Janine Kemming1, Swantje Gundlach2, Marcus Panning3, Daniela Huzly3, Jiabin Huang2, Marc Lütgehetmann2, Sven Pischke4, Julian Schulze Zur Wiesch5, Florian Emmerich6, Sian Llewellyn-Lacey7, David A Price8, Yakup Tanriver9, Klaus Warnatz10, Tobias Boettler11, Robert Thimme11, Maike Hofmann11, Nicole Fischer2, Christoph Neumann-Haefelin12. 1. Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. 2. Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany. 3. Institute of Virology, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 4. German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany; Institute of Virology, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 5. German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany; Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. 6. Institute for Transfusion Medicine and Gene Therapy, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 7. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom. 8. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom; Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom. 9. Department of Medicine IV (Nephrology and Primary Care), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 10. Department of Rheumatology and Clinical Immunology, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 11. Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 12. Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: christoph.neumann-haefelin@uniklinik-freiburg.de.
Abstract
BACKGROUND & AIMS: In immunosuppressed patients, persistent HEV infection is common and may lead to cirrhosis and liver failure. HEV clearance depends on an effective virus-specific CD8+ T-cell response; however, the knowledge gap around HEV-specific CD8+ T-cell epitopes has hindered analysis of the mechanisms of T-cell failure in persistent infection. METHODS: We comprehensively studied HEV-specific CD8+ T-cell responses in 46 patients with self-limiting (n = 34) or chronic HEV infection (n = 12), by epitope-specific expansion, functional testing, ex vivo peptide HLA class I tetramer multi-parametric staining, and viral sequence analysis. RESULTS: We identified 25 HEV-specific CD8+ T-cell epitopes restricted by 9 different HLA class I alleles. In self-limiting HEV infection, HEV-specific CD8+ T cells were vigorous, contracted after resolution of infection, and formed functional memory responses. In contrast, in chronic infection, the HEV-specific CD8+ T-cell response was diminished, declined over time, and displayed phenotypic features of exhaustion. However, improved proliferation of HEV-specific CD8+ T cells, increased interferon-γ production and evolution of a memory-like phenotype were observed upon reduction of immunosuppression and/or ribavirin treatment and were associated with viral clearance. In 1 patient, mutational viral escape in a targeted CD8+ T-cell epitope contributed to CD8+ T-cell failure. CONCLUSION: Chronic HEV infection is associated with HEV-specific CD8+ T-cell exhaustion, indicating that T-cell exhaustion driven by persisting antigen recognition also occurs in severely immunosuppressed hosts. Functional reinvigoration of virus-specific T cells is at least partially possible when antigen is cleared. In a minority of patients, viral escape also contributes to HEV-specific CD8+ T-cell failure and thus needs to be considered in personalized immunotherapeutic approaches. LAY SUMMARY: Hepatitis E virus (HEV) infection is usually cleared spontaneously (without treatment) in patients with fully functioning immune systems. In immunosuppressed patients, chronic HEV infection is common and can progress rapidly to cirrhosis and liver failure. Herein, we identified the presence of HEV-specific CD8+ T cells (a specific type of immune cell that can target HEV) in immunosuppressed patients, but we show that these cells do not function properly. This dysfunction appears to play a role in the development of chronic HEV infection in vulnerable patients.
BACKGROUND & AIMS: In immunosuppressed patients, persistent HEV infection is common and may lead to cirrhosis and liver failure. HEV clearance depends on an effective virus-specific CD8+ T-cell response; however, the knowledge gap around HEV-specific CD8+ T-cell epitopes has hindered analysis of the mechanisms of T-cell failure in persistent infection. METHODS: We comprehensively studied HEV-specific CD8+ T-cell responses in 46 patients with self-limiting (n = 34) or chronic HEV infection (n = 12), by epitope-specific expansion, functional testing, ex vivo peptide HLA class I tetramer multi-parametric staining, and viral sequence analysis. RESULTS: We identified 25 HEV-specific CD8+ T-cell epitopes restricted by 9 different HLA class I alleles. In self-limiting HEV infection, HEV-specific CD8+ T cells were vigorous, contracted after resolution of infection, and formed functional memory responses. In contrast, in chronic infection, the HEV-specific CD8+ T-cell response was diminished, declined over time, and displayed phenotypic features of exhaustion. However, improved proliferation of HEV-specific CD8+ T cells, increased interferon-γ production and evolution of a memory-like phenotype were observed upon reduction of immunosuppression and/or ribavirin treatment and were associated with viral clearance. In 1 patient, mutational viral escape in a targeted CD8+ T-cell epitope contributed to CD8+ T-cell failure. CONCLUSION: Chronic HEV infection is associated with HEV-specific CD8+ T-cell exhaustion, indicating that T-cell exhaustion driven by persisting antigen recognition also occurs in severely immunosuppressed hosts. Functional reinvigoration of virus-specific T cells is at least partially possible when antigen is cleared. In a minority of patients, viral escape also contributes to HEV-specific CD8+ T-cell failure and thus needs to be considered in personalized immunotherapeutic approaches. LAY SUMMARY: Hepatitis E virus (HEV) infection is usually cleared spontaneously (without treatment) in patients with fully functioning immune systems. In immunosuppressed patients, chronic HEV infection is common and can progress rapidly to cirrhosis and liver failure. Herein, we identified the presence of HEV-specific CD8+ T cells (a specific type of immune cell that can target HEV) in immunosuppressed patients, but we show that these cells do not function properly. This dysfunction appears to play a role in the development of chronic HEV infection in vulnerable patients.