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 HLAassociated polymorphisms involving likely known anchor residues that resulted in altered predicted binding scores. Some HLAassociated 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. G lobally, infection with hepatitis B virus (HBV) is common, and despite an effective vaccine, the number of persons with chronic HBV infection is increasing (9). Broad and effective HBVspecific T-cell responses are required to clear acute HBV infection (7, 37), but circulating HBV-specific T cells are rarely detected in chronic HBV infection (7,8). It is therefore unclear whether the adaptive immune response plays a role in controlling viral replication in chronic HBV infection and whether changes or adaptations in HBV are selected due to immune pressure.In individuals with chronic HBV infection, as many as 10 11 virus particles are produced per day (21, 30). HBV reverse transcriptase lacks proofreading activity, resulting in mutation rates estimated at 1.5 ϫ 10 Ϫ5 to 5 ϫ 10 Ϫ5 nucleotide substitutions per site per year in HBV e antigen (HBeAg)-positive individuals (32).Due to overlapping open reading frames (ORF), HBV genome evolution is constrained to maintain essential protein functions required for replication (28). There is some evidence that changes in HBV sequences can be selected due to host immune pressure (2,5,23) and that the HBV mutation rate is even higher in HBeAgnegative individuals (15, 33), possibly due to increased immune pressure prior to HBeAg loss (4, 10, 15) or due to higher levels of virus replication in the absence of HBeAg, given the known inhibitory effect of HBeAg on HBV replication at the level of n...

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