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HCV Evolution : Diversification and Convergence

HCV Evolution : Diversification and Convergence. Yury Khudyakov. Division of Viral Hepatitis Centers for Disease Control and Prevention, Atlanta, GA. Introduction. Public Health Reduction of morbidity and mortality. Medicine. - Diagnostics - Treatment - Prevention. Introduction.

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HCV Evolution : Diversification and Convergence

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  1. HCV Evolution: Diversification and Convergence Yury Khudyakov Division of Viral Hepatitis Centers for Disease Control and Prevention, Atlanta, GA

  2. Introduction Public Health Reduction of morbidity and mortality Medicine - Diagnostics - Treatment - Prevention

  3. Introduction • A high rate of mutation defines rapid HCV evolution • HCV genome continuously changes • “Arms Race” • Pervasive coevolution • Opportunity for convergence

  4. PHYLOGENETIC ANALYSISIntra-Host HCV Variants Patient 2 Patient 3 Patient 4 Patient 1

  5. K-Core Decomposition of HCV Network Network of coordinated substitutions in the HCV polyprotein

  6. Bayesian Network of HCV Polyprotein Site Interactions and Therapy Outcome

  7. Bayesian Network associating the HVR1 sites with IFN response and host demographic factors HVR1-BN

  8. Intra-Host Evolution over Many Years

  9. Patient ID Race Gender Transmission Genotype Years A White Male Transfusion 1b 8.84 B Black Female IDU 1a 18.12 C Black Male Unknown 1a 15.96 D Unknown Female IDU 1a 15.99 Sentinel County HCV Follow-up Study

  10. 20.00 10.00 0.00 0.0 5.0 10.0 15.0 HCV Quasispecies Divergence During Long-Term Chronic Infection Divergence Time A B C D Patients

  11. 0 0 0 1.5 2.8 2.8 1.6 3.0 2.3 3.3 2.0 7.9 7.9 2.3 9.0 2.5 8.8 10.1 2.7 11.2 4.8 12.2 11.6 13.4 12.1 15.3 14.0 16.2 0 15.0 17.2 0.3 16.0 18.2 7.1 8.1 9.0 10.5 11.1 14.6 15.0 16.0 HVR1 Phylogenetic Trees HVR1: patient B Time-points (Yrs) 0 - 3.3 yr HVR1: patient A Time-pints (Yrs) 0-2.8 yr 7.9-13.4 7.9-17.2 7.9-8.8 yr 15.3-18.2 HVR1: patient D HVR1: patient C Time-points (Yrs) Time-points (Yrs) 0-0.3 yr 1.5-2.7 yr 7.1-8.1 yr 9.0-16.0 yr 4.8-16.0 yr

  12. 2.00 1.50 1.00 0.50 0.00 dN/dS 0.0 5.0 10.0 15.0 Time Changes in Selection Pressures Over Time dN/dSvs. Time HVR1 – R=-0.58, p=0.0001 NS5A – R=-0.61, p=0.0001 Titer vs. Time R=0.585, p=0.0001 Titer vs.dN/dS R=-0.383, p=0.012 A B C D Patients

  13. HCV QS SEQUENCE Factors HOST HCV QS SEQUENCE Viral titer QS diversity Genomic Structure dN/dS Genetic Linkage to Viral and Host Factors

  14. Molecular Epidemiologic Data • NHANESIII: • 106 patients • 1384 HVR1 quasispecies; Genotypes 1 – 6 • HVR1: positions 1491 to 1577nt (polyprotein 488 to 516) • 5’UTR: positions 127 to 340nt • NS5B: positions 8290 to 8589nt (polyprotein 2651 to 2749) • Quantitative Structure Relationships • Probabilistic Graphical Models: • Bayesian Networks (BN) • Predictions • Causal models: • BN classifiers

  15. Bayesian Network Model Associating Sequences of HCV HVR1 Quasispecies to Viral and Host Parameters

  16. Bayesian Network Model Associating Sequences of HCV HVR1 Quasispecies to Viral and Host Parameters

  17. Bayesian Network Model Associating Sequences of HCV HVR1 Quasispecies to Viral and Host Parameters

  18. Bayesian Network Model Associating Sequences of 3 HCV Genome Regions to Viral and Host Parameters

  19. Quantitative Validation of Models Predictions: Classification Modeling ‡ Avg. accuracies † Random assignment of class labels ** 10 NHANES-3 patients; 5M and 5F; Genotypes 1a and 1b; 185nt/96aa HVR1 QS ^^ Based on dNdS 3 class or 2 class grouping

  20. Methods Multiple sequence alignment Five physicochemical properties (Atchley et al, 2005): Polarity, α-helix , Size, aa frequency, Charge Euclidean distance between every pair of sequences Visualization of distance matrix Pathfinder network (r = ∞, q = n-1)

  21. PFNET

  22. Genotype 1 Inter-genotype convergence

  23. Genotype 2 Inter-genotype convergence

  24. Genotype convergence • 24.3% of all links are between different genotypes.

  25. Cross-reactivity experiment • We immunized mice with 102 HVR1 peptides covering all high-density regions of the sequence space. • We tested the reactivity of each sera against 262 peptides (in yellow), a total of 26724 reactions

  26. There were 5039 positive reactions (blue links), which correspond to 18.85% of all tested.

  27. Three peptides (yellow) were found that collectively reacted with all 262 antigens.

  28. Relationship between the reduction of selection pressure and cross-immunoreactivity among HCV intra-host variants Patient C 60*ACR DN/DS

  29. Conclusion Public Health: Reduction of morbidity and mortality Medicine: - Diagnostics - Treatment - Prevention Many viral phenotypic traits with significant medical and public health implications are convergent rather than ancestral

  30. Thank you!

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