Exploiting the immunopathogenesis of hepatitis D virus infection to develop superior immunotherapeutic treatment options

The hepatitis D virus (HDV) is a defective RNA virus dependent on the hepatitis B virus (HBV) for its envelopment and spread. HDV infection causes the most severe form of chronic viral hepatitis, often progressing to end-stage liver disease, such as liver cirrhosis and hepatocellular carcinoma, in a much faster manner compared to other viral liver infections. It is accepted, that the inability of T cells to clear the virus leads to the establishment of chronic infection, and there is evidence that this rapid progression to advanced liver disease is immune-mediated. Therapeutic options remain limited with the entry inhibitor bulevirtide and the off-label use of pegylated interferon, with the former still not available in all parts of the world. This review aims to summarize current knowledge on HDV-mediated immunopathogenesis and highlight treatment strategies from an immunological perspective. This will allow to identify the most promising therapeutic approaches to achieve HDV control. • Immunopathogenesis of HDV infection is incompletely understood on a mechanistic level. • Therapies targeting the HDV replication cycle are challenging, as HDV exploits host enzymes for its propagation. • Several therapies are undergoing clinical trials, showing promising results, especially when used in combinatorial approaches. • Vaccination strategies against HDV infection need to identify the optimal approach to overcome exhaustion of chronic infection. • T-cell therapeutics and vaccines hold the potential to achieve superior adaptive immunity.