Sequence Variation Upstream of Precore Translation Initiation Codon Reduces Hepatitis B Virus e Antigen Production

SangHoon Ahn, Anna Kramvis, Shigenobu Kawai, Hans Christian Spangenberg, Jisu Li, Gerald Kimbi, Michael Kew, Jack Wands, Shuping Tong

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Most South African hepatitis B virus strains harbor point mutations immediately upstream of the precore AUG codon. The aim of this study was to determine their effect on hepatitis B e antigen expression. Methods: The hepatitis B virus DNA sequence around the precore region was determined from sera of 45 black South Africans. The South African mutations were introduced into hepatitis B virus dimers of the same genotype, and hepatitis B e antigen was quantified from culture medium of transfected HepG2 or Huh7 cells. Results: The South African sequence changes were easily detectable in the acute, hepatitis B e antigen-positive phase of infection, suggesting that they were stable traits and were not selected by immune pressure. Triple mutations at the -5, -3, and -2 positions of the AUG codon severely impaired hepatitis B e antigen expression (P < 0.001). The frequent double mutation at the -5 and -2 positions moderately reduced hepatitis B e antigen levels (P < 0.001) to an extent comparable to that of the common core promoter mutations (1762T1764A). The presence of both South African and core promoter mutations diminished hepatitis B e antigen expression in an additive manner. It is interesting to note that the triple South African mutations enabled core protein translation from precore messenger RNA, which could rescue the replication defect of a hepatitis B virus genome with an ablated core gene. Conclusions: We have identified a novel class of hepatitis B e antigen variants with reduced hepatitis B e antigen translation by a ribosomal leaky scanning mechanism. Reduction in hepatitis B e antigen expression may contribute to accelerated seroconversion from hepatitis B e antigen to its antibody in black South Africans infected with hepatitis B virus very early in life.

Original languageEnglish
Pages (from-to)1370-1378
Number of pages9
JournalGastroenterology
Volume125
Issue number5
DOIs
Publication statusPublished - 2003 Jan 1

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Hepatitis B e Antigens
Initiator Codon
Hepatitis B virus
Mutation
Codon
Protein Biosynthesis
Point Mutation
Culture Media
Genotype
Genome
Pressure
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Ahn, SangHoon ; Kramvis, Anna ; Kawai, Shigenobu ; Spangenberg, Hans Christian ; Li, Jisu ; Kimbi, Gerald ; Kew, Michael ; Wands, Jack ; Tong, Shuping. / Sequence Variation Upstream of Precore Translation Initiation Codon Reduces Hepatitis B Virus e Antigen Production. In: Gastroenterology. 2003 ; Vol. 125, No. 5. pp. 1370-1378.
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abstract = "Background & Aims: Most South African hepatitis B virus strains harbor point mutations immediately upstream of the precore AUG codon. The aim of this study was to determine their effect on hepatitis B e antigen expression. Methods: The hepatitis B virus DNA sequence around the precore region was determined from sera of 45 black South Africans. The South African mutations were introduced into hepatitis B virus dimers of the same genotype, and hepatitis B e antigen was quantified from culture medium of transfected HepG2 or Huh7 cells. Results: The South African sequence changes were easily detectable in the acute, hepatitis B e antigen-positive phase of infection, suggesting that they were stable traits and were not selected by immune pressure. Triple mutations at the -5, -3, and -2 positions of the AUG codon severely impaired hepatitis B e antigen expression (P < 0.001). The frequent double mutation at the -5 and -2 positions moderately reduced hepatitis B e antigen levels (P < 0.001) to an extent comparable to that of the common core promoter mutations (1762T1764A). The presence of both South African and core promoter mutations diminished hepatitis B e antigen expression in an additive manner. It is interesting to note that the triple South African mutations enabled core protein translation from precore messenger RNA, which could rescue the replication defect of a hepatitis B virus genome with an ablated core gene. Conclusions: We have identified a novel class of hepatitis B e antigen variants with reduced hepatitis B e antigen translation by a ribosomal leaky scanning mechanism. Reduction in hepatitis B e antigen expression may contribute to accelerated seroconversion from hepatitis B e antigen to its antibody in black South Africans infected with hepatitis B virus very early in life.",
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Ahn, S, Kramvis, A, Kawai, S, Spangenberg, HC, Li, J, Kimbi, G, Kew, M, Wands, J & Tong, S 2003, 'Sequence Variation Upstream of Precore Translation Initiation Codon Reduces Hepatitis B Virus e Antigen Production', Gastroenterology, vol. 125, no. 5, pp. 1370-1378. https://doi.org/10.1016/j.gastro.2003.07.016

Sequence Variation Upstream of Precore Translation Initiation Codon Reduces Hepatitis B Virus e Antigen Production. / Ahn, SangHoon; Kramvis, Anna; Kawai, Shigenobu; Spangenberg, Hans Christian; Li, Jisu; Kimbi, Gerald; Kew, Michael; Wands, Jack; Tong, Shuping.

In: Gastroenterology, Vol. 125, No. 5, 01.01.2003, p. 1370-1378.

Research output: Contribution to journalArticle

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T1 - Sequence Variation Upstream of Precore Translation Initiation Codon Reduces Hepatitis B Virus e Antigen Production

AU - Ahn, SangHoon

AU - Kramvis, Anna

AU - Kawai, Shigenobu

AU - Spangenberg, Hans Christian

AU - Li, Jisu

AU - Kimbi, Gerald

AU - Kew, Michael

AU - Wands, Jack

AU - Tong, Shuping

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N2 - Background & Aims: Most South African hepatitis B virus strains harbor point mutations immediately upstream of the precore AUG codon. The aim of this study was to determine their effect on hepatitis B e antigen expression. Methods: The hepatitis B virus DNA sequence around the precore region was determined from sera of 45 black South Africans. The South African mutations were introduced into hepatitis B virus dimers of the same genotype, and hepatitis B e antigen was quantified from culture medium of transfected HepG2 or Huh7 cells. Results: The South African sequence changes were easily detectable in the acute, hepatitis B e antigen-positive phase of infection, suggesting that they were stable traits and were not selected by immune pressure. Triple mutations at the -5, -3, and -2 positions of the AUG codon severely impaired hepatitis B e antigen expression (P < 0.001). The frequent double mutation at the -5 and -2 positions moderately reduced hepatitis B e antigen levels (P < 0.001) to an extent comparable to that of the common core promoter mutations (1762T1764A). The presence of both South African and core promoter mutations diminished hepatitis B e antigen expression in an additive manner. It is interesting to note that the triple South African mutations enabled core protein translation from precore messenger RNA, which could rescue the replication defect of a hepatitis B virus genome with an ablated core gene. Conclusions: We have identified a novel class of hepatitis B e antigen variants with reduced hepatitis B e antigen translation by a ribosomal leaky scanning mechanism. Reduction in hepatitis B e antigen expression may contribute to accelerated seroconversion from hepatitis B e antigen to its antibody in black South Africans infected with hepatitis B virus very early in life.

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