Metabolic Reprogramming and CD8⁺ T-Cell Exhaustion During Chronic HBV Infection

HBV is an enveloped DNA virus that exclusively infects hepatocytes of humans and some non-human primates. During its viral life cycle, HBV and its structural components can directly regulate the metabolism of hepatocytes, which may reshape the liver immune microenvironment. CD8⁺ T-cells, well known as cytotoxic T lymphocytes for their antiviral immunity, can undergo metabolic reprogramming during chronic HBV infection. Increasing evidence demonstrates that metabolic reprogramming promotes T-cell exhaustion, which is a hallmark of HBV infection. Additionally, complicated metabolites (e.g., glucose, lipids, amino acids and nucleic acids) secreted from hepatocytes or T-cells contribute to the communication between these two cell types, which may facilitate HBV infection and hinder antiviral immune response. In recent years, supplementation of certain specific metabolic substrates or targeting metabolic enzyme genes has been reported to mitigate HBV replication and induce antiviral immune response, holding promise as effective strategies for curing chronic HBV infection. This review provides a thorough overview of recent advances in the metabolic characteristics of hepatocytes and T-cells during HBV infection, discusses the relationship between CD8⁺ T-cell exhaustion and metabolic reprogramming, and emphasises the therapeutic potential of metabolic approaches in the HBV clinical landscape.