Is the course of perinatal hepatitis B virus infection influenced by genetic heterogeneity of the virus?

Raimondo, Giovanni; Tanzi, Elisabetta; Brancatelli, Santa; Campo, Salvatore; Sardo, M.A.; Rodinò, Giuseppina; Pernice, Maurizio; Zanetti, Alessandro

doi:10.1002/jmv.1890400202

Cited by 41 publications

(17 citation statements)

References 18 publications

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“…However, we reason that the major impediment to monoinfection by genotype G may be its inability to express HBeAg, a molecule believed to play an immunomodulatory function critical for the establishment of persistent infection (10,30). It has been reported that children with maternal transmission of pure wild-type virus became chronically infected, while those infected with a mixture of wild-type virus and an HBeAg-negative mutant resolved the acute infection (35). Similarly, the precore-defective mutant of woodchuck hepatitis virus induced only transient infection in the animals (9).…”

Section: Discussionmentioning

confidence: 99%

Critical Role of the 36-Nucleotide Insertion in Hepatitis B Virus Genotype G in Core Protein Expression, Genome Replication, and Virion Secretion

Zoulim

Pichoud

et al. 2007

J Virol

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Frequent coinfection of hepatitis B virus genotype G with genotype A suggests that genotype G may require genotype A for replication or transmission. In this regard, genotype G is unique in having a 12-amino-acid extension in the core protein due to a 36-nucleotide insertion near the core gene translation initiation codon. The insertion alters base pairing in the lower stem of the pregenome encapsidation signal, which harbors the core gene initiator, and thus has the potential to affect both core protein translation and pregenomic RNA encapsidation. Genotype G is also unusual for possessing two nonsense mutations in the precore region, which together with the core gene encode a secreted nonstructural protein called hepatitis B e antigen (HBeAg). We found that genotype G clones were indeed incapable of HBeAg expression but were competent in RNA transcription, genome replication, and virion secretion. Interestingly, the 36-nucleotide insertion markedly increased the level of core protein, which was achieved at the level of protein translation but did not involve alteration in the mRNA level. Consequently, the variant core protein was readily detectable in patient blood. The 12-amino-acid insertion also enhanced the genome maturity of secreted virus particles, possibly through less efficient envelopment of core particles. Cotransfection of genotypes G and A did not lead to mutual interference of genome replication or virion secretion. Considering that HBeAg is an immunotolerogen required for the establishment of persistent infection, its lack of expression rather than a replication defect could be the primary determinant for the rare occurrence of genotype G monoinfection.

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Section: Discussionmentioning

confidence: 99%

Critical Role of the 36-Nucleotide Insertion in Hepatitis B Virus Genotype G in Core Protein Expression, Genome Replication, and Virion Secretion

Zoulim

Pichoud

et al. 2007

J Virol

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“…The biological role of HBeAg in the life cycle of the virus remains to be elucidated. It has been suggested that HBeAg secretion may play a pivotal role in the persistence of HBV by inducing immunologic tolerance (20,30,31,42). Certain precore mutants may have an inherent replicative advantage (5,26), although this issue is controversial (12).…”

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confidence: 99%

In Vitro Study of the Effects of Precore and Lamivudine-Resistant Mutations on Hepatitis B Virus Replication

Heipertz¹,

Miller²,

Kelley³

et al. 2007

J Virol

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Understanding the consequences of mutation in the hepatitis B virus (HBV) genome on HBV replication is critical for treating chronic HBV infection. In this study, HBV replication in HepG2 cells initiated by transduction with precore (PC), rtM204I, and wild-type (wt) HBV recombinant baculoviruses was compared. The pattern and magnitude of HBV replication initiated by the PC HBV recombinant baculovirus were similar to those observed for wt HBV throughout the time course examined. In contrast, when the rtM204I mutation was introduced into wt HBV, by day 10 postinfection the levels of intra-and extracellular HBV DNA were markedly reduced compared to those for wt HBV. Although the rtM204I mutation reduced the production of HBV replicative intermediates, no effect on the level of covalently closed circular DNA or HBV transcripts was observed at late time points. Coinfection studies with different ratios of wt and rtM204I baculoviruses showed that the rtM204I variant did not produce a product that inhibited HBV replication. However, the combination of the wt and rtM204I baculoviruses yielded HBV DNA levels at late time points that were greater than those for the wt alone, suggesting that wt polymerase may function in trans to boost rtM204I replication. We concluded that the rtM204I mutation generates a polymerase that is not only resistant to lamivudine but also replicates nucleic acids to lower levels in vitro.

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“…In these carriers, HBV genome usually harbors mutations that prevent the production of HBeAg (4 -6). These HBeAg-negative variants are often found in acute fulminant rather than chronic HBV infection in neonatal infection and in fulminant hepatitis than in self-limited hepatitis in adult acute infection (7)(8)(9)(10)(11). During chronic infection in some patients, the emergence of HBeAg-negative variants correlates with an exacerbation of liver injury and sometimes even with viral clearance (12)(13)(14)(15).…”

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confidence: 99%

Human Hepatitis B Viral e Antigen Interacts with Cellular Interleukin-1 Receptor Accessory Protein and Triggers Interleukin-1 Response

Yang¹,

Kuo²,

Ting³

2006

Journal of Biological Chemistry

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Human hepatitis B virus (HBV),2 a hepatotropic and noncytopathic DNA virus, is a leading cause of human hepatitis.Patients with persistent HBV infection are at a high risk of developing chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) (1, 2). HBV e antigen (HBeAg), a 17-kDa secreted protein, is not a structural component of virion nor is it required for viral assembly, replication, or infection. However, conservation of HBeAg in genomes of all hepadnaviruses suggests an important role of HBeAg in HBV infection. The presence of HBeAg in the sera of patients generally indicates ongoing HBV replication and host liver disease. Most individuals with anti-e antibodies tend to have lower levels of viremia and remission of liver disease (3). However, a significant number of HBeAg-negative carriers have elevated levels of HBV and active liver disease. In these carriers, HBV genome usually harbors mutations that prevent the production of HBeAg (4 -6). These HBeAg-negative variants are often found in acute fulminant rather than chronic HBV infection in neonatal infection and in fulminant hepatitis than in self-limited hepatitis in adult acute infection (7-11). During chronic infection in some patients, the emergence of HBeAg-negative variants correlates with an exacerbation of liver injury and sometimes even with viral clearance (12)(13)(14)(15). In murine models, HBeAg preferentially elicits Th2-like response and has the potential to preferentially deplete HBeAg-and core-specific Th1 cells (16,17). These results suggest that HBeAg plays an immunoregulatory role and promotes viral persistence. With regard to hepatocellular carcinogenesis, HBeAg-positive patients have significantly elevated risk of developing HCC (18). Taken together, these findings suggest that HBeAg plays an important role in the chronicity and carcinogenesis of HBV infection. Despite these important clinical implications, the functional involvement of HBeAg in HBV infection and the molecular mechanism of HBeAg-host interactions remain largely unknown. In this study, we show that HBeAg can interact with host interleukin-1 receptor accessary protein (IL-1RAcP) and activate IL-1 signaling pathway.The proinflammatory cytokine interleukin-1 (IL-1) initiates a wide spectrum of immunological responses to infection, * This work was supported by research grants from the National Science Council, Taiwan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom correspondence should be addressed. Tel.: 886-2-28267106; Fax:886-2-28212880; E-mail: lpting@ym.edu.tw. 2 The abbreviations used are: HBV, human hepatitis B virus; HBeAg, e antigen of HBV; mIL-1RAcP, membrane form of interleukin-1 receptor accessory protein; IL-1, interleukin-1; IL-1RI, type 1 interleukin-1 receptor; MyD88, myeloid differentiation factor 88; NF-B, nuclear factor-B; IB, inhibitor of NF-B; HCC, hepat...

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Is the course of perinatal hepatitis B virus infection influenced by genetic heterogeneity of the virus?

Cited by 41 publications

References 18 publications

Critical Role of the 36-Nucleotide Insertion in Hepatitis B Virus Genotype G in Core Protein Expression, Genome Replication, and Virion Secretion

Critical Role of the 36-Nucleotide Insertion in Hepatitis B Virus Genotype G in Core Protein Expression, Genome Replication, and Virion Secretion

In Vitro Study of the Effects of Precore and Lamivudine-Resistant Mutations on Hepatitis B Virus Replication

Human Hepatitis B Viral e Antigen Interacts with Cellular Interleukin-1 Receptor Accessory Protein and Triggers Interleukin-1 Response

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