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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. - PowerPoint PPT Presentation
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HCV Evolution: Diversification and Convergence
Yury Khudyakov
Division of Viral HepatitisCenters for Disease Control and Prevention, Atlanta, GA
Public Health
Reduction of morbidity and mortality
- Diagnostics- Treatment- Prevention
Medicine
Introduction
A high rate of mutation defines rapid HCV evolution
HCV genome continuously changes
“Arms Race”
Pervasive coevolution
Opportunity for convergence
Introduction
PHYLOGENETIC ANALYSISIntra-Host HCV Variants
Patient 1
Patient 2
Patient 3
Patient 4
Network of coordinated substitutions in the HCV polyprotein
K-Core Decomposition of HCV Network
Bayesian Network of HCV Polyprotein Site Interactions and Therapy Outcome
Bayesian Network associating the HVR1 sites with IFN response and host demographic factors
HVR1-BN
Intra-Host Evolution over
Many Years
15.991aIDUFemaleUnknownD
15.961aUnknownMaleBlackC
18.121aIDUFemaleBlackB
8.841bTransfusionMaleWhiteA
YearsGenotypeTransmissionGenderRacePatient ID
Sentinel County HCV Follow-up Study
0.0 5.0 10.0 15.0
0.00
10.00
20.00
Dive
rgen
ce
Time
DBA C
HCV Quasispecies Divergence During Long-Term Chronic Infection
Patients
HVR1: patient ATime-pints (Yrs)
0
8.8
2.8
7.92.3
0-2.8 yr
7.9-8.8 yr
HVR1: patient B
0
17.218.2
11.2
15.3
12.213.4
10.19.07.93.33.02.8
16.2
Time-points (Yrs) 0 - 3.3 yr
7.9-13.4
7.9-17.2
15.3-18.2
HVR1: patient DTime-points (Yrs)
0
16.0
1.5
2.52.74.8
2.3
1.62.0
11.612.114.015.0
1.5-2.7 yr
4.8-16.0 yr
HVR1: patient CTime-points (Yrs)
0
9.0
16.0
7.1
15.0
8.1
14.6
10.5
0.3
11.1
0-0.3 yr
7.1-8.1 yr
9.0-16.0 yr
HVR1 Phylogenetic Trees
DBA C
0.0 5.0 10.0 15.0
0.00
0.50
1.00
1.50
2.00
dN/d
S
Time
Changes in Selection Pressures Over Time
dN/dS vs. TimeHVR1 – R=-0.58, p=0.0001NS5A – R=-0.61, p=0.0001
Titer vs. TimeR=0.585, p=0.0001
Titer vs. dN/dSR=-0.383, p=0.012
Patients
Genetic Linkage to Viral and Host Factors
Genomic StructureQS diversity
HCV QS SEQUENCE HOST
Viral titer
dN/dS
HCV QS SEQUENCE Factors
I. 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)
II. Quantitative Structure Relationships• Probabilistic Graphical Models:
• Bayesian Networks (BN)
III. Predictions• Causal models:
• BN classifiers
Bayesian Network Model Associating Sequences of HCV HVR1 Quasispecies to Viral and Host Parameters
Bayesian Network Model Associating Sequences of HCV HVR1 Quasispecies to Viral and Host Parameters
Bayesian Network Model Associating Sequences of HCV HVR1 Quasispecies to Viral and Host Parameters
Bayesian Network Model Associating Sequences of 3 HCV Genome Regions to Viral and Host Parameters
Target classes 10-fold-CV ‡
(%) Acc.randTest †
(10-fold-CV ‡)TestSet**
Genotype 99.9% 0.3286 100%
dN/dS^^ (3-bin) (2-bin)
94.4%92.2%
0.4020 0.5120
70.3%82.7%
NQSaa-hvr1 88.0% 0.3887 70.3%
NQSnt-hvr1 87.7% 0.3978 72.4%
Viral Titer 97.2% 0.6031 52.40%
‡ 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
Quantitative Validation of Models
Predictions: Classification Modeling
Five physicochemical properties (Atchley et al, 2005):
Polarity, α-helix , Size, aa frequency, Charge
Multiple sequence alignment
Euclidean distance between every pair of sequences
Visualization of distance matrix Pathfinder network (r = ∞, q = n-1)
Methods
PFNET
Inter-genotype convergence
Genotype 1
Genotype 2
Inter-genotype convergence
• 24.3% of all links are between different genotypes.
Genotype convergence
• 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
Cross-reactivity experiment
• There were 5039 positive reactions (blue links), which correspond to 18.85% of all tested.
• Three peptides (yellow) were found that collectively reacted with all 262 antigens.
Relationship between the reduction of selection pressure and cross-immunoreactivity among HCV intra-host variants
Patient Correlation between DN/DS and ACR
p-value
Patient B -0.6262 0.0166Patient C -0.9101 0.0003Patient D -0.476 0.1001
60*ACR
DN/DS
Patient C
Public Health: Reduction of morbidity and mortality
- Diagnostics- Treatment- Prevention
Medicine:
Conclusion
Many viral phenotypic traits with significant medical and public healthimplications are convergent rather than ancestral
Thank you!