Beerenwinkel Günthard Metzner

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Completed research project

Title / Titel Ultra-deep sequencing of HIV: a pilot study evaluating the benefit for predicting therapy outcome
PDF Abstract (PDF, 14 KB)
Summary / Zusammenfassung Ultra-deep sequencing refers to a new generation of high-throughput DNA sequencing techniques that produce very high coverage by sequencing many short reads in parallel. This technology has the potential to resolve intra-host HIV populations at unprecedented detail by direct sequencing of the mixture of viral clones. Ultra-deep sequencing may become relevant for HIV genotypic drug resistance testing, because it can detect low-frequency variants, it can be used to infer co-occurrences of drug resistance mutations, and it allows for estimating viral genetic diversity. All of these features are known to play a role in the evolution of drug resistance, but none of them can be assessed by traditional population sequencing.
Study Aims
The aim of this pilot study is to evaluate whether there are patient subgroups in the SHCS database that would benefit from ultra-deep genotypic resistance testing as opposed to standard Sanger population sequencing. Ultra-deep sequencing is considered beneficial, if it reveals additional genetic information that would lead to different treatment recommendations.
Study Design
We will analyze virus populations from previously treatment-naïve patients who have failed a boosted protease inhibitor (PI) based antiretroviral therapy. Using a predictive model of therapy outcome based on the viral genotype [1], we will screen the SHCS database to select 30 samples that were obtained prior to an observed therapy failure despite a retrospective prediction of success with high confidence. These drug combinations with discrepant predicted and observed outcome are candidates for improved predictions based on ultra-deep sequencing data (provided that there are no other obvious explanations of failure, such as lack of compliance). As controls, we select 10 matched samples that resulted in successful treatments. The 40 virus populations are analyzed by ultra-deep sequencing followed by computational haplotype inference [2]. Several predictors are derived from the populations and compared between candidates and controls, including haplotype-based predictions of clinical response, estimates of the genetic barrier, and measures of viral diversity.
Keywords / Suchbegriffe HIV drug resistance, minority quasispecies, ultra-deep sequencing, population sequencing, therapeutic failure
Project leadership and contacts /
Projektleitung und Kontakte
Prof. Niko Beerenwinkel, Ph.D. (Project Leader)
Prof. Huldrych Günthard, M.D. (Project Leader)
Dr. Viktor von Wyl, Ph.D.
PD Karin Metzner, M.D. (Project Leader)
Funding source(s) /
Unterstützt durch
In collaboration with /
In Zusammenarbeit mit
Study centers and sites of the Swiss HIV Cohort Study Switzerland
Duration of Project / Projektdauer Nov 2008 to Oct 2012