HOW TO HIT THEM ALL IN ONE BLOW

Transcription

1 HOW TO HIT THEM ALL IN ONE BLOW

2 HCV

3 THE DISEASE More than 4 million Americans (1.3% of the U.S. population) and 170 million individuals in the world (3% worldwide) are infected with hepatitis C virus The prevalence of hepatitis C virus in Scandinavia is less than 0.5% of the population, whereas the prevalence in Egypt is over 20% 85% of individuals initially infected with this virus will become chronically infected Chronic hepatitis C virus infection causes an inflammation of the liver called chronic hepatitis. This condition can progress to scarring of the liver, called fibrosis, or more advanced scarring, called cirrhosis. Some patients with cirrhosis will go on to develop liver failure or the complications of cirrhosis, including liver cancer.

4 HCV GENOTYPES

5 THE GENOME

6 GENOTYPE VARIATION

7 HCV GENOTYPE DISTRIBUTION

8 HCV IS HIGHLY VARIABLE

9 GENOTYPE VARIATION de Oliveira et al., Nature 444, (14 December 2006) HIV-1 CRF02_AG (a), HCV genotype 4 (b) and HCV genotype 1 (c)

10 EPITOPE SELECTION FOR MAXIMAL STRAIN COVERAGE Use high performing Epitope predictions to predict potential epitopes for all supertypes Select top scoring peptides Use EpiSelect tool for maximal strain coverage

11 EPISELECT - GENOCOVER Top Scoring Peptides Genotype 1 Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Select peptide with maximal coverage Select peptide with maximal coverage preferring uncovered strains Select peptide with maximal coverage preferring lowest covered strains Repeat until the desired number of peptides is selected

12 Peptides Peptide Predicted affinity (nm) Genome Coverage Genotype 1 Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 QPRGRRQPI SPRGSRPSW 43 DPRRRSRNL 66 3 RARAVRAKL TPAETTVRL 38 3 Of the 5 selected B7 peptides 2 has been verified CTL epitopes and are included in the Los Alamos database. HCV RESULTS -B7

13 POPULATION DIVERSITY

14 HLA-A*0101 HLA-A*0201 HLA-A*0301 HLA-B*0702 HLA-B*2705 HLA-B*4402 Select peptide with maximal MHC coverage Select peptide with maximal MHC coverage preferring uncovered MHCs Select peptide with maximal MHC coverage preferring lowest covered HLAs Repeat until the desired number of peptides is selected MHCCOVER

15 POPULATION DIVERSITY

16 ALLELE FREQUENCY XZ Y YZ XY XZ X X Y Z = 5/12 = 0.42 = 4/12 = 0.33 = 3/12 = 0.25

17 ALLELE COVERAGE X Z Y Y ZY XY XZ X Y Z = 4/6 = 0.66 = 3/6 = 0.5 = 3/6 = 0.5 XX Phenotypic frequency

18 FREQUENCY TO COVERAGE X i = q i + ((1 q i ) q i ) X i =2q i q 2 i Assumption: Alleles are independently distributed

19 COVERAGE OF PEPTIDE INDING TO MULTIPLE ALLELES Assumption: Independent distribution Cjk = Xj + (1-Xj) x Xk Cjk = Xj + Xk - XjXk

20 Population Coverage How to calculate

21 From allelefrequencies.net Use either allele frequency or phenotypic frequency or both Allele frequencies are re-calculated to phenotypic frequencies Use the average frequency observed within the population for the given allele

22 Calculate phenotypic frequency Allele frequency = q Phenotypic frequency = X X = 2xq - q 2

23 Your chosen alleles Allele X 1 X 1 2 X 2 3 X 3 4 X 4

24 Population coverage Uncovered = U 0 = 1 Do iteratively: U 1 = U 0 - (U 0 x X 1 ) U 2 = U 1 - (U 1 x X 2 ) U 3 = U 2 - (U 2 x X 3 ) U 4 = U 3 - (U 3 x X 4 ) Total coverage = 1 - U 4

25 HANDOUT HLA-A*0101 has a frequency of xx in the european population HLA-A*0301 has a frequency of yy in the european population What are the population coverage of each of the two allele What are the total coverage of the two alleles

26 MHC-POPCOVER Top Scoring Peptides HLA-A*0101 HLA-A*0201 HLA-A*0301 HLA-B*0702 HLA-B*2705 HLA-B*4402 Select peptide with maximal population coverage Select peptide with maximal coverage preferring uncovered MHCs with highest population coverage Select peptide with maximal coverage preferring lowest covered HLAs with highest population coverage Repeat until the desired number of peptides is selected

27 POPCOVER Genotype 1 HLA-A*0101 Genotype 2 HLA-A*0201 Genotype 3 HLA-A*0301 Genotype 4 HLA-B*0702 Genotype 5 HLA-B*2705 Genotype 6 HLA-B*4402 Select peptide with maximal population coverage and maximal genotype coverage Select peptide with maximal coverage preferring uncovered MHCs with highest population coverage and maximal genotype coverage Select peptide with maximal coverage preferring lowest covered HLAs with highest population coverage and maximal genotype coverage Repeat until the desired number of peptides is selected

28 REACHING OPTIMAL COVERAGE HCV Genotypes