Focus on Dysregulated Adaptive Immunity in Chronic Hepatitis B: A Promising Direction for Immunotherapy

Abstract Hepatitis B virus (HBV) infection is a public health problem that endangers global health and is the leading cause for the occurrence and death due to hepatocellular carcinoma. Although nucleotide analogs are excellent in controlling virus replication, they have little effect on the production, stability, and transcription of covalently closed circular DNA (cccDNA) in infected hepatocytes. Moreover, only a small fraction of patients with chronic hepatitis B are cured by interferon therapy. During HBV infection, HBV-specific B cells and T cells are produced. HBV-specific T cells exert antiviral effects through cell lysis and non-cytolytic effector functions, reducing viral intermediates and cccDNA. In addition, HBV-specific B cells produce antibodies that eliminate HBV-infected liver cells through antibody-dependent cell-mediated cytotoxicity of natural killer cells. They can also bind to the hepatitis B surface antigen on the surface of the virus particle, inducing antibody-dependent phagocytosis by Kupffer cells. These responses could be combined with immunotherapy based on antiviral therapy, which may achieve a complete cure for hepatitis B. However, patients with chronic hepatitis B have immune dysfunctions, which challenges immunotherapy implementation. This review focuses on advances in adaptive immunotherapy for chronic viral hepatitis B.