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Novel mechanisms of HIV control in the infected cell

English title Novel mechanisms of HIV control in the infected cell
Applicant Trono Didier
Number 149724
Funding scheme Project funding
Research institution EPFL-SV-GHI-LVG
Institution of higher education University of Lausanne - LA
Main discipline Medical Microbiology
Start/End 01.12.2013 - 30.11.2015
Approved amount 329'000.00
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All Disciplines (2)

Discipline
Medical Microbiology
Experimental Microbiology

Keywords (6)

Antiretroviral restrition; HIV; zebrafish; primate SIV infection; Evolutionary genetics; primary cells

Lay Summary (French)

Lead
Le virus du Sida, utilise les composantes de la cellule humaine pour sa réplication. La cellule s’oppose à l’infection par le biais des gènes antiviraux. On a évalué les caractéristiques des gènes capables de cibler le VIH après l’invasion de la cellule : une trentaine de gènes dans le génome humain sont des facteurs antiviraux. Une analyse approfondie de leurs activités nous a permis de confirmer que plusieurs candidats sont de véritables acteurs de l’immunité innée contre les virus.
Lay summary

Contenu et objectifs du travail de recherche

Ce nouveau projet a comme but (i) la caractérisation détaillée de chaque gène candidat et (ii) une réévaluation du génome humain avec de nouveaux outils informatiques pour déceler d’éventuels candidats additionnels.

 Le premier objectif implique l’évaluation du spectre d’activités antivirales des candidats (contre un panel de lentivirus des primates), l’activité du gène homologue de plusieurs primates, le site d’interaction entre virus et la protéine antivirale, et une capacité potentielle de contre-attaque par des protéines virales accessoires. Les gènes seront également silenciées dans les cellules primaires (lymphocyte CD4 et macrophages).

Le deuxième objectif demande l’application des algorithmes génomiques et transcriptomiques pour l’identification des facteurs antiviraux. Ici, on explore les paramètres qui ont été identifiés par le biais de l’analyse de plusieurs centaines de gènes d’immunité innée. La nouvelle série de candidats serait par la suite évaluée dans un screen « gain of function » (surexpression de gènes).

Contexte scientifique et social du projet de recherche

Notre travail contribuera à une meilleure compréhension de la susceptibilité humaine au VIH. D’un côté, la cellule aurait la capacité de défense et malgré tout, l’être humain resterait susceptible. Cet échappement serait le résultat de l’action des protéines virales avec une capacité de neutralisation. D’autre part, notre travail amènera une meilleure compréhension du réseau de l’immunité innée dédiée au contrôle des pathogènes.

Keywords

VIH, immunité innée, facteurs de restriction, génomique évolutive.

Direct link to Lay Summary Last update: 10.12.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Single-cell analysis identifies cellular markers of the HIV permissive cell
Rato Sylvie, Rausell Antonio, Muñoz Miguel, Telenti Amalio, Ciuffi Angela (2017), Single-cell analysis identifies cellular markers of the HIV permissive cell, in PLOS Pathogens, 13(10), e1006678-e1006678.
Innate immune defects in HIV permissive cell lines
Rausell Antonio, Muñoz Miguel, Martinez Raquel, Roger Thierry, Telenti Amalio, Ciuffi Angela (2016), Innate immune defects in HIV permissive cell lines, in Retrovirology, 13(1), 43-43.
Guanylate Binding Protein (GBP) 5 Is an Interferon-Inducible Inhibitor of HIV-1 Infectivity.
Krapp Christian, Hotter Dominik, Gawanbacht Ali, McLaren Paul J, Kluge Silvia F, Stürzel Christina M, Mack Katharina, Reith Elisabeth, Engelhart Susanne, Ciuffi Angela, Hornung Veit, Sauter Daniel, Telenti Amalio, Kirchhoff Frank (2016), Guanylate Binding Protein (GBP) 5 Is an Interferon-Inducible Inhibitor of HIV-1 Infectivity., in Cell host & microbe, 19(4), 504-14.
Discovery and Characterization of an Endogenous CXCR4 Antagonist
Zirafi Onofrio, Kim Kyeong-Ae, Staendker Ludger, Mohr Katharina B., Sauter Daniel, Heigele Anke, Kluge Silvia F., Wiercinska Eliza, Chudziak Doreen, Richter Rudolf, Moepps Barbara, Gierschik Peter, Vas Virag, Geiger Hartmut, Lamla Markus, Weil Tanja, Burster Timo, Zgraja Andreas, Daubeuf Francois, Frossard Nelly, Hachet-Haas Muriel, Heunisch Fabian, Reichetzeder Christoph, Galzi Jean-Luc, Perez-Castells Javier (2015), Discovery and Characterization of an Endogenous CXCR4 Antagonist, in CELL REPORTS, 11(5), 737-747.
Evolutionary genomics and HIV restriction factors.
Pyndiah Nitisha, Telenti Amalio, Rausell Antonio (2015), Evolutionary genomics and HIV restriction factors., in Current opinion in HIV and AIDS, 10(2), 79-83.
Genomics of HIV infection.
Telenti Amalio (2015), Genomics of HIV infection., in Current opinion in HIV and AIDS, 10(2), 77-8.
HIV-1 immune activation induces Siglec-1 expression and enhances viral trans-infection in blood and tissue myeloid cells.
Pino Maria, Erkizia Itziar, Benet Susana, Erikson Elina, Fernández-Figueras Maria Teresa, Guerrero Dolores, Dalmau Judith, Ouchi Dan, Rausell Antonio, Ciuffi Angela, Keppler Oliver T, Telenti Amalio, Kräusslich Hans-Georg, Martinez-Picado Javier, Izquierdo-Useros Nuria (2015), HIV-1 immune activation induces Siglec-1 expression and enhances viral trans-infection in blood and tissue myeloid cells., in Retrovirology, 12, 37-37.
Identification of potential HIV restriction factors by combining evolutionary genomic signatures with functional analyses.
McLaren Paul J, Gawanbacht Ali, Pyndiah Nitisha, Krapp Christian, Hotter Dominik, Kluge Silvia F, Götz Nicola, Heilmann Jessica, Mack Katharina, Sauter Daniel, Thompson Danielle, Perreaud Jérémie, Rausell Antonio, Munoz Miguel, Ciuffi Angela, Kirchhoff Frank, Telenti Amalio (2015), Identification of potential HIV restriction factors by combining evolutionary genomic signatures with functional analyses., in Retrovirology, 12, 41-41.
Sincell: an R/Bioconductor package for statistical assessment of cell-state hierarchies from single-cell RNA-seq
Julia Miguel, Telenti Amalio, Rausell Antonio (2015), Sincell: an R/Bioconductor package for statistical assessment of cell-state hierarchies from single-cell RNA-seq, in BIOINFORMATICS, 31(20), 3377-3379.
The Genomic Signature of Population Reconnection Following Isolation: From Theory to HIV.
Alcala Nicolas, Jensen Jeffrey D, Telenti Amalio, Vuilleumier Séverine (2015), The Genomic Signature of Population Reconnection Following Isolation: From Theory to HIV., in G3 (Bethesda, Md.), 6(1), 107-20.
Genomics of host-pathogen interactions.
Rausell Antonio, Telenti Amalio (2014), Genomics of host-pathogen interactions., in Sanger Ruth (ed.), Elsevier, United Kingdom, 32-8.
GuavaH: a compendium of host genomic data in HIV biology and disease.
Bartha István, McLaren Paul J, Ciuffi Angela, Fellay Jacques, Telenti Amalio (2014), GuavaH: a compendium of host genomic data in HIV biology and disease., in Retrovirology, 11, 6-6.
HIV: The mixed blessing of interferon.
Telenti Amalio (2014), HIV: The mixed blessing of interferon., in Nature, 511(7511), 537-8.

Collaboration

Group / person Country
Types of collaboration
Jean-Pierre Levraud / Institut Pasteur France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Jacques Fellay / EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Frank Kirchhoff / University of Ulm Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
147665 Defining a repertoire of innate immunity genes contributing to intracellular defense against pathogens 01.08.2013 Sinergia
132863 Host evolutionary genomics of HIV-1 and other retroviruses 01.11.2010 Project funding

Abstract

This proposal represents the continuation of the SNF grant “Host evolutionary genomics of HIV-1 and other retroviruses, 2010-2013”. It aims at understanding the cellular and antiviral function of genes that were identified through integrative genomic analyses that used evolutionary genetics, transcriptome and protein interaction data, and functional screens. Of 21389 human genes, 841 (4%) were identified because of features of positive selection in primates. In half of those genes we also detected evidence of codon-specific selection pressure. Among those genes, only 30 genes/proteins (0.14%) were identified through orthogonal datasets as being upregulated during HIV infection in vivo, and/or plausibly interacting with HIV proteins. When overexpressed, several of the 30 genes associated with a profound reduction of HIV replication in the cotransfected cell. siRNA led to the opposing phenotype for some genes that were constitutively transcribed. In addition to traditional components of the interferon response, we identified genes associated with apoptosis and immunomodulatory networks. Importantly, two genes strongly enhanced viral production.To advance in the understanding of cellular function and role in innate immunity of the identified genes, the current proposal aims to:•Explore the role of the candidate host genes in the regulation of the viral replication cycle. •Study the specificity of candidate host genes against HIV, by exploiting the use of primate orthologs and various lentiviral strains, and other retroviruses.•For confirmed anti(retro)viral genes, we aim at exploring a counteracting role of viral accessory proteins, and mapping the site of interaction of host and virus.•Extend analyses to primary cell systems.•Explore novel models of in vivo analysis of antiviral genes.Thus, this project fulfills the goals of previous research that served to identifying novel factors that limit viral replication; it exploits prior results, tools and datasets created in the framework of Swiss National Science Foundation projects. The current research may lead to better understanding of cellular defense against HIV and other retroviruses. The approach can serve as a model for the study of other major human pathogens.
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