TP02: Virus-specific CD8+ T cell responses in hepatitis B/D virus co-infection: mechanisms of failure and strategies for restoration

In the current funding period, we demonstrated that HDAg-specific CD8+ T cells can be partially restored during bulevirtide (BLV) therapy. However, in the majority of patients, HDV has evaded from the HDAg-specific CD8+ T cell response by escape mutations within the targeted T cell epitopes. The absence of functional HDAg-specific CD8+ T cells targeting conserved viral epitopes thus helps to explain why BLV mono-therapy does not induce sustained virus elimination in the majority of patients. In the next funding period, we aim to define the role of immunity in the context of novel treatment strategies that aim at HBV and HDV cure. Immune cells that are less or not prone to viral escape will be of special interest (e.g. CD8+ T cells targeting HBsAg; CD4+ T cells; NK cells and MAIT cells).

Dr. Hendrik Luxenburger

Prof. Dr. Christoph Neumann-Haefelin

Urban S*, Neumann-Haefelin C*, Lampertico P. (2021) Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease. Gut. 70(9):1782-1794. doi: 10.1136/gutjnl-2020-323888.

Anolli MP, Degasperi E, Allweiss L, Sangiovanni A, Maggioni M, Scholtes C, Oberhardt V, Neumann-Haefelin C, Dandri M, Zoulim F, Lampertico P. (2023) A 3-year course of bulevirtide monotherapy may cure HDV infection in cirrhotics. J Hepatol. 78(4): 876-880. doi: 10.1016/j.jhep.2022.12.023.

Karimzadeh H, Kiraithe MM, Kosinska AD, Glaser M, Fiedler M, Oberhardt V, Salimi Alizei E, Hofmann M, Mok JY, Nguyen M, van Esch WJE, Budeus B, Grabowski J, Homs M, Olivero A, Keyvani H, Rodríguez-Frías F, Tabernero D, Buti M, Heinold A, Alavian SM, Bauer T, Schulze Zur Wiesch J, Raziorrouh B, Hoffmann D, Smedile A, Rizzetto M, Wedemeyer H, Timm J, Antes I, Neumann-Haefelin C, Protzer U, Roggendorf M. (2018) Amino acid substitutions within HLA-B*27-restricted T cell epitopes prevent recognition by hepatitis delta virus-specific CD8+ T cells. J Virol. 92:e01891-17. doi: 10.1128/JVI.01891-17.

Karimzadeh H*, Kiraithe MM*, Oberhardt V*, Salimi Alizei E, Bockmann J, Schulze Zur Wiesch J, Budeus B, Hoffmann D, Wedemeyer H, Cornberg M, Krawczyk A, Rashidi-Alavijeh J, Rodríguez-Frías F, Casillas R, Buti M, Smedile A, Alavian SM, Heinold A, Emmerich F, Panning M, Gostick E, Price DA, Timm J, Hofmann M, Raziorrouh B, Thimme R, Protzer U, Roggendorf M*, Neumann-Haefelin C*. (2019) Mutations in hepatitis D virus allow it to escape detection by CD8+ T cells and evolve at the population level. Gastroenterology. 156(6):1820-1833. doi: 10.1053/j.gastro.2019.02.003.

Oberhardt V, Hofmann M, Thimme R, Neumann-Haefelin C. (2022) Adaptive immune responses, immune escape and immune-mediated pathogenesis during HDV infection. Viruses. 14(2):198. doi: 10.3390/v14020198.

Kohsar M, Landahl J, Neumann-Haefelin C*, Schulze Zur Wiesch J*. (2021) Human hepatitis D virus-specific T cell epitopes. JHEP Rep. 3(4):100294. doi: 10.1016/j.jhepr.2021.100294.

Schulien I*, Kemming J*, Oberhardt V*, Wild K*, Seidel LM*, Killmer S, Sagar, Daul F, Salvat Lago M, Decker A, Luxenburger H, Binder B, Bettinger D, Sogukpinar O, Rieg S, Panning M, Huzly D, Schwemmle M, Kochs G, Waller CF, Nieters A, Duerschmied D, Emmerich F, Mei HE, Schulz AR, Llewellyn-Lacey S, Price DA, Boettler T*, Bengsch B*, Thimme R*, Hofmann M*, Neumann-Haefelin C*. (2021) Characterization of pre-existing and induced SARS-CoV-2-specific CD8+ T cells. Nat Med. 27(1):78-85. doi: 10.1038/s41591-020-01143-2.

Oberhardt V*, Luxenburger H*, Kemming J*, Schulien I*, Ciminski K*, Giese S*, Csernalabics B, Lang-Meli J, Janowska I, Staniek J, Wild K, Basho K, Marinescu MS, Fuchs J, Topfstedt F, Janda A, Sogukpinar O, Hilger H, Stete K, Emmerich F, Bengsch B, Waller CF, Rieg S, Sagar, Boettler T, Zoldan K, Kochs G, Schwemmle M, Rizzi M, Thimme R*, Neumann-Haefelin C*, Hofmann M*. (2021) Rapid and stable mobilization of CD8+ T cells by SARS-CoV-2 mRNA vaccine. Nature. 597(7875):268-273. doi: 10.1038/s41586-021-03841-4.

Lang-Meli J*, Luxenburger H*, Wild K, Karl V, Oberhardt V, Salimi Alizei E, Graeser A, Reinscheid M, Roehlen N, Reeg DB, Giese S, Ciminski K, Götz V, August D, Rieg S, Waller CF, Wengenmayer T, Staudacher D, Huzly D, Bengsch B, Kochs G, Schwemmle M, Emmerich F, Boettler T, Thimme R*, Hofmann M*, Neumann-Haefelin C*. (2022) SARS-CoV-2-specific T-cell epitope repertoire in convalescent and mRNA- vaccinated individuals. Nat Microbiol. 7(5):675-679. doi: 10.1038/s41564-022-01106-y.

Luxenburger H*, Reeg DB*, Lang-Meli J*, Reinscheid M, Eisner M, Bettinger D, Oberhardt V, Salimi Alizei E, Wild K, Graeser A, Karl V, Sagar, Emmerich F, Klein F, Panning M, Huzly D, Bengsch B, Boettler T, Elling R, Thimme R*, Hofmann M*, Neumann-Haefelin C*. (2023) Boosting compromised SARS-CoV-2-specific immunity with mRNA vaccination in liver transplant recipients. J Hepatol. 78(5):1017-1027. doi: 10.1016/j.jhep.2023.02.007.

Project in detail +

Hepatitis B virus (HBV)/hepatitis D virus (HDV) co-infection leads to cirrhosis within 5-10 years in 50% of patients. The only available treatment options for HBV/HDV co-infection are pegylated interferon-alfa (pegIFN) and the HBV/HDV entry inhibitor bulevirtide (BLV) that has been approved in the EU in 2023. PegIFN induces sustained response in 3 years is most likely required and sustained response rates are not yet defined. In our preliminary results of the current funding period, we demonstrated that BLV therapy is able to partially restore exhausted HDV antigen (HDAg)-specific CD8+ T cell responses, with a shift from a terminally exhausted to a memory-like T cell phenotype. However, in the majority of patients, HDV has evaded from the HDAg-specific CD8+ T cell response by escape mutations within the targeted CD8+ T cell epitopes. These results explain why BLV treatment cannot be stopped after viral suppression, because in the absence of functional HDAg-specific CD8+ T cells targeting con-served viral epitopes, viral relapse is inevitable. New treatment options thus need to
1) more effectively restore HDAg-specific CD8+ T cells,
2) restore CD8+ T cells targeting HBsAg, another antigen included in the HDV virion that is less prone to viral escape, and/or
3) target immune cells that are not affected by viral escape mutations such as CD4+ T cells (that are more promiscuous in epitope targeting, limiting viral escape), NK cells or MAIT cells.

In this funding period, we aim to define the fate and role of HDAg- versus HBsAg-specific CD8+ T cells in novel treatments of chronically infected patients aiming at HBV and HDV cure, such as combination treatment with BLV + pegIFN or REP-2139 (a nucleic acid polymer inhibiting assembly and secretion of HBV subviral particles) + pegIFN. Importantly, at our Gerok Liver Center in Freiburg, we treat patients with BLV alone (n=5, further recruitment ongoing) or with the combination of BLV + pegIFN (n=5, further recruitment ongoing). In addition, we treat one patient with failure of BLV + pegIFN with the combination of REP-2139 with pegIFN as compassionate use. These pa-tients are followed closely, including plasma and PBMC collection. In addition, we obtain patient samples through collaborations with Pietro Lampertico (Milano) and the French REP-2139 compassionate use program. To define the immunological correlates of HBV and HDV cure, we will ana-lyse HDAg- and HBsAg-specific CD8+ T cells by high dimensional cytometry, low input/ single cell RNAseq (with Hofmann, Thimme and Z03), and metabolic analysis (with Bengsch). These studies will be complemented by intrahepatic analyses from liver biopsies and fine-needle aspirates (with Urban/Nkongolo, Z02 and Z03). In addition, we will address the interplay with other innate (e.g., NK cells with Cerwenka; MAIT cells with Böttcher) and adaptive (e.g., CD4+ T cells with Böttler) immune cells in patients eliminating HBV and HDV under these antiviral treatments.
Taken together, these studies will clarify if novel treat-ment options require innate and/or adaptive immunity targeting HDAg and/or HBsAg in order to achieve sustained virological response and thus, cure of chronic HBV and HDV infection.