Project

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24 hours in the life of HIV-1

Applicant Telenti Amalio
Number 130699
Funding scheme Project funding
Research institution Institut de Microbiologie Faculté de Biologie et Médecine CHUV/Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Medical Microbiology
Start/End 01.04.2010 - 31.03.2012
Approved amount 377'088.00
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All Disciplines (2)

Discipline
Medical Microbiology
Genetics

Keywords (7)

viral cycle; reprogramming; miRNA; deep sequencing; RNA-seq; ChIP-seq; dynamic Bayesian netowrks

Lay Summary (English)

Lead
Lay summary
The life cycle of HIV-1, the AIDS virus, in the cell is generally completed in 24 hours. During this period of time, the virus invades the cell, and uses its machinery to complete the necessary steps for a productive infection. The cell is profoundly disturbed by this action. On its turn, the cell can mount antiviral responses that aim at limiting the progression of the viral life cycle, and inform other cells of the presence of a pathogen. This proposal aims at the in-depth characterization of the reprogramming of the cell upon HIV infection. The analysis will cover, through repeated measurements, the life cycle of the virus. During this period, the virus undergoes entry and uncoating, reverse transcription, nuclear import, integration, transcription, export of viral transcripts, translation, and viral assembly and release. Each step can be assessed precisely and in a quantitative fashion. The host cellular environment is greatly perturbed following viral invasion, with numerous parameters that can be measured and matched temporarily to the progression of the viral cycle. The present proposal will address the timing of key steps of the viral cycle in the context of cellular responses, as assessed by the analysis of expression reprogramming and the mounting of antiviral defense, including cellular miRNA responses. To achieve this goal, we will integrate the molecular profiling time series into a single interaction model. Probabilistic graphical models, including dynamic Bayesian networks and factorial hidden Markov models, will be applied to capture the temporal dynamics among the molecular events during the HIV life cycle. This project represents a step towards understanding the viral life cycle and the modification of the cellular environment by the infection. This represents a unique opportunity to integrate host and viral aspects in a temporal frame in an effort towards modeling of the HIV life cycle. The analyses will provide a scaffold and reference to in vivo large scale genome and cellular screens.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
24 Hours in the Life of HIV-1 in a T Cell Line
Mohammadi Pejman, Desfarges Sébastien, Bartha István, Joos Beda, Zangger Nadine, Muñoz Miguel, Günthard Huldrych F., Beerenwinkel Niko, Telenti Amalio, Ciuffi Angela (2013), 24 Hours in the Life of HIV-1 in a T Cell Line, in PLoS Pathogens, 9(1), e1003161-e1003161.
Analysis of HIV-1 expression level and sense of transcription by high-throughput sequencing of the infected cell.
Lefebvre Gregory, Desfarges Sébastien, Uyttebroeck Frédéric, Muñoz Miguel, Beerenwinkel Niko, Rougemont Jacques, Telenti Amalio, Ciuffi Angela, Analysis of HIV-1 expression level and sense of transcription by high-throughput sequencing of the infected cell., in Journal of virology, 85(13), 6205-11.

Datasets

SAGE data

Author Mohammadi, Pejman
Publication date 13.12.2012
Persistent Identifier (PID) http://peachi.labtelenti.org/
Repository PEACHI website
Abstract
user-friendly open access website allowing customized queries.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
4th Swiss Virology Meeting. Talk given at a conference Dynamics models in HIV 05.02.2013 Thun, Switzerland Ciuffi Angela; Telenti Amalio;
Department of Pharmaceutical and Pharmacological Sciences, Faculty of Medicine. Individual talk Dynamic models in HIV 07.12.2012 KU Leuven, Leuven, Belgium Ciuffi Angela;
Club de Pathologie Infectieuse and Swiss HIV Cohort Study Scientific Forum Joint Meeting. Talk given at a conference Analysis of HIV-1 expression level and sense of transcription by high-throughput sequencing of the infected cell 23.08.2012 Inselspital, Bern, Switzerland Ciuffi Angela; Telenti Amalio;
Host-Parasite Interactions Seminars. Individual talk 24h in the life of HIV-1 01.03.2012 Swiss Tropical and Public Health Institute, Basel, Switzerland Ciuffi Angela;
HIV seminars. Individual talk Host transcriptional reprogramming by HIV 08.12.2011 University Bordeaux 2, Bordeaux, France Ciuffi Angela;
Indo-Swiss Symposium on Infectious Diseases. Talk given at a conference Host transcriptional reprogramming during the HIV-1 life cycle 01.04.2011 EPFL, lausanne, Switzerland Ciuffi Angela; Telenti Amalio;
HIV Pathogenesis Keystone Meeting. Talk given at a conference Host transcriptional reprogramming during the HIV-1 life cycle 20.03.2011 Whistler, British Columbia, Canada Telenti Amalio; Ciuffi Angela;
Department of Pathology and Laboratory Medicine Research Day. Talk given at a conference 24 hours in the life cycle of HIV-1 01.12.2010 Lausanne, Switzerland Ciuffi Angela;
Cellular and Biomedical Sciences Seminars. Individual talk 24 hours in the life of HIV-1 07.05.2010 University of Bern, Switzerland Ciuffi Angela;
Functional Genomics Technologies Seminars. Individual talk 24 hours in the life of HIV-1 23.04.2010 University of Zurich, Switzerland Ciuffi Angela;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television 24 heures avec un VIH: itinéraire d'un destructeur RTS - emission CQFD Western Switzerland 2013

Awards

Title Year
Janssen virology award 2012

Associated projects

Number Title Start Funding scheme
141234 Pharmacologie clinique et pharmacogénétique de la prise en charge complexe des sujets infectés par HIV ou co-infectés par HIV et HCV 01.04.2012 Project funding (special)
132863 Host evolutionary genomics of HIV-1 and other retroviruses 01.11.2010 Project funding
188877 Dynamics of HIV latency and reactivation at population and single-cell level 01.10.2019 Project funding (special)
110012 Host genetic and genomic determinants of susceptibility to HIV-1 01.11.2005 Project funding

Abstract

This proposal aims at the in-depth characterization of expression reprogramming of the cell upon HIV infection. The analysis will cover, through repeated measurements, the classical 24-hour life cycle of the virus. During this period, the virus undergoes entry and uncoating, reverse transcription, nuclear import, integration, transcription, Rev-mediated export of viral transcripts, translation, and viral assembly and release. Each step can be assessed precisely and in a quantitative fashion. The host cellular environment is greatly perturbed following viral invasion, with numerous parameters that can be measured and matched temporarily with the progression of the viral cycle. Members of the research team and collaborators have in the past assessed, separately, many of the steps of the viral cycle, as well as changes in the cellular response, in vitro and in vivo. This has also required the development and implementation of all the necessary tools and techniques needed to follow the various viral and host parameters. The current proposal aims at increasing both the depth of the analysis, and the frequency of measurements required for high temporal resolution of viral and cellular corresponding measurements. For this, we propose to assess every two hours over 24 hours, in an in vitro cellular infection model, the following parameters:VIRUSHOSTReverse transcription (early and late RT products)Reprogramming by viral proteins (ChIP-Seq)Integration (2-LTR circles, proviral DNA)Gene expression profiling (RNA-seq)Transcription and splicing (unspliced, multiply spliced, 5' transcripts, main intronic transcripts)microRNA expression (RNA-seq)Translation (GFP expression, cell-associated p24)Release (extracellular p24)The present proposal will address the timing of key steps of the viral cycle in the context of cellular responses, as assessed by the analysis of expression reprogramming and the mounting of antiviral defense, including cellular miRNA responses. To achieve this goal, we will integrate the molecular profiling time series into a single interaction model. Probabilistic graphical models, including dynamic Bayesian networks and factorial hidden Markov models, will be applied to capture the temporal dynamics among the molecular events during the HIV life cycle. This project represents an additional step towards understanding the viral life cycle and the modification of the cellular environment by the infection. Beyond the interest of conducting the individual analyses discussed above, there is an opportunity to increasingly integrate host and viral aspects in a temporal frame in an effort towards modeling of the HIV life cycle. The analyses will provide a scaffold and reference to in vivo large scale genome and cellular screens.
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