Immunopathogenesis of hepatitis B persistent infection: implications for immunotherapeutic strategies

It has been shown that cellular immunity, especially by cytotoxic T lymphocytes (CTLs), NK cells and NK-T cells, plays a central role in the control of virus infection. In addition, CD4+ T cells facilitate both CTL and B-cell responses. Hyporesponsiveness of HBV-specific T cells in peripheral blood has been shown in patients with chronic HBV infection. Interferon and nucleos(t)ide analogs, such as lamivudine, adefovir, entecavir and tenofovir, are the currently available treatments. Unfortunately, the efficacy of nucleos(t)ide analogs is limited by viral reactivation by the emergence of escaped mutants in cases of prolonged treatment. Therefore, immunotherapy is one of the significant options to eradicate or control HBV replication without drugs. The aim of immunotherapies is to decrease the levels of viral replication and to eradicate infected hepatocytes. For this reason, new strategies for immunotherapies by vaccination target not only the induction or stimulation of CD4+ and CD8+ T cell responses, but also the induction of proinflammatory cytokines capable of controlling viral replication. We will review the immunopathogenesis of persistent HBV infection, especially focusing on the mechanisms of immune suppression. Then we will review the immunotherapy for HBV persistent infection.