Li, J. S. et al. Hepatitis B virus genotype A rarely circulates as an HBe- mutant: possible contribution of a single nucleotide in the precore region. J. Virol. 67, 5402-5410

Unité de Recherche sur les Hepatites, le SIDA et les Retrovirus Humains, Institut National de la Santé et de la Recherche Médicale 271, Lyon, France.
Journal of Virology (Impact Factor: 4.44). 10/1993; 67(9):5402-10.
Source: PubMed


The emergence of HBe-minus hepatitis B virus (HBV) mutants, usually through a UAG nonsense mutation at codon 28 of the precore region, helps the virus to survive the anti-HBe immune response of the host. Host and viral factors that predispose to the emergence of such mutants are not well characterized. The fact that the precore region forms a hairpin structure essential for the packaging of viral pregenomic RNA may explain the extremely high prevalence of the UAG mutation at codon 28. It converts a wobble U-G pair in the packaging signal between nucleotide 3 of codon 15 (CCU) and nucleotide 2 of codon 28 (UGG) into a U-A pair. Since genotype A of HBV has a CCC sequence at codon 15, the UAG mutation would, instead, disrupt a C-G pair present in the wild-type virus. This alteration was shown by transfection experiments to greatly compromise the packaging of pregenomic RNA. The implication of this finding was elucidated by molecular epidemiological studies. Genotype A was found to be the most prevalent genotype in the wild-type virus populations in France but was found in only 1 of the 46 isolates of HBe-minus mutants found there. These mutants were contributed chiefly by genotype D, the second most prevalent genotype in France, which is characterized by a CCU sequence at codon 15. The role of the single nucleotide at codon 15 was confirmed by the finding of the single genotype A isolate in which both wild-type and mutant viruses were present. Interestingly, nearly all of the mutants had a codon 15 sequence of CCU instead of the CCC present in the wild-type viruses. Our results suggest that genotype A of HBV rarely circulates as HBe-minus mutants, probably because of a requirement for a simultaneous sequence change at codon 15. These data, together with the virtual absence of genotype A in the Chinese samples examined, may provide some insights into the uneven prevalence of HBe-minus mutants in the world.

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Available from: Shuping Tong, Dec 19, 2013
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    • "The majority of the HBeAg-negativity was as a result of the classical G1896A, which abolishes HBeAg expression [44] and occurs in genotype D or E but not A because the encapsidation signal secondary structure precludes this mutation in genotype A [45,46]. Other mutations including transcriptional A1762T/G1764A and translation initiation mutations were responsible of HBeAg-negativity in a number of patients. "
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    ABSTRACT: Hepatitis B virus is hyperendemic in Sudan. Our aim was to molecularly characterize hepatitis B virus from Sudanese individuals, with and without liver disease, because genotypes play an important role in clinical manifestation and treatment management. Ninety-nine patients - 30 asymptomatic, 42 cirrhotic, 15 with hepatocellular carcinoma, 7 with acute hepatitis and 5 with chronic hepatitis- were enrolled. Sequencing of surface and basic core promoter/precore regions and complete genome were performed. The mean +/- standard deviation, age was 45.7+/-14.8 years and the male to female ratio 77:22. The median (interquartile range) of hepatitis B virus DNA and alanine aminotransferase levels were 2.8 (2.2-4.2) log IU/ml and 30 (19--49) IU/L, respectively. Using three genotyping methods, 81/99 (82%) could be genotyped. Forty eight percent were infected with genotype D and 24% with genotype E, 2% with putative D/E recombinants and 7% with genotype A. Patients infected with genotype E had higher frequency of hepatitis B e antigen-positivity and higher viral loads compared to patients infected with genotype D. Basic core promoter/precore region mutations, including the G1896A in 37% of HBeAg-negative individuals, could account for hepatitis B e antigen-negativity. Pre-S deletion mutants were found in genotypes D and E. Three isolates had the vaccine escape mutant sM133T. Sudanese hepatitis B virus carriers were mainly infected with genotypes D or E, with patients infected with genotype E having higher HBeAg-positivity and higher viral loads. This is the first study to molecularly characterize hepatitis B virus from liver disease patients in Sudan.
    Full-text · Article · Jul 2013 · BMC Infectious Diseases
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    • "Rather, single nucleotide mutations occur in ''wobble'' stop codons in the 3 0 end of ORF7 (Fig. 3). A codon ''wobble'' position mutation also has been observed in hepatitis B virus (Li et al., 1993; Tong et al., 1993). Interestingly, the pronounced plasticity of the "
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    ABSTRACT: Porcine reproductive and respiratory syndrome virus (PRRSV) is a major threat to European swine production. The existence of extensive genetic variation in endemic strains and the presence of highly virulent strains in other geographic regions pose the threat of devastating epidemic outbreaks. Here we describe the current knowledge of genetic variation in European PRRSV isolates, the implications for PRRSV evolution, and the presence of multiple genetic lineages of Type 2 (North American genotype) isolates in Europe. In Type 1 (European genotype) PRRSV, three genetic subtypes are recognized and a fourth subtype appears to be present. Type 2 PRRSV was considered to be genetically homogenous in Europe due to a unique presence of an introduced vaccine strain, but independent introductions of virulent Type 2 field viruses are now evident. In Type 1 PRRSV, only subtype 1 (Lelystad virus-like) circulates in Central and Western Europe and globally. In Eastern Europe, all subtypes are present. The subtypes of Type 1 PRRSV also exhibit length differences in the nucleocapsid protein, ranging in size from 124 to 132 amino acids depending on subtype. This size heterogeneity is unparalleled in the nucleocapsid proteins of Type 2 PRRSV or other viruses. Surprisingly, it affects the C-terminus, otherwise thought to be under strong structural constraints. Finally, divergent subtypes of Type 1 PRRSV have produced high rates of false-negative RT-PCR results in diagnostic tests, and may also degrade the reliability of serodiagnostic assays using the nucleocapsid protein antigen. In summary, the extensive genetic diversity of Type 1 PRRSV is of relevance for understanding nucleocapsid protein structure/function relationships. Further, the extensive genetic diversity of Type 1 PRRSV in Europe, and the presence of diverse Type 2 PRRSV strains, together emphasize the importance of relevant validation of PRRSV diagnostics. More extensive and systematic molecular phylogeny studies are needed to fully understand PRRSV diversity in Europe, to provide swine producers with reliable diagnostics, and to better assess the potential consequences of endemic spread and exotic introductions.
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    • "Because of the polymorphism at position 1858, the prevalence of the G1896A mutation was found to be genotype-dependent (Table 3). Therefore, genotype A with C1858 rarely circulates as an HBeAg-negative mutant because 1896A would disrupt the preexisting C:G pair and impair HBV genome replication.28,29 When the G1896A mutation develops, a compensatory C1858T mutation has to occur to maintain base pairing. "
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    ABSTRACT: Hepatitis B virus (HBV) causes a chronic infection in 350 million people worldwide and greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. The majority of chronic HBV carriers live in Asia. HBV can be divided into eight genotypes with unique geographic distributions. Mutations accumulate during chronic infection or in response to external pressure. Because HBV is an RNA-DNA virus the emergence of drug resistance and vaccine escape mutants has become an important clinical and public health concern. Here, we provide an overview of the molecular biology of the HBV life cycle and an evaluation of the changing role of hepatitis B e antigen (HBeAg) at different stages of infection. The impact of viral genotypes and mutations/deletions in the precore, core promoter, preS, and S gene on the establishment of chronic infection, development of fulminant hepatitis and liver cancer is discussed. Because HBV is prone to mutations, the biological properties of drug-resistant and vaccine escape mutants are also explored.
    Full-text · Article · Mar 2013 · Emerging Microbes and Infections
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