Project

Back to overview

HIV-1 whole-genome quasispecies analysis in longitudinal clinical samples

Applicant Beerenwinkel Niko
Number 146331
Funding scheme Interdisciplinary projects
Research institution Computational Systems Biology Department of Biosystems, D-BSSE ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Information Technology
Start/End 01.04.2013 - 31.07.2014
Approved amount 170'000.00
Show all

All Disciplines (3)

Discipline
Information Technology
Internal Medicine
Molecular Biology

Keywords (10)

graphical models; haplotype inference; HIV-1; virus evolution; next-generation sequencing; genome assembly; antiretroviral therapy; ultra-deep sequencing; drug resistance; Bayesian statistics

Lay Summary (German)

Lead
Viele Krankheitserreger existieren innerhalb eines befallenen Wirtsorganismus als sehr heterogenen Populationen. Diese genetische Vielfalt ist oft mitverantwortlich für einen schlechten Krankheitsverlauf, für das Versagen der körpereigenen Immunabwehr und für die Unwirksamkeit von Medikamenten aufgrund von Resistenzen. Für eine optimale Behandlung von Infektionskrankheiten ist daher die genaue Bestimmung der genetische Diversität der Pathogenpopulation eine notwendige Voraussetzung.
Lay summary

Inhalt und Ziel des Forschungsprojekts

In diesem Projekt benutzen wir moderne Hochdurchsatz-DNA-Sequenziertechnologien für die genetische Analyse von Viruspopulationen in HIV-infizierten Patienten. Unser Ziel ist es, die Virus-Diagnostik und –Behandlung zu verbessern. Dazu werden wir isolierte HIV-Populationen (sogenannte Quasispezies) genomweit rekonstruieren, einschliesslich niederfrequenter genetischer Varianten, die für den Therapieerfolg wichtig sein können. Das interdisziplinäre Projekt umfasst den Entwurf und die Implementierung sowohl experimenteller Protokolle als auch bioinformatischer Methoden für die Datenanalyse, sowie deren klinische Anwendung. 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unsere Arbeit ist ein Beitrag zur personalisierten Medizin im Bereich der Infektionskrankheiten. Mit den hier entwickelten Methoden werden Pathogenpopulationen weitaus detailreicher charakterisiert und Therapieoptionen genauer bestimmt werden können.

Direct link to Lay Summary Last update: 11.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A Comprehensive Analysis of Primer IDs to Study Heterogeneous HIV-1 Populations
Seifert David, Di Giallonardo Francesca, Töpfer Armin, Singer Jochen, Schmutz Stefan, Günthard Huldrych F., Beerenwinkel Niko, Metzner Karin J. (2016), A Comprehensive Analysis of Primer IDs to Study Heterogeneous HIV-1 Populations, in Journal of Molecular Biology, 428(1), 238-250.
A framework for inferring fitness landscapes of patient-derived viruses using quasispecies theory.
Seifert David, Di Giallonardo Francesca, Metzner Karin J, Günthard Huldrych F, Beerenwinkel Niko (2015), A framework for inferring fitness landscapes of patient-derived viruses using quasispecies theory., in Genetics, 199(1), 191-203.
Challenges in RNA virus bioinformatics.
Marz Manja, Beerenwinkel Niko, Drosten Christian, Fricke Markus, Frishman Dmitrij, Hofacker Ivo L, Hoffmann Dieter, Middendorf Martin, Rattei Thomas, Stadler Peter F, Töpfer Armin (2014), Challenges in RNA virus bioinformatics., in Bioinformatics (Oxford, England), 30(13), 1793-9.
Viral quasispecies assembly via maximal clique enumeration.
Töpfer Armin, Marschall Tobias, Bull Rowena A, Luciani Fabio, Schönhuth Alexander, Beerenwinkel Niko (2014), Viral quasispecies assembly via maximal clique enumeration., in PLoS Computational Biology, 10(3), 1003515-1003515.
HIV Haplotype Inference Using a Propagating Dirichlet Process Mixture Model.
Prabhakaran Sandhya, Rey Melanie, Zagordi Osvaldo, Beerenwinkel Niko, Roth Volker (2013), HIV Haplotype Inference Using a Propagating Dirichlet Process Mixture Model., in IEEE/ACM transactions on computational biology and bioinformatics / IEEE, ACM, 11(1), 182-191.
Next-Generation Sequencing of HIV-1 RNA Genomes: Determination of Error Rates and Minimizing Artificial Recombination
Di Giallonardo Francesca, Zagordi Osvaldo, Duport Yannick, Leemann Christine, Joos Beda, Künzli-Gontarczyk Marzanna, Bruggmann Rémy, Beerenwinkel Niko, Günthard Huldrych F., Metzner Karin J. (2013), Next-Generation Sequencing of HIV-1 RNA Genomes: Determination of Error Rates and Minimizing Artificial Recombination, in PLoS ONE, 8(9), e74249-e74249.
Full-length haplotype reconstruction to infer the structure of heterogeneous virus populations.
Giallonardo Francesca Di, Töpfer Armin, Rey Melanie, Prabhakaran Sandhya, Duport Yannick, Leemann Christine, Schmutz Stefan, Campbell Nottania K, Joos Beda, Lecca Maria Rita, Patrignani Andrea, Däumer Martin, Beisel Christian, Rusert Peter, Trkola Alexandra, Günthard Huldrych F, Roth Volker, Beerenwinkel Niko, Metzner Karin J, Full-length haplotype reconstruction to infer the structure of heterogeneous virus populations., in Nucleic acids research.

Collaboration

Group / person Country
Types of collaboration
Christian Beisel (ETH Zurich, D-BSSE) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Osvaldo Zagordi (University of Zurich) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Alexander Schönhuth (CWI, Amsterdam) Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Fabio Luciani (UNSW) Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Ralph Schlapbach (Functional Genomics Center Zurich) Switzerland (Europe)
- Research Infrastructure
Martin Däumer (Institut fuer Immunologie und Genetik, Kaiserslautern) Germany (Europe)
- Publication
Tobias Marschall (MPI Informatik, Saarbruecken) Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Thomas J. Fuchs (California Institute of Technology) United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
International Conference on Machine Learning -- ICML'14 Talk given at a conference Sparse meta-Gaussian information bottleneck. 21.06.2014 Beijing, China Roth Volker; Rey Melanie;
4th ICCABS (IEEE) Talk given at a conference Viral quasispecies assembly from paired-end reads 02.06.2014 Miami, FL, United States of America Töpfer Armin;
International Symposium on the Control and Eradication of Viral Hepatitis B and C Talk given at a conference Challenges of ultra-deep sequencing for studying low-frequency mutants 30.05.2014 Barcelona, Spain Beerenwinkel Niko;
RECOMB 2014 Talk given at a conference Viral quasispecies assembly via maximal clique enumeration 02.04.2014 Pittsburgh, PA , United States of America Töpfer Armin;
Mathematical, Statistical and Computational Aspects of Metagenomics Workshop, Talk given at a conference Estimating within-host viral genetic diversity from next-generation sequencing data 24.03.2014 Issac Newton Institute, Cambridge, UK, Great Britain and Northern Ireland Beerenwinkel Niko;
CROI 2014 Poster Full-length HIV-1 Haplotype Reconstruction from Heterogeneous Virus Populations 03.03.2014 Boston, MA, United States of America Töpfer Armin; Metzner Karin; Günthard Huldrych Fritz;
Swiss Meeting for Infectious Disease Dynamics (SMIDDY) Talk given at a conference Global haplotype prediction of HIV-1 13.09.2013 Zurich, Switzerland Töpfer Armin;
EMBO workshop on Integrating Omics Approaches to Understand Host Cell Pathogen Interactions Talk given at a conference Estimating the genetic diversity of pathogens from next-generation sequencing data 25.06.2013 Liverpool, Great Britain and Northern Ireland Beerenwinkel Niko;
3rd ICCABS (IEEE) Talk given at a conference Probing of viral diversity by global haplotype prediction 12.06.2013 New Orleans, United States of America Töpfer Armin;
2nd CHAIN Next Generation Sequencing Working Group Meeting Talk given at a conference Computational and Statistical Challenges of Ultradeep Sequencing of Viral Quasispecies 22.05.2013 Rome, Italy Metzner Karin; Töpfer Armin;
Statistical Genomics and Data Integration for Personalized Medicine Poster Probing of viral diversity by global haplotype prediction 12.05.2013 Ascona, Switzerland Roth Volker; Töpfer Armin; Beerenwinkel Niko;


Self-organised

Title Date Place

Awards

Title Year
CROI Young Investigator Scholarship 2014

Associated projects

Number Title Start Funding scheme
148522 Swiss HIV Cohort Study (SHCS) 01.01.2014 Cohort Studies Large
127017 HIV-1 whole-genome quasispecies analysis by ultra-deep sequencing and computational haplotype inference to determine the mechanisms of drug resistance development 01.01.2010 Interdisciplinary projects
159868 HIV-1 Transmission in Switzerland: viral transmission traits, superinfection and drug resistance 01.05.2015 Project funding (special)

Abstract

Genetic diversity is a hallmark of pathogen populations, associated with disease progression, immune escape, and drug resistance. We propose to use next-generation sequencing (NGS) for the analysis of viral populations within infected patients to improve viral diagnostics and treatment decisions by reconstructing the entire population structure, including low-frequency mutants and co-occurring mutations.Based on the achievements in the predecessor project (CR32I2_127017), we will develop experimental protocols and computational methods for the analysis of NGS data obtained from intra-patient HIV-1 populations. Our goal is to infer the haplotype sequences and their frequencies over the full length of the 9.2 kb HIV genome. Since the limited read length of current NGS platforms turned out to be the main bottleneck in this endeavor, we will develop two major extensions of our software tools ‘PredictHaplo’ and ‘QuasiRecomb’ to address this limitation. Firstly, we will use Illumina’s paired-end option to generate read pairs of 2x250bp length covering the HIV genome. These data are informative about long-range phasing of single-nucleotide variants (SNVs) and will be integrated into probabilistic global haplotype reconstruction using either soft constraints on SNV linkage (PredictHaplo) or silent delete states for the insert (QuasiRecomb). Secondly, we will explore Pacific Biosciences’ PacBio RS technology as an alternative long-read sequencing platform with an average read length of 1,500 bp. Using these improved experimental and computational tools, we will analyze and interpret genetic diversity in the context of HIV-1 drug resistance. Specifically, 100 samples from 40 patients will be analyzed for pre- versus post-treatment changes of viral populations, for low-frequency drug resistant variants and their role in treatment failure, for linkage among drug resistance mutations and evolutionary escape pathways, for recombinants, and for viral phenotypes such as drug resistance and co-receptor usage. Our full-length haplotype approach provides, for the first time, a complete picture of the virus population and will yield new insights into drug resistance development.
-