title: Viral adaptation to host immune responses occurs in chronic hepatitis B virus (HBV) infection, and adaptation is greatest in HBV e antigen-negative disease.
abstract: Hepatitis B virus (HBV)-specific T-cell responses are important in the natural history of HBV infection. The number of known HBV-specific T-cell epitopes is limited, and it is not clear whether viral evolution occurs in chronic HBV infection. We aimed to identify novel HBV T-cell epitopes by examining the relationship between HBV sequence variation and the human leukocyte antigen (HLA) type in a large prospective clinic-based cohort of Asian patients with chronic HBV infection recruited in Australia and China (n = 119). High-resolution 4-digit HLA class I and II typing and full-length HBV sequencing were undertaken for treatment-naïve individuals (52% with genotype B, 48% with genotype C, 63% HBV e antigen [HBeAg] positive). Statistically significant associations between HLA types and HBV sequence variation were identified (n = 49) at 41 sites in the HBV genome. Using prediction programs, we determined scores for binding between peptides containing these polymorphisms and associated HLA types. Among the regions that could be tested, HLA binding was predicted for 14/18 (78%). We identified several HLA-associated polymorphisms involving likely known anchor residues that resulted in altered predicted binding scores. Some HLA-associated polymorphisms fell within known T-cell epitopes with matching HLA restriction. Enhanced viral adaptation (defined as the presence of the relevant HLA and the escaped amino acid) was independently associated with HBeAg-negative disease (P = 0.003). Thus, HBV appears to be under immune pressure in chronic HBV infection, particularly in HBeAg-negative disease.
authors.affiliation: Department of Gastroenterology, The Alfred, Melbourne, Australia.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Desmond
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaudieri
authors.forename: Ian R
authors.initials: IR
authors.lastname: James
authors.forename: Katja
authors.initials: K
authors.lastname: Pfafferott
authors.forename: Abha
authors.initials: A
authors.lastname: Chopra
authors.forename: George K
authors.initials: GK
authors.lastname: Lau
authors.forename: Jennifer
authors.initials: J
authors.lastname: Audsley
authors.forename: Caroline
authors.initials: C
authors.lastname: Day
authors.forename: Sarah
authors.initials: S
authors.lastname: Chivers
authors.forename: Adam
authors.initials: A
authors.lastname: Gordon
authors.forename: Peter A
authors.initials: PA
authors.lastname: Revill
authors.forename: Scott
authors.initials: S
authors.lastname: Bowden
authors.forename: Anna
authors.initials: A
authors.lastname: Ayres
authors.forename: Paul V
authors.initials: PV
authors.lastname: Desmond
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Roberts
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Locarnini
authors.forename: Simon A
authors.initials: SA
authors.lastname: Mallal
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
mesh_terms: D000220:Adaptation, Biological; D000595:Amino Acid Sequence; D001315:Australia; D002681:China; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology*; D006513:Hepatitis B e Antigens / Q000097:blood* / Q000235:genetics / Q000276:immunology; D006515:Hepatitis B virus / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D011110:Polymorphism, Genetic; D011446:Prospective Studies
chemical_list: D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D006513:Hepatitis B e Antigens
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