SLIDE 1
Impact of HBV sequence diversity on CD8+ T cell immunity
1
2
Stages of chonic HBV infection
« Inactive carrier » « tolerance »
serum HBV DNA [IU/ml]
102 103 106 107 108 109 104 105
HBeAg + Hepatitis B HBeAg - Hepatitis B
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 - - 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
SLIDE 2
SLIDE 3
3
therapy therapy
„STOP Nuke“
SLIDE 4
4
Adaptation of HBV to CD8 T cell selection pressure
Kefalakes et al., 2015, Hepatology
SLIDE 5
5
SeqFeatR
Budeus et al. PLoS One 2016, Kefalakes et al. Hepatology 2015
HLA-A*01 “HLA-footprint”
SLIDE 6
6
HBV cohort
n=320
62% 38%
HBeAg status
HBeAg negative (W28*) HBeAg positive
A D E C B
scale 0.01
SLIDE 7
7
Identification of novel CD8 T cell epitopes in HBV
SeqFeatR
HLA-A*68
10-8 10-7 10-6 10-5 10-4 10-3 10-2 10-1 100
p-value
50 100 150
position
SLIDE 8
8
HBV-D-17 HLA-A*68
negative control
0.071% 2.05%
STLPETTVVRR
CD8 IFN-γ
+ peptide + anti-CD28 + IL-2
PBMC
expansion
Identification of novel CD8 T cell epitopes in HBV
SLIDE 9
9
Novel HBV epitopes
polymerase
B*40 B*35
envelope
A*02
core
A*01 B*41 B*44 A*24 A*26 A*33 B*07 A*11 A*68 A*02 B*49 B*15 B*15 A*33
SLIDE 10
10
SeqFeatR analysis of HBV
Alignment position p-values
200 400 600 800 1000 1200 1400 10- 1 0 10- 9 10- 8 10- 7 10- 6 10- 5 10- 4 10- 3 10- 2 10- 1
A*01 A*11 A*32 B*49 A*68 B*41A*26 A*33 A*02 B*35 A*24 B*40 B*07
core polymerase envelope
B*15 A*33 B*15 n=189
SLIDE 11
11
The influence of sequence polymorphisms on clinical HBV parameters
SLIDE 12
12
Substitution frequency in HBeAg-negative and HBeAg- positive patients
relative frequency HBeAg- HBeAg+ HBeAg- HBeAg+ HBeAg+
0.0 0.2 0.4 0.6 0.8 1.0
HLA allele present HLA allele absent
**** *** ***
acute HBV
magnitude of HBVcore18-27 specific CD8 T cells frequency of escape mutations
HBeAg- HBeAg+ 1 2 3 4 10 20 30 40
**
% IFNγ+ CD8+ T cells
SLIDE 13
13
Correlation between HBV DNA concentration and number of HLA-footprints
number of HLA-footprints HBV DNA concentration [IU/ml]
1 ≥2 101 102 103 104 105 106 107 108 109 101 0
* ***
SLIDE 14
14
therapy therapy
„STOP Nuke“
SLIDE 15
15 Institute of Virology Düsseldorf Tatjana Schwarz Andreas Walker Janine Brinkmann Alexandra Graupner Christine Thöns Christopher Menne Eugen Bäcker Tina Senff Ramona Grothmann Wiebke Moskorz Institute for Transfusion Medicine, Essen Falko Heinemann Research Group Bioinformatics, Essen Daniel Hoffmann Department of Medicine Freiburg Robert Thimme Christoph Neumann-Häfelin Department of Gastroenterology, Hepatology and Endocrinology, Hannover Anke Kraft Markus Cornberg Department of Medicine Hamburg-Eppendorf Julian Schulze zur Wiesch Clinic for Gastroenterology, Hepatology and Infectious Diseases, Düsseldorf Verena Keitel-Anselmino Hans Bock Dieter Häussinger Massachusetts General Hospital, Boston USA. Georg Lauer