91
Views
0
CrossRef citations to date
0
Altmetric
Review

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

ORCID Icon, &
Pages 77-89 | Received 14 Nov 2023, Accepted 29 Jan 2024, Published online: 07 Feb 2024

References

  • Lampertico P, Agarwal K, Berg T, et al. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–398. doi: 10.1016/j.jhep.2017.03.021
  • Chen H-Y, Shen D-T, Ji D-Z, et al. Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis. Gut. 2019;68(3):512–521. doi: 10.1136/gutjnl-2018-316601
  • Miao Z, Zhang S, Ou X, et al. Estimating the global prevalence, disease progression, and clinical outcome of hepatitis delta virus infection. J Infect Dis. 2020;221(10):1677–1687. doi: 10.1093/infdis/jiz633
  • Stockdale AJ, Kreuels B, Henrion MYR, et al. The global prevalence of hepatitis D virus infection: systematic review and meta-analysis. J Hepatol. 2020;73(3):523–532. doi: 10.1016/j.jhep.2020.04.008
  • Pawlotsky J-M, Negro F, Aghemo A, et al. Clinical practice guidelines panel: chair: , EASL governing board representative: , et al. EASL recommendations on treatment of hepatitis C: final update of the series☆. J Hepatol. 2020;73(5):1170–1218. doi: 10.1016/j.jhep.2020.08.018
  • Dalton HR, Kamar N, Baylis SA, et al. EASL clinical practice guidelines on hepatitis E virus infection. J Hepatol. 2018;68(6):1256–1271. doi: 10.1016/j.jhep.2018.03.005
  • Im SJ, Hashimoto M, Gerner MY, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537(7620):417–421. doi: 10.1038/nature19330
  • Alfei F, Kanev K, Hofmann M, et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature. 2019;571(7764):265–269. doi: 10.1038/s41586-019-1326-9
  • Maini MK, Burton AR. Restoring, releasing or replacing adaptive immunity in chronic hepatitis B. Nat Rev Gastroenterol Hepatol. 2019;16(11):662–675. doi: 10.1038/s41575-019-0196-9
  • Garnelo M, Tan A, Her Z, et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut. 2017;66(2):342–351. doi: 10.1136/gutjnl-2015-310814
  • Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–1905. doi: 10.1056/NEJMoa1915745
  • Zhu AX, Abbas AR, de Galarreta MR, et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat Med. 2022;28(8):1599–1611. doi: 10.1038/s41591-022-01868-2
  • Sadelain M, Rivière I, Riddell S. Therapeutic T cell engineering. Nature. 2017;545(7655):423–431. doi: 10.1038/nature22395
  • Ghaffari S, Khalili N, Rezaei N. CRISPR/Cas9 revitalizes adoptive T-cell therapy for cancer immunotherapy. J Exp Clin Cancer Res CR. 2021;40(1):269. doi: 10.1186/s13046-021-02076-5
  • Legut M, Dolton G, Mian AA, et al. CRISPR-mediated TCR replacement generates superior anticancer transgenic T cells. Blood. 2018;131(3):311–322. doi: 10.1182/blood-2017-05-787598
  • Wieland S, Thimme R, Purcell RH, et al. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A. 2004;101(17):6669–6674. doi: 10.1073/pnas.0401771101
  • Suslov A, Boldanova T, Wang X, et al. Hepatitis B virus does not interfere with innate immune responses in the human liver. Gastroenterology. 2018;154(6):1778–1790. doi: 10.1053/j.gastro.2018.01.034
  • Thimme R, Wieland S, Steiger C, et al. CD8 + T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003;77(1):68–76. doi: 10.1128/JVI.77.1.68-76.2003
  • Boni C, Fisicaro P, Valdatta C, et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol. 2007;81(8):4215–4225. doi: 10.1128/JVI.02844-06
  • Maini MK, Boni C, Lee CK, et al. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med. 2000;191(8):1269–1280. doi: 10.1084/jem.191.8.1269
  • Tseng T-C, Liu C-J, Yang H-C, et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology. 2013;57(2):441–450. doi: 10.1002/hep.26041
  • Suslov A, Meier M-A, Ketterer S, et al. Transition to HBeAg-negative chronic hepatitis B virus infection is associated with reduced cccDNA transcriptional activity. J Hepatol. 2021;74(4):794–800. doi: 10.1016/j.jhep.2020.11.003
  • Heim K, Binder B, Null S, et al. TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection. Gut. 2020;70(8):1550–1560. doi: 10.1136/gutjnl-2020-322404
  • Schuch A, Salimi Alizei E, Heim K, et al. Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load. Gut. 2019;68(5):905–915. doi: 10.1136/gutjnl-2018-316641
  • Hoogeveen RC, Robidoux MP, Schwarz T, et al. Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection. Gut. 2019;68(5):893–904. doi: 10.1136/gutjnl-2018-316644
  • Winkler F, Hipp AV, Ramirez C, et al. Enolase represents a metabolic checkpoint controlling the differential exhaustion programmes of hepatitis virus-specific CD8+ T cells. Gut. 2023;72:1971–1984.
  • Le Bert N, Gill US, Hong M, et al. Effects of hepatitis B surface antigen on virus-specific and global T cells in patients with chronic hepatitis B virus infection. Gastroenterology. 2020;159(2):652–664. doi: 10.1053/j.gastro.2020.04.019
  • de Beijer MTA, Jansen DTSL, Dou Y, et al. Discovery and selection of hepatitis B virus-derived T cell epitopes for global immunotherapy based on viral indispensability, conservation, and HLA-Binding strength. J Virol. 2020;94(7):e01663–19. doi: 10.1128/JVI.01663-19
  • Zhao F, Xie X, Tan X, et al. The functions of hepatitis B virus encoding proteins: viral persistence and liver pathogenesis. Front Immunol. 2021;12:691766. doi: 10.3389/fimmu.2021.691766
  • Bénéchet AP, De Simone G, Di Lucia P, et al. Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming. Nature. 2019;574(7777):200–205. doi: 10.1038/s41586-019-1620-6
  • Rehermann B, Pasquinelli C, Mosier SM, et al. Hepatitis B virus (HBV) sequence variation of cytotoxic T lymphocyte epitopes is not common in patients with chronic HBV infection. J Clin Invest. 1995;96(3):1527–1534. doi: 10.1172/JCI118191
  • Locarnini S, Zoulim F. Molecular genetics of HBV infection. Antivir Ther. 2010;15(Suppl 3):3–14. doi: 10.3851/IMP1619
  • Desmond CP, Gaudieri S, James IR, et al. Viral adaptation to host immune responses occurs in chronic hepatitis B virus (HBV) infection, and adaptation is greatest in HBV e antigen-negative disease. J Virol. 2012;86(2):1181–1192. doi: 10.1128/JVI.05308-11
  • Kefalakes H, Budeus B, Walker A, et al. Adaptation of the hepatitis B virus core protein to CD8(+) T-cell selection pressure. Hepatology. 2015;62(1):47–56. doi: 10.1002/hep.27771
  • Walker A, Schwarz T, Brinkmann-Paulukat J, et al. Immune escape pathways from the HBV core18-27 CD8 T cell response are driven by individual HLA class I alleles. Front Immunol. 2022;13:1045498. doi: 10.3389/fimmu.2022.1045498
  • Dusheiko G, Agarwal K, Maini MK, et al. New approaches to chronic hepatitis B. N Engl J Med. 2023;388(1):55–69. doi: 10.1056/NEJMra2211764
  • Cavenaugh JS, Awi D, Mendy M, et al. Partially randomized, non-blinded trial of DNA and MVA therapeutic vaccines based on hepatitis B virus surface protein for chronic HBV infection. PLoS One. 2011;6(2):e14626. doi: 10.1371/journal.pone.0014626
  • Zoulim F, Fournier C, Habersetzer F, et al. Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial. Hum Vaccines Immunother. 2020;16(2):388–399. doi: 10.1080/21645515.2019.1651141
  • Boni C, Janssen HLA, Rossi M, et al. Combined GS-4774 and tenofovir therapy can improve HBV-Specific T-Cell responses in patients with chronic hepatitis. Gastroenterology. 2019;157(1):227–241.e7. doi: 10.1053/j.gastro.2019.03.044
  • Fontaine H, Kahi S, Chazallon C, et al. Anti-HBV DNA vaccination does not prevent relapse after discontinuation of analogues in the treatment of chronic hepatitis B: a randomised trial—ANRS HB02 VAC-ADN. Gut. 2015;64(1):139–147. doi: 10.1136/gutjnl-2013-305707
  • Xu D-Z, Wang X-Y, Shen X-L, et al. Results of a phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings. J Hepatol. 2013;59(3):450–456. doi: 10.1016/j.jhep.2013.05.003
  • Al Mahtab M, Akbar SMF, Aguilar JC, et al. Treatment of chronic hepatitis B naïve patients with a therapeutic vaccine containing HBs and HBc antigens (a randomized, open and treatment controlled phase III clinical trial). PLoS One. 2018;13(8):e0201236. doi: 10.1371/journal.pone.0201236
  • Al Mahtab M, Akbar SMF, Aguilar JC, et al. Safety profile, antiviral capacity, and liver protection of a nasal therapeutic vaccine in patients with chronic hepatitis B: five-year-follow-up outcomes after the end of treatment. Front Med. 2023;10:1032531. doi: 10.3389/fmed.2023.1032531
  • Fisicaro P, Valdatta C, Massari M, et al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology. 2010;138(2):682–693, 693.e1–4. doi: 10.1053/j.gastro.2009.09.052
  • Schurich A, Khanna P, Lopes AR, et al. Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-prone CD8 T cells in persistent hepatitis B virus infection. Hepatology. 2011;53(5):1494–1503. doi: 10.1002/hep.24249
  • Raziorrouh B, Schraut W, Gerlach T, et al. The immunoregulatory role of CD244 in chronic hepatitis B infection and its inhibitory potential on virus-specific CD8+ T-cell function. Hepatology. 2010;52(6):1934–1947. doi: 10.1002/hep.23936
  • Bengsch B, Martin B, Thimme R. Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. J Hepatol. 2014;61(6):1212–1219. doi: 10.1016/j.jhep.2014.07.005
  • Bengsch B, Ohtani T, Khan O, et al. Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells. Immunity. 2018;48(5):1029–1045.e5. doi: 10.1016/j.immuni.2018.04.026
  • Utzschneider DT, Legat A, Fuertes Marraco SA, et al. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat Immunol. 2013;14(6):603–610. doi: 10.1038/ni.2606
  • Utzschneider DT, Delpoux A, Wieland D, et al. Active maintenance of T cell memory in acute and chronic viral infection depends on continuous expression of FOXO1. Cell Rep. 2018;22(13):3454–3467. doi: 10.1016/j.celrep.2018.03.020
  • Gane E, Verdon DJ, Brooks AE, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study. J Hepatol. 2019;71(5):900–907. doi: 10.1016/j.jhep.2019.06.028
  • Acerbi G, Montali I, Ferrigno GD, et al. Functional reconstitution of HBV-specific CD8 T cells by in vitro polyphenol treatment in chronic hepatitis B. J Hepatol. 2021;74(4):783–793. doi: 10.1016/j.jhep.2020.10.034
  • Fisicaro P, Barili V, Montanini B, et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat Med. 2017;23(3):327–336. doi: 10.1038/nm.4275
  • Schmidt NM, Wing PAC, Diniz MO, et al. Targeting human acyl-CoA: cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint. Nat Commun. 2021;12(1):2814. doi: 10.1038/s41467-021-22967-7
  • Yl F, Sn Z, H W, et al. Metabolic interventions improve HBV envelope-specific T-cell responses in patients with chronic hepatitis B. Hepatol Int. 2023;17. Internet [cited 2024 Jan 8]. Available from: https://pubmed.ncbi.nlm.nih.gov/36976426/
  • Rossi M, Vecchi A, Tiezzi C, et al. Phenotypic CD8 T cell profiling in chronic hepatitis B to predict HBV-specific CD8 T cell susceptibility to functional restoration in vitro. Gut. 2023;72(11):2123–2137. doi: 10.1136/gutjnl-2022-327202
  • Gehring AJ, Xue S-A, Ho ZZ, et al. Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. J Hepatol. 2011;55(1):103–110. doi: 10.1016/j.jhep.2010.10.025
  • Bohne F, Chmielewski M, Ebert G, et al. T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes. Gastroenterology. 2008;134(1):239–247. doi: 10.1053/j.gastro.2007.11.002
  • Krebs K, Böttinger N, Huang L-R, et al. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology. 2013;145(2):456–465. doi: 10.1053/j.gastro.2013.04.047
  • Wisskirchen K, Kah J, Malo A, et al. T cell receptor grafting allows virological control of hepatitis B virus infection. J Clin Invest. 2019;129(7):2932–2945. doi: 10.1172/JCI120228
  • Kah J, Koh S, Volz T, et al. Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection. J Clin Invest. 2017;127(8):3177–3188. doi: 10.1172/JCI93024
  • Koh S, Kah J, Tham CYL, et al. Nonlytic lymphocytes engineered to express virus-specific T-Cell receptors limit HBV infection by activating APOBEC3. Gastroenterology. 2018;155(1):180–193.e6. doi: 10.1053/j.gastro.2018.03.027
  • Otano I, Escors D, Schurich A, et al. Molecular recalibration of PD-1+ antigen-specific T cells from blood and liver. Mol Ther J Am Soc Gene Ther. 2018;26(11):2553–2566. doi: 10.1016/j.ymthe.2018.08.013
  • Qasim W, Brunetto M, Gehring AJ, et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J Hepatol. 2015;62(2):486–491. doi: 10.1016/j.jhep.2014.10.001
  • Tan AT, Yang N, Lee Krishnamoorthy T, et al. Use of expression profiles of HBV-DNA integrated into genomes of hepatocellular carcinoma cells to select T cells for immunotherapy. Gastroenterology. 2019;156(6):1862–1876.e9. doi: 10.1053/j.gastro.2019.01.251
  • Meng F, Zhao J, Tan AT, et al. Immunotherapy of HBV-related advanced hepatocellular carcinoma with short-term HBV-specific TCR expressed T cells: results of dose escalation, phase I trial. Hepatol Int. 2021;15(6):1402–1412. doi: 10.1007/s12072-021-10250-2
  • Giersch K, Allweiss L, Volz T, et al. Hepatitis delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection. J Hepatol. 2015;63(2):346–353. doi: 10.1016/j.jhep.2015.03.011
  • Zhang Z, Filzmayer C, Ni Y, et al. Hepatitis D virus replication is sensed by MDA5 and induces IFN-β/λ responses in hepatocytes. J Hepatol. 2018;69(1):25–35. doi: 10.1016/j.jhep.2018.02.021
  • Landahl J, Bockmann JH, Scheurich C, et al. Detection of a broad range of low-level major histocompatibility complex class II–restricted, hepatitis delta virus (HDV)–specific T-Cell responses regardless of clinical status. J Infect Dis. 2019;219(4):568–577. doi: 10.1093/infdis/jiy549
  • Kefalakes H, Koh C, Sidney J, et al. Hepatitis D virus-specific CD8+ T cells have a memory-like phenotype associated with viral immune escape in patients with chronic hepatitis D virus infection. Gastroenterology. 2019;156(6):1805–1819.e9. doi: 10.1053/j.gastro.2019.01.035
  • Karimzadeh H, Kiraithe MM, Oberhardt V, et al. Mutations in hepatitis D virus allow it to escape detection by CD8+ T cells and evolve at the population level. Gastroenterology. 2019;156(6):1820–1833. doi: 10.1053/j.gastro.2019.02.003
  • Karimzadeh H, Kiraithe MM, Kosinska AD, et al. Amino acid substitutions within HLA-B*27-restricted T cell epitopes prevent recognition by hepatitis delta virus-specific CD8+ T cells. J Virol. 2018;92(13):e01891–17. doi: 10.1128/JVI.01891-17
  • Salimi Alizei E, Hofmann M, Thimme R, et al. Mutational escape from cellular immunity in viral hepatitis: variations on a theme. Curr Opin Virol. 2021;50:110–118. doi: 10.1016/j.coviro.2021.08.002
  • Wedemeyer H, Aleman S, Brunetto MR, et al. A phase 3, randomized trial of bulevirtide in chronic hepatitis D. N Engl J Med. 2023;389(1):22–32. doi: 10.1056/NEJMoa2213429
  • Hsu Y-C, Suri V, Nguyen MH, et al. Inhibition of viral replication reduces transcriptionally active distinct hepatitis B virus integrations with implications on host gene dysregulation. Gastroenterology. 2022;162(4):1160–1170.e1. doi: 10.1053/j.gastro.2021.12.286
  • Maravelia P, Frelin L, Ni Y, et al. Blocking entry of hepatitis B and D viruses to hepatocytes as a novel immunotherapy for treating chronic infections. J Infect Dis. 2021;223(1):128–138. doi: 10.1093/infdis/jiaa036
  • Burm R, Maravelia P, Ahlen G, et al. Novel prime-boost immune-based therapy inhibiting both hepatitis B and D virus infections. Gut. 2023;72(6):1186–1195. doi: 10.1136/gutjnl-2022-327216
  • Lempp FA, Volz T, Cameroni E, et al. Potent broadly neutralizing antibody VIR-3434 controls hepatitis B and D virus infection and reduces HBsAg in humanized mice. J Hepatol. 2023;79(5):1129–1138. doi: 10.1016/j.jhep.2023.07.003
  • Tham CYL, Kah J, Tan AT, et al. Hepatitis delta virus acts as an immunogenic adjuvant in hepatitis B virus-infected hepatocytes. Cell Rep Med. 2020;1(4):100060. doi: 10.1016/j.xcrm.2020.100060
  • Schirdewahn T, Grabowski J, Owusu Sekyere S, et al. The third signal cytokine interleukin 12 rather than immune checkpoint inhibitors contributes to the functional restoration of hepatitis D virus-specific T cells. J Infect Dis. 2017;215:139–149. doi: 10.1093/infdis/jiw514
  • Bigger CB, Brasky KM, Lanford RE. DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J Virol. 2001;75(15):7059–7066. doi: 10.1128/JVI.75.15.7059-7066.2001
  • Colasanti O, Burm R, Huang H-E, et al. Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation. J Hepatol. 2023;79(3):645–656. doi: 10.1016/j.jhep.2023.04.023
  • Thimme R, Bukh J, Spangenberg HC, et al. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci U S A. 2002;99(24):15661–15668. doi: 10.1073/pnas.202608299
  • Shoukry NH, Grakoui A, Houghton M, et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med. 2003;197(12):1645–1655. doi: 10.1084/jem.20030239
  • Thimme R, Oldach D, Chang KM, et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med. 2001;194(10):1395–1406. doi: 10.1084/jem.194.10.1395
  • Bengsch B, Seigel B, Ruhl M, et al. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog. 2010;6(6):e1000947. doi: 10.1371/journal.ppat.1000947
  • Rutebemberwa A, Ray SC, Astemborski J, et al. High-programmed death-1 levels on hepatitis C virus-specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection. J Immunol Baltim Md 1950. 2008;181(12):8215–8225. doi: 10.4049/jimmunol.181.12.8215
  • Cox AL, Mosbruger T, Mao Q, et al. Cellular immune selection with hepatitis C virus persistence in humans. J Exp Med. 2005;201(11):1741–1752. doi: 10.1084/jem.20050121
  • Neumann-Haefelin C, Frick DN, Wang JJ, et al. Analysis of the evolutionary forces in an immunodominant CD8 epitope in hepatitis C virus at a population level. J Virol. 2008;82(7):3438–3451. doi: 10.1128/JVI.01700-07
  • Erickson AL, Kimura Y, Igarashi S, et al. The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity. 2001;15(6):883–895. doi: 10.1016/S1074-7613(01)00245-X
  • Kasprowicz V, Kang Y-H, Lucas M, et al. Hepatitis C virus (HCV) sequence variation induces an HCV-specific T-cell phenotype analogous to spontaneous resolution. J Virol. 2010;84(3):1656–1663. doi: 10.1128/JVI.01499-09
  • Martinello M, Solomon SS, Terrault NA, et al. Hepatitis C. Lancet Lond Engl. 2023;402:1085–1096. doi: 10.1016/S0140-6736(23)01320-X
  • Wang W, Wang Y, Qu C, et al. The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response. Hepatology. 2018;67(6):2096–2112. doi: 10.1002/hep.29702
  • Bremer W, Blasczyk H, Yin X, et al. Resolution of hepatitis E virus infection in CD8+ T cell-depleted rhesus macaques. J Hepatol. 2021;75(3):557–564. doi: 10.1016/j.jhep.2021.04.036
  • Suneetha PV, Pischke S, Schlaphoff V, et al. Hepatitis E virus (HEV)-specific T-cell responses are associated with control of HEV infection. Hepatology. 2012;55(3):695–708. doi: 10.1002/hep.24738
  • Al-Ayoubi J, Behrendt P, Bremer B, et al. Hepatitis E virus ORF 1 induces proliferative and functional T-cell responses in patients with ongoing and resolved hepatitis E. Liver Int Off J Int Assoc Study Liver. 2018;38(2):266–277. doi: 10.1111/liv.13521
  • Kemming J, Gundlach S, Panning M, et al. Mechanisms of CD8+ T-cell failure in chronic hepatitis E virus infection. J Hepatol. 2022;77(4):978–990. doi: 10.1016/j.jhep.2022.05.019
  • Brown A, Halliday JS, Swadling L, et al. Characterization of the specificity, functionality, and durability of host T-Cell responses against the full-length hepatitis E virus. Hepatology. 2016;64(6):1934–1950. doi: 10.1002/hep.28819
  • Kamar N, Selves J, Mansuy J-M, et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med. 2008;358(8):811–817. doi: 10.1056/NEJMoa0706992
  • Soon CF, Behrendt P, Todt D, et al. Defining virus-specific CD8+ TCR repertoires for therapeutic regeneration of T cells against chronic hepatitis E. J Hepatol. 2019;71(4):673–684. doi: 10.1016/j.jhep.2019.06.005
  • Sangro B, Chan SL, Meyer T, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol. 2020;72(2):320–341. doi: 10.1016/j.jhep.2019.10.021
  • Silva DN, Chrobok M, Rovesti G, et al. Process development for adoptive cell therapy in academia: a pipeline for clinical-scale manufacturing of multiple TCR-T cell products. Front Immunol. 2022;13:896242. doi: 10.3389/fimmu.2022.896242

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.