Vincent Mallet1, Julie Bruneau2, Julien Zuber3, Cécile Alanio4, Stéphanie Leclerc-Mercier5, Anne-Marie Roque-Afonso6, Anke R M Kraft7, Lucile Couronné8, Dominique Roulot9, Heiner Wedemeyer7, Matthew L Albert10, Patrick Hillon11, Liliane Laroche12, Stanislas Pol13, Olivier Hermine8. 1. Université Paris Descartes-Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Cochin - Port Royal, Hepatology Service, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 1223, Institut Pasteur, Paris, France. Electronic address: vincent.mallet@aphp.fr. 2. Université Paris Descartes-Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker - Enfants Malades, Pathology Department, Paris, France; Institut National de la Santé et de la Recherche Médicale Unité 1163, Centre National de la Recherche Scientifique, Equipes de Recherche Labellisées 8254, Institut Imagine, Paris, France. 3. Université Paris Descartes-Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker - Enfants Malades, Renal Transplantation Service, Paris, France. 4. Institut National de la Santé et de la Recherche Médicale, Unité 1223, Institut Pasteur, Paris, France; Immunobiology of Dendritic Cells Unit, Institut Pasteur, Paris, France. 5. Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker - Enfants Malades, Pathology Department, Paris, France. 6. Université Paris-Sud, Orsay, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Virology Department, Hôpital Paul Brousse, Villejuif, France; Institut National de la Santé et de la Recherche Médicale Unite, Unite 1193, Villejuif, France. 7. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School; German Center for Infection Research (DZIF), Hannover, Germany. 8. Université Paris Descartes-Sorbonne Paris Cité, Paris, France; Institut National de la Santé et de la Recherche Médicale Unité 1163, Centre National de la Recherche Scientifique, Equipes de Recherche Labellisées 8254, Institut Imagine, Paris, France; Assistance Publique-Hopitaux de Paris (AP-HP), Hôpital Necker - Enfants Malades, Haematology Service, Paris, France. 9. Assistance Publique-Hopitaux de Paris (AP-HP), Hôpital Avicenne, Hepatology Service, Bobigny, France. 10. Institut National de la Santé et de la Recherche Médicale, Unité 1223, Institut Pasteur, Paris, France; Immunobiology of Dendritic Cells Unit, Institut Pasteur, Paris, France; Department of Cancer Immunology, Genentech, South San Francisco, CA, USA. 11. Université Bourgogne Franche-Comté, Dijon, France; Hôpîtal Le Bocage, Hepatology and Gastroenterology Service, Dijon, France. 12. Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Avicenne, Department of Dermatology, Bobigny, France. 13. Université Paris Descartes-Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Cochin - Port Royal, Hepatology Service, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 1223, Institut Pasteur, Paris, France.
Abstract
BACKGROUND & AIM: Several types of unexplained extra-hepatic manifestations, including haematological disorders, have been reported in the context of hepatitis E virus (HEV) infection. However, the underlying mechanism(s) of these manifestations are unknown. We provide evidence that HEV has an extra-hepatic endothelial tropism that can engage cutaneous T cells towards clonality. METHODS: A patient with a CD30(+) cutaneous T cell lymphoproliferative disorder (T-LPD) and biopsy-proven chronic HEV infection received three rounds of oral ribavirin treatment, administered either without or with interferon, and eventually achieved a sustained virologic response (SVR). Pathologic, virologic and immunologic investigations were carried out on biopsied skin lesion, and peripheral blood mononuclear cells between the 2nd and 3rd round of antiviral treatment and biopsied liver. RESULTS: Remission of T-LPD was observed upon antiviral treatment, and the patient remained in complete remission after achieving SVR. The T cell analysis showed large CD30(+) lymphocytes surrounding the blood vessels within the CD8(+) T cell infiltrate. HEV was detected within dermal microvascular endothelial cells using immunofluorescence staining, in situ hybridisation and electron microscopy. Infiltrating T cells mostly comprised memory CD8(+) T cells with a tissue-resident memory T cell phenotype. Overall, 98% of extracted T cells were CD8(+) T cells with aVβ signature skewed towards Vβ4 and with an oligoclonal profile. T cell clones from T-LPD were more like T cells in the liver than T cells in the blood [odds ratio=4.55, (3.70-5.60), p<0.0001]. No somatic mutations were found in the T-LPD exomes. CONCLUSION: HEV has an extra-hepatic tissue tropism in humans, including dermal endothelium, and can induce CD30(+) T-LPD that is sensitive to antivirals. LAY SUMMARY: Hepatitis E virus (HEV) has an extra-hepatic tissue tropism and should be added to the list of viruses associated with lymphoproliferative disorders. As such, HEV should be part of the laboratory workup of any lymphoproliferation, particularly those of the T cell phenotype that involve the skin. In the context of HEV-associated cutaneous T cell lymphoproliferative disorders, antiviral treatment could be considered a first-line treatment instead of chemotherapy.
BACKGROUND & AIM: Several types of unexplained extra-hepatic manifestations, including haematological disorders, have been reported in the context of hepatitis E virus (HEV) infection. However, the underlying mechanism(s) of these manifestations are unknown. We provide evidence that HEV has an extra-hepatic endothelial tropism that can engage cutaneous T cells towards clonality. METHODS: A patient with a CD30(+) cutaneous T cell lymphoproliferative disorder (T-LPD) and biopsy-proven chronic HEV infection received three rounds of oral ribavirin treatment, administered either without or with interferon, and eventually achieved a sustained virologic response (SVR). Pathologic, virologic and immunologic investigations were carried out on biopsied skin lesion, and peripheral blood mononuclear cells between the 2nd and 3rd round of antiviral treatment and biopsied liver. RESULTS: Remission of T-LPD was observed upon antiviral treatment, and the patient remained in complete remission after achieving SVR. The T cell analysis showed large CD30(+) lymphocytes surrounding the blood vessels within the CD8(+) T cell infiltrate. HEV was detected within dermal microvascular endothelial cells using immunofluorescence staining, in situ hybridisation and electron microscopy. Infiltrating T cells mostly comprised memory CD8(+) T cells with a tissue-resident memory T cell phenotype. Overall, 98% of extracted T cells were CD8(+) T cells with aVβ signature skewed towards Vβ4 and with an oligoclonal profile. T cell clones from T-LPD were more like T cells in the liver than T cells in the blood [odds ratio=4.55, (3.70-5.60), p<0.0001]. No somatic mutations were found in the T-LPD exomes. CONCLUSION:HEV has an extra-hepatic tissue tropism in humans, including dermal endothelium, and can induce CD30(+) T-LPD that is sensitive to antivirals. LAY SUMMARY:Hepatitis E virus (HEV) has an extra-hepatic tissue tropism and should be added to the list of viruses associated with lymphoproliferative disorders. As such, HEV should be part of the laboratory workup of any lymphoproliferation, particularly those of the T cell phenotype that involve the skin. In the context of HEV-associated cutaneous T cell lymphoproliferative disorders, antiviral treatment could be considered a first-line treatment instead of chemotherapy.
Authors: Thomas Horvatits; Julian Schulze Zur Wiesch; Marc Lütgehetmann; Ansgar W Lohse; Sven Pischke Journal: Viruses Date: 2019-07-05 Impact factor: 5.048