HBV Shows Different Levels of Adaptation to HLA Class I-associated Selection Pressure Correlating with Markers of Replication

BACKGROUND & AIMS:Immune responses by CD8 T cells are essential for control of HBV replication. Although selection of escape mutations in CD8 T-cell epitopes has previously been described in HBV infection, its overall influence on HBV sequence diversity and correlation with markers of HBV replication remain unclear. METHODS:Whole-genome sequencing was applied to HBV isolates from 532 patients with chronic HBV infection and high-resolution HLA class I genotyping. Using a Bayesian model (HAMdetector) for identification of HLA-associated mutational states (HAMs), the frequency and location of residues under CD8 T-cell selection pressure were determined and the levels of adaptation of individual isolates were quantified. RESULTS:Using previously published thresholds for the identification of HAMs, a total of 295 residues showed evidence of CD8 T-cell escape, the majority of which were located in previously unidentified epitopes. Interestingly, HAMs were highly enriched in the HBV core protein compared to all other proteins. When individual HBV isolates were compared, different levels of adaptation to HLA class I immune pressure were noted. The level of adaptation increased with patient age and correlated with markers of replication, with low levels of adaptation in HBeAg-positive infection. Furthermore, the levels of adaptation negatively correlated with HBV viral load and HBsAg levels, consistent with high levels of HLA class I-associated selection pressure in patients with low replication levels. CONCLUSIONS:HBV sequence diversity is shaped by HLA class I-associated selection pressure with the HBV core protein being a predominant target of selection. Importantly, different levels of adaptation to immune pressure were observed between HBV infection stages, which need to be considered in the context of T-cell-based therapies. IMPACT AND IMPLICATIONS:The immune response mediated by CD8 T cells plays a critical role in controlling HBV infection and shows promise for therapeutic strategies aimed at achieving a functional cure. This study demonstrates that mutational escape within CD8 T-cell epitopes is common in HBV and represents a key factor in the failure of immune control. Notably, the HBV core protein emerges as the primary target of CD8 T-cell selection pressure. Additionally, the observed correlation between HBV adaptation levels and viral replication markers indicates that CD8 T-cell immunity may influence transitions between phases of chronic HBV infection.