HIV-1 Resistance Evolution K. Theys Rega Institute for Medical Research Introduction Rega Institute for Medical Research Treatment Methods Kristof Theys Design Bayesian Network Fitness Landscape Case study Clinical and Epidemiological Virology Damvil Study Katholieke Universiteit Leuven April, 24th Arevir Meeting, Bonn
Outline HIV-1 Resistance Evolution Introduction 1 K. Theys Rega Institute for Medical Research Introduction Treatment of HIV-1 infection Rega Institute for Medical Research Treatment Understanding HIV evolution under selective pressure of 2 Methods Design HIV therapy Bayesian Network Fitness Landscape General overview of applied techniques Case study Bayesian Network Learning Damvil Study Estimation of Fitness Landscape 3 Current Research Baseline CD4 and VL in naive patients
Outline HIV-1 Resistance Evolution Introduction 1 K. Theys Rega Institute for Medical Research Introduction Treatment of HIV-1 infection Rega Institute for Medical Research Treatment Understanding HIV evolution under selective pressure of 2 Methods Design HIV therapy Bayesian Network Fitness Landscape General overview of applied techniques Case study Bayesian Network Learning Damvil Study Estimation of Fitness Landscape 3 Current Research Baseline CD4 and VL in naive patients
Clinical and Epidemiological Virology HIV-1 Resistance Evolution K. Theys Research interests Introduction Factors that influence therapy response of HIV infected Rega Institute for Medical Research patients Treatment Methods viral resistance against HIV drugs Design Molecular evolution and epidemiology of HIV Bayesian Network Fitness Landscape subtype diversity of HIV Case study tracing the origin of HIV Damvil Study Combined approach enables to study the evolution of HIV during selective pressure of HIV
Rega analysis tools HIV-1 Resistance Evolution K. Theys Rega algorithm Introduction genotypic resistance interpretation system Rega Institute for Medical Research Rega HIV subtyping tool Treatment Methods Sequence analysis tools Design Bayesian Network Alignment Fitness Landscape Translation to amino acids Case study Damvil Study Resistance interpretation All accessible at http://jose.med.kuleuven.be All integrated in RegaDB
Outline HIV-1 Resistance Evolution Introduction 1 K. Theys Rega Institute for Medical Research Introduction Treatment of HIV-1 infection Rega Institute for Medical Research Treatment Understanding HIV evolution under selective pressure of 2 Methods Design HIV therapy Bayesian Network Fitness Landscape General overview of applied techniques Case study Bayesian Network Learning Damvil Study Estimation of Fitness Landscape 3 Current Research Baseline CD4 and VL in naive patients
Therapy Response HIV-1 Resistance Evolution Many factors influence therapy outcome K. Theys adherence Introduction Rega Institute for dosis Medical Research Treatment drug interactions Methods metabolism - absorption Design complexity - toxicity Bayesian Network Fitness Landscape antiviral resistance Case study Damvil Study Keyrole for antiviral resistance cause and consequence of failure Avoid development of resistance irreversible proces cross-resistance
Selecting the optimal combination Life-long HIV antiviral treatment HIV-1 Resistance Evolution K. Theys Planning successful drug sequencing strategies Introduction Rega Institute for Dual requirements for combination Medical Research Treatment Short term Methods be potent (virological suppression) Design Bayesian Network forgiving (minimally affected by adherene) Fitness Landscape high genetic barrier** to resistance Case study Long term Damvil Study minimally cross-resistance Sequencing strategies most applicable for drug naive
Rega’s objectives HIV-1 Resistance Evolution Optimalisation is necessary for succesful lifelong therapy K. Theys Time to failure of combination therapy Introduction Optimal therapy options after therapy failure Rega Institute for Medical Research Treatment Methods Design Bayesian Network Fitness Landscape Case study Damvil Study
Rega’s methods HIV-1 Resistance Better understanding how resistance develops and Evolution K. Theys evolves under the selective pressure of (combination) therapy. Introduction Rega Institute for Influences on resistance evolution Medical Research Treatment Impact of genetic variability ( inter/intra ) Methods Interactions between mutations Design Bayesian Network Genetic barrier of a drug/combination Fitness Landscape Case study Damvil Study Time to therapy failure Evolutionary distance to resistance Genetic barrier Potency of the combination (activity) Phenotype, adherence, . . .
Outline HIV-1 Resistance Evolution Introduction 1 K. Theys Rega Institute for Medical Research Introduction Treatment of HIV-1 infection Rega Institute for Medical Research Treatment Understanding HIV evolution under selective pressure of 2 Methods Design HIV therapy Bayesian Network Fitness Landscape General overview of applied techniques Case study Bayesian Network Learning Damvil Study Estimation of Fitness Landscape 3 Current Research Baseline CD4 and VL in naive patients
Applied techniques and applications HIV-1 Resistance Bayesian network learning for resistance development Evolution K. Theys role of mutations and polymorphisms in treatment failure Introduction influence of subtype diversity on resistance Rega Institute for Medical Research improve genotypic interpretation systems Treatment Methods Estimation of fitness landscapes Design model of HIV evolution under the selective pressure of Bayesian Network Fitness Landscape treatment Case study predict evolution of HIV Damvil Study Calculate genetic barrier define the genotypic correlates which influence genetic barrier Prediction of therapy response genotypic predictors based on estimated fitness
Outline HIV-1 Resistance Evolution Introduction 1 K. Theys Rega Institute for Medical Research Introduction Treatment of HIV-1 infection Rega Institute for Medical Research Treatment Understanding HIV evolution under selective pressure of 2 Methods Design HIV therapy Bayesian Network Fitness Landscape General overview of applied techniques Case study Bayesian Network Learning Damvil Study Estimation of Fitness Landscape 3 Current Research Baseline CD4 and VL in naive patients
Bayesian Network Analysis HIV-1 Resistance Probabilistic Graphical Models Evolution K. Theys Finds minimal set of direct dependencies that together explain most observed correlation Introduction Rega Institute for Medical Research Represent direct dependencies in a directed graph Treatment Methods A Bayesian Network refactors the JPD of multivariable Design data in product of CPDs: Bayesian Network Fitness Landscape Case study n Damvil Study � P ( A 1 , . . . , A n ) = P ( A i | parents ( A i )) i by assuming conditional independencies Refactoring of JPD P ( 30 N , 71 V , 88 D , 90 M ) = P ( 71 V | 30 N ) xP ( 88 D | 30 N ) xP ( 30 N ) xP ( 90 M )
Bayesian Network learning On amino acid sequence data HIV-1 Resistance Evolution A Bayesian Network can be “learned“ from data K. Theys Can be used as a blue-print for amino acid interactions Introduction for an emperical fitness function Rega Institute for Medical Research Treatment Can be interpreted semantically Methods Design mutations connected to drug node Bayesian Network Fitness Landscape presence is directly influenced by drug Case study major mutation Damvil Study mutations connected to each other presence is influenced by other mutation minor mutation in resistance pathway mutations connected to polymorphisms presence is influenced by natural variation
Bayesian Network of Nelfinavir resistance HIV-1 Resistance Evolution K. Theys Introduction Rega Institute for Medical Research Treatment Methods Design Bayesian Network Fitness Landscape Case study Damvil Study
Outline HIV-1 Resistance Evolution Introduction 1 K. Theys Rega Institute for Medical Research Introduction Treatment of HIV-1 infection Rega Institute for Medical Research Treatment Understanding HIV evolution under selective pressure of 2 Methods Design HIV therapy Bayesian Network Fitness Landscape General overview of applied techniques Case study Bayesian Network Learning Damvil Study Estimation of Fitness Landscape 3 Current Research Baseline CD4 and VL in naive patients
Darwinian Fitness HIV-1 Resistance Evolution K. Theys Defines the ability to replicate in a given environment Introduction dependent on virus (replication capacity) Rega Institute for Medical Research dependent on environment (CTL response, therapy, ...) Treatment Methods concepts Design Replication Capacity = Darwinian fitness in patient off Bayesian Network Fitness Landscape treatment Case study sometimes referred as fitness Damvil Study Fitness (during treatment) = Darwinian fitness in patients taking treatment combination of phenotype and replication capacity
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