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Drivers of HCV evolution
- lessons from a single source outbreak
Drivers of HCV evolution - lessons from a single source outbreak - - PowerPoint PPT Presentation
Drivers of HCV evolution - lessons from a single source outbreak - - PowerPoint PPT Presentation
Drivers of HCV evolution - lessons from a single source outbreak Jrg Timm AREVIR 2017 What is the East-German Anti-D cohort? "Anti-D" November 1977 acute HCV?? Source February 1978 March 1978 Infusion of contaminated IgG to
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Phylogenetic analysis of sequences from the Anti-D outbreak
Patient Sequences after 30 years Sequences from patients and the source
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Source of distinct clades? What is the origin of the different clades in the source?
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Sequences of 4 immunoglobulin donors
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p<0.0001 p<0.0001
IL28B Genotype – impact on outcome
Tillmann et al. Gastroenterology. 2010
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IL28B Genotype – impact on clinical presentation
Tillmann et al. Gastroenterology. 2010
C/C not C/C
p=0.032
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HCV evolution in the Anti-D cohort
3% selected Y93H in NS5A!!
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Adaptation of HCV to CD8 T-cell immune pressure
5 10 15 20 25 30 35
H P N I E E V A L
B35 negative B35 positive
p=0.00074
% not consensus
B35 NS31359-1367
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synonymous non-synonymous
p<0.001
inside
- utside
inside
- utside
Substitution rate in the non-structural proteins NS3-NS5B
Ruhl et al. Gastroenterology. 2010
Substitution rate – Inside vs. Outside known CD8 epitopes
Substitutions per codon Substitutions per codon
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NS3/4A NS5B
3.8 fold
inside
- utside
inside
- utside
3.6 fold
About 30% of the mutations in NS3 and NS5B are located inside previously described CD8 epitopes.
Substitution rate – Inside vs. Outside known CD8 epitopes
Substitutions per codon Substitutions per codon Ruhl et al. Gastroenterology. 2010
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5 10 15 20 25
A L S T T G E I P F Y G K A I P L E
B51 negative B51 positive
% not consensus
p=0.000016
B51 NS31373-1380 S1368P
Selection of a substitution that impairs antigen processing
Walker et al., J Virol 2016
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Did the HLA class I genotype impact clade selection upon transmission?
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HLA-B*07 footprint in a novel CD8 T cell epitope
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HLA-B*07 positive patients are preferentially infected by an escape variant in the epitope
Sequence differences in the infection source Frequency of HLA-B*07
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