Impact of HBV sequence diversity on CD8 + T cell immunity 1 Stages - PowerPoint PPT Presentation

Impact of HBV sequence diversity on CD8 + T cell immunity 1

Stages of chonic HBV infection HBeAg positive HBeAg negative 10 9 serum HBV DNA [IU/ml] 10 8 W28* mutation « tolerance » 10 7 HBeAg - HBeAg + 10 6 Hepatitis B Hepatitis B 10 5 10 4 10 3 « Inactive carrier » 10 2 2

„STOP Nuke“ therapy therapy 3

Adaptation of HBV to CD8 T cell selection pressure 4 Kefalakes et al., 2015, Hepatology

HLA-A*01 SeqFeatR “HLA-footprint” 5 Budeus et al. PLoS One 2016, Kefalakes et al. Hepatology 2015

HBV cohort n=320 HBeAg status E A 38% D 62% B HBeAg negative (W28*) HBeAg positive C scale 0.01 6

Identification of novel CD8 T cell epitopes in HBV 10 -8 HLA-A*68 10 -7 10 -6 10 -5 p-value SeqFeatR 10 -4 10 -3 10 -2 10 -1 10 0 0 50 100 150 position 7

Identification of novel CD8 T cell epitopes in HBV + peptide + anti-CD28 expansion + IL-2 PBMC negative control STLPETTVVRR 0.071% 2.05% HBV-D-17 HLA-A*68 CD8 IFN- γ 8

Novel HBV epitopes B*49 A*02 B*41 B*15 A*33 B*15 A*11 A*68 B*35 B*40 A*01 B*44 A*33 A*24 A*26 B*07 core polymerase envelope A*02 9

SeqFeatR analysis of HBV 10 - 1 0 core polymerase envelope A*01 10 - 9 A*11 A*32 10 - 8 B*49 10 - 7 A*68 p-values 10 - 6 B*41A*26 A*24 A*33 10 - 5 B*35 B*15 A*02 10 - 4 A*33 B*40 B*07 B*15 10 - 3 10 - 2 10 - 1 0 200 400 600 800 1000 1200 1400 Alignment position n=189 10

The influence of sequence polymorphisms on clinical HBV parameters 11

Substitution frequency in HBeAg-negative and HBeAg- positive patients magnitude of HBVcore 18-27 frequency of escape mutations specific CD8 T cells **** ** *** *** 40 1.0 30 % IFN γ + CD8 + T cells 20 relative frequency 0.8 10 4 0.6 3 0.4 2 0.2 1 0 0.0 HBeAg- HBeAg+ HBeAg- HBeAg+ HBeAg- HBeAg+ HBeAg+ acute HLA allele HLA allele HBV present absent 12

Correlation between HBV DNA concentration and number of HLA-footprints *** HBV DNA concentration [IU/ml] 10 1 0 * 10 9 10 8 10 7 10 6 10 5 10 4 10 3 10 2 10 1 ≥ 2 0 1 number of HLA-footprints 13

„STOP Nuke“ therapy therapy 14

Acknowledgment Institute of Virology Düsseldorf Tatjana Schwarz Andreas Walker Janine Brinkmann Alexandra Graupner Christine Thöns Christopher Menne Eugen Bäcker Tina Senff Ramona Grothmann Wiebke Moskorz Department of Medicine Clinic for Gastroenterology, Hepatology Hamburg-Eppendorf and Infectious Diseases, Düsseldorf Research Group Bioinformatics, Julian Schulze zur Wiesch Verena Keitel-Anselmino Essen Hans Bock Daniel Hoffmann Massachusetts General Hospital, Dieter Häussinger Boston USA. Department of Gastroenterology, Georg Lauer Institute for Transfusion Medicine, Hepatology and Endocrinology, Essen Hannover Department of Medicine Falko Heinemann Anke Kraft Freiburg Markus Cornberg Robert Thimme Christoph Neumann-Häfelin 15