Hepatitis B virus (HBV) is a non-cytopathic, hepatotropic virus with the potential to cause a persistent infection, ultimately leading to cirrhosis and hepatocellular carcinoma. Over the past four decades, the basic principles of HBV gene expression and replication as well as the viral and host determinants governing infection outcome have been largely uncovered. Whereas HBV appears to induce little or no innate immune activation, the adaptive immune response mediates both viral clearance as well as liver disease. Here, we review our current knowledge on the immunobiology and pathogenesis of HBV infection, focusing in particular on the role of CD8+ T cells and on several recent breakthroughs that challenge current dogmas. For example, we now trust that HBV integration into the host genome often serves as a relevant source of hepatitis B surface antigen (HBsAg) expression during chronic infection, possibly triggering dysfunctional T cell responses and favouring detrimental immunopathology. Further, the unique haemodynamics and anatomy of the liver — and the changes they frequently endure during disease progression to liver fibrosis and cirrhosis — profoundly influence T cell priming, differentiation and function. We also discuss why therapeutic approaches that limit the intrahepatic inflammatory processes triggered by HBV-specific T cells might be surprisingly beneficial for patients with chronic infection.
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The authors thank M. Silva for secretarial assistance, F. Andreata for help with figure preparation and the members of the Iannacone and Guidotti laboratories for helpful discussions. They apologize to all authors whose work they could not cite due to space constraints. M.I. is supported by the European Research Council (ERC) Consolidator Grant 725038, ERC Proof of Concept Grant 957502, Italian Association for Cancer Research (AIRC) Grants 19891 and 22737, Italian Ministry of Health (MoH) Grants RF-2018-12365801 and COVID-2020-12371617, Lombardy Foundation for Biomedical Research (FRRB) Grant 2015-0010, the European Molecular Biology Organization Young Investigator Program and a Funded Research Agreement from Gilead Sciences. L.G.G. is supported by the AIRC Grant 22737, Lombardy Open Innovation Grant 229452, PRIN Grant 2017MPCWPY from the Italian Ministry of Education, University and Research, and Funded Research Agreements from Gilead Sciences, Avalia Therapeutics and CNCCS SCARL.
M.I. participates in advisory boards/consultancies for Gilead Sciences, Roche, Third Rock Ventures, Amgen, Asher Bio and Allovir. L.G.G is a member of the board of directors at Genenta Science and Epsilon Bio and participates in advisory boards/consultancies for Gilead Sciences, Roche and Arbutus Biopharma. M.I. and L.G.G. are inventors on patents filed, owned and managed by San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Telethon Foundation on technology related to work discussed in this manuscript (WO2020/016434, WO2020/016427, WO2020/030781, WO2020/234483, EU patent applications n. 19211249.8 and n. 20156716.1, and UK patent application n. 1907493.9).
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The final stage of fibrosis in which fibrous septa surrounding nodules of regenerating hepatocytes induce profound architectural distortion of the liver and functional insufficiency.
A functional outcome of cross-presentation (the presentation of extracellular antigens on MHC class I molecules), whereby antigen-specific naive CD8+ T cells are activated by antigen-presenting cells to become effector cells.
- Checkpoint inhibitor therapy
A form of cancer immunotherapy targeting immune checkpoints (for example, PD1, CTLA4).
- SSB/La-dependent mechanism
T cell-induced cytokines such as IFNγ and TNF have been shown to induce the post-transcriptional downregulation of hepatitis B virus (HBV) RNAs in vivo. This process appears to rely on the degradation of the full-length SSB/La protein, which normally functions as a HBV RNA stabilizer in the nucleus of the hepatocyte.
- sALT values
The serum concentrations of the liver enzyme alanine aminotransferase. Commonly measured clinically as a biomarker for liver damage.
- Space of Disse
(Also referred to as perisinusoidal space). The space that lies between the hepatocytes and the sinusoids.
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Iannacone, M., Guidotti, L.G. Immunobiology and pathogenesis of hepatitis B virus infection. Nat Rev Immunol (2021). https://doi.org/10.1038/s41577-021-00549-4