Targeting virus-specific CD8+ T cells for treatment of chronic viral hepatitis: from bench to bedside

ABSTRACT

Introduction

More than 350 million people worldwide live with chronic viral hepatitis and are thus at risk for severe complications like liver cirrhosis and hepatocellular carcinoma (HCC). To meet the goals of the World Health Organization (WHO) global hepatitis strategy, there is an urgent need for new immunotherapeutic approaches. These are particularly required for chronic hepatitis B virus infection and – B/D coinfection.

Areas covered

This review summarizes data on mechanisms of CD8+ T cells failure in chronic hepatitis B, D, C and E virus infection. The relative contribution of the different concepts (viral escape, CD8+ T cell exhaustion, defective priming) will be discussed. On this basis, examples for future therapeutic approaches targeting virus-specific CD8+ T cells for the individual hepatitis viruses will be discussed

Expert opinion

Immunotherapeutic approaches targeting virus-specific CD8+ T cells have the potential to change clinical practice, especially in chronic hepatitis B virus infection. Further clinical development, however, requires a more detailed understanding of T cell immunology in chronic viral hepatitis. Some important conceptual questions remain to be addressed, e.g. regarding heterogeneity of exhausted virus-specific CD8+ T cells.

Plain Language Summary

Chronic viral hepatitis is a global health issue with an urgent need for new therapeutic approaches. Cytotoxic T killer cells (virus-specific CD8+ T cells) are key players in mediating control of viral hepatitis, and chronic infection is associated with dysfunction of these cells. Therefore, reconstitution of virus-specific CD8+ T cells by immunotherapy is an interesting therapeutic approach for chronic viral hepatitis. In this review, we will compare data on different mechanisms contributing to CD8+ T cell dysfunction in chronic hepatitis B, C, D, and E virus infection, respectively. Furthermore, preclinical and clinical studies for the individual hepatitis viruses will be discussed.

KEYWORDS:

• Viral hepatitis
• CD8+ T cell
• hepatitis B
• T cell exhaustion
• immunotherapy

Article highlights

• CD8+ T cells are central for control and clearance of viral hepatitis.

• Chronic viral hepatitis is associated with dysfunction of virus-specific CD8+ T cells, mediated mainly by CD8+ T cell exhaustion, viral escape and defective priming.

• The relative contribution of different mechanisms that cause virus-specific CD8+ T cell dysfunction varies between the different hepatitis viruses (B, C, D and E).

• A growing body of preclinical and early clinical data addresses the urgent need for new immunotherapeutic approaches, especially for treatment of chronic HBV infection.

• Major challenges for immunotherapeutic approaches to treat chronic viral hepatitis include heterogeneity of virus-specific CD8+ T cell failure and pragmatic obstacles (e.g. safety concerns, costs).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A peer reviewer on this manuscript has received an honorarium from Expert Opinion on Biological Therapy for their review work. The reviewers have no other relevant financial relationships to disclose.

Acknowledgments

We thank all members of the Thimme/Hofmann/Neumann-Haefelin lab for fruitful discussions. Figures were created with BioRender.com

Additional information

Funding

This paper was funded by the Deutsche Forschungsgemeinschaft (nos. 256073931 and 272983813, IMM Pact stipend project number 413517907) and the Else Kröner Memorialstipendium (2023_EKMS.17).