Source Department of Gastroenterology, The Alfred, Melbourne, Australia.

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 unclear if 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 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 was undertaken in treatment-naïve individuals (52% genotype B, 48% genotype C, 63% 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 binding scores between peptides containing these polymorphisms and associated HLA types. Of the regions able to be tested, HLA binding was predicted for 14/18 (78%). We identified several HLA-associated polymorphisms that involved likely known anchor residues which 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=.003). Thus, HBV appears to be under immune pressure in chronic HBV infection, particularly in HBeAg-negative disease.