Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: New perspectives for immune therapy

The hepatitis B virus (HBV) cytotoxic T lymphocyte (CTL) response in patien ts with chronic HBV infection is generally weak or totally undetectable. Th is inability to mount protective CTL responses is believed to be a crucial determinant of viral persistence, and its correction represents an importan t objective of immune therapies for chronic hepatitis B. However, amplifica tion of CTL responses in vivo may be ineffective if HBV-specific CD8 cells are either absent or nonresponsive to exogenous stimulation, In this study, we asked whether antiviral treatments able to inhibit viral replication an d to reduce viral and antigen load can successfully reconstitute CTL respon ses creating the appropriate conditions for their therapeutic stimulation. For this purpose, the HBV-specific CTL response before and during lamivudin e therapy was studied longitudinally in 6 HLA-A2-positive patients with HBe Ag+ chronic hepatitis B. Both HBV-specific cytotoxic T cell activity measur ed by chromium release assay on peptide stimulation in vitro and CD8+ T cel l frequency measured ex vivo by HLA-A2/peptide tetramer staining were signi ficantly augmented by lamivudine therapy, This enhancement followed the rec onstitution of CD4 reactivity and the decline of viral load induced by ther apy. Our study shows that lamivudine treatment in chronic hepatitis B can r estore CTL reactivity, making CTL susceptible to exogenous stimulation. Thi s effect may enhance the probability that T cell-based immune therapies del ivered after lamivudine treatment can successfully reconstitute a protectiv e CTL response able to cure chronic HBV infection.