Drivers of HCV evolution - lessons from a single source outbreak Jörg 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 2850 women between 8/1978 and 1/1979
Phylogenetic analysis of sequences from the Anti-D outbreak Patient Sequences after 30 years Sequences from patients and the source
What is the origin of the different clades in the source? Source of distinct clades?
Sequences of 4 immunoglobulin donors
IL28B Genotype – impact on outcome p<0.0001 p<0.0001 Tillmann et al. Gastroenterology. 2010
IL28B Genotype – impact on clinical presentation p=0.032 not C/C C/C Tillmann et al. Gastroenterology. 2010
HCV evolution in the Anti-D cohort 3% selected Y93H in NS5A!!
Adaptation of HCV to CD8 T-cell immune pressure B35 NS3 1359-1367 p=0.00074 35 % not consensus 30 25 B35 negative 20 B35 positive 15 10 5 0 H P N I E E V A L
Substitution rate – Inside vs. Outside known CD8 epitopes Substitution rate in the non-structural proteins NS3-NS5B non-synonymous synonymous Substitutions per codon Substitutions per codon p<0.001 inside outside inside outside Ruhl et al. Gastroenterology. 2010
Substitution rate – Inside vs. Outside known CD8 epitopes NS3/4A NS5B 3.6 fold 3.8 fold Substitutions per codon Substitutions per codon inside outside inside outside About 30% of the mutations in NS3 and NS5B are located inside previously described CD8 epitopes. Ruhl et al. Gastroenterology. 2010
Selection of a substitution that impairs antigen processing 25 S1368P % not consensus p=0.000016 20 15 B51 negative B51 positive 10 5 0 A L S T T G E I P F Y G K A I P L E B51 NS3 1373-1380 Walker et al., J Virol 2016
Did the HLA class I genotype impact clade selection upon transmission?
HLA-B*07 footprint in a novel CD8 T cell epitope
HLA-B*07 positive patients are preferentially infected by an escape variant in the epitope Sequence differences in Frequency of HLA-B*07 the infection source
Acknowledgment East-German HCV Study Group Manfred Wiese Berg T, Ende K, Frimmel S, Göbel U, Grüngreiff Hannelore Tenckhoff K, Güthoff W, Herrmann A, Konig I, Kullig U, Lafrenz M, Loebermann M, Meyer-Siegert E, Eckart Schreier Oesen U, Porst H, Schiefke I, Schmidt U, Helga Meisel Tenckhoff H, Walther T, Wollschläger S, Wiegand J, Wiese M, Zipprich A. Centre for Medical Biotechnology, Bioinformatics Daniel Hoffmann and Team Virology Essen/Düsseldorf Andreas Walker Marianne Ruhl Susanne Ziegler Sergei Viazov Michael Roggendorf
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