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Hepatitis B virus genotype A rarely circulates as an HBe-minus mutant: Possible contribution of a single nucleotide in the precore region

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: 4.65). 10/1993; 67(9):5402-10.
Source: PubMed

ABSTRACT 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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    • "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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    • "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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