T cells, especially robust viral specific T cell responses are believed to play a critical role in the control of hepatitis B virus (HBV) replication and infection. However, in chronic hepatitis B (CHB)，T cell tolerance and exhaustion are driven by long-term intensive viral antigenic stimulation, andthe underlying mechanisms of the weak and impaired T cell activity in CHB remain largely undefined. Further understanding the molecular defects underlying T cell impairment in CHB will allow the development of new strategies for the establishment of immune therapeutic regimen by targeted reversal ofimpaired mechanisms.

A study from Dr. MENG Songdong’s group showed that miR-146a expression in T cells was significantly up-regulated in CHB compared with healthy controls. Stat1, a key transcriptional factor required for T cell effector activity, was identified as a miR-146a target that is involved in antiviral cytokines production and cytotoxic function of CD4+ and CD8+ T cells. Thus, miR-146a up-regulation in CHB contributes to intrinsic defects of T cell tolerance and exhaustion in CHB.

Interestingly, they also identified a novel epitope-generating mutation of L60V in HBV core protein (HBc). In contrast to most mutations employed by HBV to evade immune detection, HBcL60V mutation led to antiviral specific CTL responses both in transgenic mice and HBV-infected patients.

Further study showed that HBc L60V mutation enhances HBV replication by facilitating viral capsid assembly. These data reveal the impact of the HBc L60V mutation in the complex regulatory networks that orchestrate HBV replication, T-cell immune responses, and immunopathogenesis in chronic viral infections. As the HBc L60V mutation is correlated with dramatically higher viral and ALT levels, detection of the mutation will allow us to predict the progress of the liver diseasein CHB patients.

The above studies were published in Journal of Immunology and Journal of Virology, respectively.