks a proofreading function, HBV has a low fidelity in replication and thus tends to produce sequence variants at a high frequency. Naturally occurring mutations in HBV have been hypothesized to play a role in the pathology of HBV-related diseases and in the persistence of HBV infection (23, 27, 59, 60, 68, 69). As a major T-cell target (13, 42), the core protein accumulates frequent mutations in chronic carrier patients with active liver disease (1,5,8,14,15,16,27).Within the core protein, the most frequent mutation occurs at amino acid 97 (1,5,14,15,16,17,21,22,27,29,33,40,41,43,48,50,61,64,65,70). The codon 97 mutation changes the wild-type amino acid from a phenylalanine to a leucine in the ayw subtype (F97L) or from an isoleucine to a leucine in the adr subtype (I97L). Previously, we identified an "immature secretion" phenotype for capsid variant 97L (referring to both I97L and F97L), which is characterized by secretion of an excessive amount of Dane particles containing immature singlestranded DNA intermediates in both the ayw and adr subtypes (70, 71). ...

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Section: Vol 76 2002 Host Factor Independence Of Hbv Core Mutant I9mentioning

confidence: 88%

mentioning

confidence: 99%

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Replication Advantage and Host Factor-Independent Phenotypes Attributable to a Common Naturally Occurring Capsid Mutation (I97L) in Human Hepatitis B Virus

Suk

Lin

Newman

et al. 2002

J Virol

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“…HBV core internal deletion (CID) is a common type of mutation (1,2,12,13,17,20,26,27,28). In some patients, HBV CID mutants emerged in association with severe liver diseases.…”

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confidence: 99%

Replication of Naturally Occurring Woodchuck Hepatitis Virus Deletion Mutants in Primary Hepatocyte Cultures and after Transmission to Naive Woodchucks

Hilken

Yang

et al. 2001

J Virol

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Woodchuck hepatitis virus (WHV) mutants with core internal deletions (CID) occur naturally in chronically WHV-infected woodchucks, as do hepatitis B virus mutants in humans.We studied the replication of WHV deletion mutants in primary woodchuck hepatocyte cultures and in vivo after transmission to naive woodchucks. By screening 14 wild-caught, chronically WHV-infected woodchucks, two woodchucks, WH69 and WH70, were found to harbor WHV CID mutants. Consistent with previous results, WHV CID mutants from both animals had deletions of variable lengths (90 to 135 bp) within the middle of the WHV core gene. In woodchuck WH69, WHV CID mutants represented a predominant fraction of the viral population in sera, normal liver tissues, and to a lesser extent, in liver tumor tissues. In primary hepatocytes of WH69, the replication of wild-type WHV and CID mutants was maintained at least for 7 days. Although WHV CID mutants were predominant in fractions of cellular WHV replicative intermediates, mutant covalently closed circular DNAs (cccDNAs) appeared to be a small part of cccDNA-enriched fractions. Analysis of cccDNAenriched fractions from liver tissues of other woodchucks confirmed that mutant cccDNA represents only a small fraction of the total cccDNA pool. Four naive woodchucks were inoculated with sera from woodchuck WH69 or WH70 containing WHV CID mutants. All four woodchucks developed viremia after 3 to 4 weeks postinoculation (p.i.). They developed anti-WHV core antigen (WHcAg) antibody, lymphoproliferative response to WHcAg, and anti-WHV surface antigen. Only wild-type WHV, but no CID mutant, was found in sera from these woodchucks. The WHV CID mutant was also not identified in liver tissue from one woodchuck sacrificed in week 7 p.i. Three remaining woodchucks cleared WHV. Thus, the presence of WHV CID mutants in the inocula did not significantly change the course of acute self-limiting WHV infection. Our results indicate that the replication of WHV CID mutants might require some specific selective conditions. Further investigations on WHV CID mutants will allow us to have more insight into hepadnavirus replication.Mutations within the core gene of hepatitis B virus (HBV) were often found in chronically HBV-infected patients (3,5,8,21; for a review, see reference 14). HBV core internal deletion (CID) is a common type of mutation (1,2,12,13,17,20,26,27,28). In some patients, HBV CID mutants emerged in association with severe liver diseases. For example, HBV CID mutants occurred in renal allograft recipients who suffered from endstage liver diseases (12,13,18). CID mutations lead to the expression of truncated, unstable core proteins (24, 29). Thus, HBV CID mutants are defective in replication and require trans-complementation by wild-type virus (22,29). This fact explains why HBV CID mutants always co-occurred with wildtype virus in patients examined so far. However, our knowledge about the replication of HBV CID mutants in the host is limited. It is also not known whether the presence of HBV CID mutants influences ...

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“…One HBV genome with only 15 * Author for correspondence. Fax + 33 1 69 82 43 08. e-mail ROSSIGNOL_JM @CIT 12.FR arginine residues within 33 amino acids of the argininerich domain has also been described (Miska et al, 1993). The signal sequence directs the precore protein (P25) to the endoplasmic reticulum (ER).…”

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confidence: 99%

Importance of the C terminus of the hepatitis B virus precore protein in secretion of HBe antigen

Carlier

Jean-Jean²,

Fouillot

et al. 1995

Journal of General Virology

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The hepatitis B virus (HBV) e antigen (HBeAg) is a 15 kDa soluble antigen derived from a precursor protein (precore protein) by two processing events, cleavage of the N-terminal signal peptide and cleavage of the Cterminal 34 amino acids. So far, the role of the Cterminal sequences in secretion has not been analysed in full. In this study deletion of the last 60 amino acids was found to abrogate HBeAg secretion whereas deletions of the last 10, 25 or 39 amino acids decreased its secretion rate. These data demonstrate that C-terminal precore protein sequences are crucial for HBe secretion and determine its secretion rate.

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Heterogeneity of hepatitis B virus C-gene sequences: Implications for amplification and sequencing

Cited by 20 publications

References 28 publications

Replication Advantage and Host Factor-Independent Phenotypes Attributable to a Common Naturally Occurring Capsid Mutation (I97L) in Human Hepatitis B Virus

Replication Advantage and Host Factor-Independent Phenotypes Attributable to a Common Naturally Occurring Capsid Mutation (I97L) in Human Hepatitis B Virus

Replication of Naturally Occurring Woodchuck Hepatitis Virus Deletion Mutants in Primary Hepatocyte Cultures and after Transmission to Naive Woodchucks

Importance of the C terminus of the hepatitis B virus precore protein in secretion of HBe antigen

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