"Dinucleotide-pattern" G→A Hypermutations in the pre-Core 5′-GGGG Tetrad of HBeAg Negative Variants of Hepatitis B Virus

Mohammad Khalid Parvez

Abstract


The natural G→A substitutions in the HBV pre-Core gene with HBeAg negative phenotype is implicated in the chronic hepatitis and disease severity. Liver ‘apolipoprotein B mRNA-editing enzymecatalytic polypeptide-like (APOBEC)’ protein mediated G→A "mononucleotide" hypermutations have been reported in HBV pre-Core gene that prefer 5’GGGG tetrad substrate, as an antiviral-innate immune mechanism. The pre-Core nucleotide sequence analysis of twelve HBe negative viral isolates from chronic hepatitis B patients, showed classical G1896A mutations in 3 samples. Of these, one viral sequence showed an additional G1897A substitution, representing a ‘dinucleotide-pattern’ hypermutation resulting in pre-Core stop codon (UGG→UAA) in the 5’GGGG tetrad. In another sample, a second G1899A substitution was also identified in the same tetrad stretch, but in the next codon (UGGGGC→UAGGAC). These results therefore, suggest that the pre-C 5’GGGG stretch appears as a favorable spot for ‘dinucleotide-pattern’ G→A hypermutation that could have been introduced by APOBEC enzyme(s) in HBe negative HBV variants.

Keywords


Hepatitis B virus; HBV; Pre-Core; HBe negative; G →A hypermutations

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