title: Selection pressure on the hepatitis B virus pre-S/S and P open reading frames in Tongan subjects with a chronic hepatitis B virus infection.
abstract: Identification of the full repertoire of hepatitis B virus (HBV) peptides that are presented to CD8+ T cells by common HLA class I alleles will be useful for designing immunotherapies for chronic hepatitis B. One hundred and seventy five cloned sequences containing the pre-S/S and P open reading frames (ORF) of the HBV were obtained from serum HBV-DNA of HBeAg-positive (n=4) and HBeAg-negative (inactive healthy carriers (IHC), n=16) Tongan subjects with an inactive chronic HBV infection. In addition, 34 and 32 sequences were obtained 5.2±1.4 (mean±SD) years apart from eight subjects. PAML was used to identify codons in the pre-S/S and P ORFs that were under positive selection pressure (ω>1). The number of non-synonymous substitutions in these codons was compared in IHC who were homozygous for either HLA-B∗4001 (n=9) or HLA-B*5602 (n=7), and who were either positive (n=6) or negative (n=10) for HLA-A*02. 34 codons in the pre-S/S and 11 codons in the P ORFs were under positive selection pressure. There was a higher number of non-synonymous substitutions in these codons in HBeAg-negative versus HBeAg-positive subjects in the P (p=0.02) but not the pre-S/S (p=0.64) ORF. There was no association between any HLA class I allele and non-synonymous substitutions in these codons. There was no increase in positive selection pressure on the pre-S/S and P ORFs with time. In conclusion, we could not find HLA class I-restricted selection pressure on any pre-S/S or P ORF amino acid; raising the possibility that peptide-based immunotherapies for chronic hepatitis B may not require peptides from these ORFs.
authors.affiliation: The New Zealand Liver Transplant Unit, Auckland City Hospital, Private Bag 92-024, Auckland, New Zealand. wabbott@adhb.govt.nz
authors.forename: William G H
authors.initials: WG
authors.lastname: Abbott
authors.forename: Peter
authors.initials: P
authors.lastname: Tsai
authors.forename: Howard A
authors.initials: HA
authors.lastname: Ross
authors.forename: Malakai
authors.initials: M
authors.lastname: 'Ofanoa
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Trevarton
authors.forename: John
authors.initials: J
authors.lastname: Hornell
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Munn
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D015684:Gene Products, pol / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D020125:Mutation, Missense; D016366:Open Reading Frames; D012641:Selection, Genetic; D044967:Serum / Q000821:virology; D014759:Viral Envelope Proteins / Q000235:genetics*
chemical_list: D015684:Gene Products, pol; D015395:Histocompatibility Antigens Class I; C066027:P protein, Hepatitis B virus; C118669:S envelope protein, hepatitis B virus; D014759:Viral Envelope Proteins