title: Identification of potential HIV restriction factors by combining evolutionary genomic signatures with functional analyses.
abstract: BACKGROUND
  Known antiretroviral restriction factors are encoded by genes that are under positive selection pressure, induced during HIV-1 infection, up-regulated by interferons, and/or interact with viral proteins. To identify potential novel restriction factors, we performed genome-wide scans for human genes sharing molecular and evolutionary signatures of known restriction factors and tested the anti-HIV-1 activity of the most promising candidates.
  
  
  RESULTS
  Our analyses identified 30 human genes that share characteristics of known restriction factors. Functional analyses of 27 of these candidates showed that over-expression of a strikingly high proportion of them significantly inhibited HIV-1 without causing cytotoxic effects. Five factors (APOL1, APOL6, CD164, TNFRSF10A, TNFRSF10D) suppressed infectious HIV-1 production in transfected 293T cells by >90% and six additional candidates (FCGR3A, CD3E, OAS1, GBP5, SPN, IFI16) achieved this when the virus was lacking intact accessory vpr, vpu and nef genes. Unexpectedly, over-expression of two factors (IL1A, SP110) significantly increased infectious HIV-1 production. Mechanistic studies suggest that the newly identified potential restriction factors act at different steps of the viral replication cycle, including proviral transcription and production of viral proteins. Finally, we confirmed that mRNA expression of most of these candidate restriction factors in primary CD4+ T cells is significantly increased by type I interferons.
  
  
  CONCLUSIONS
  A limited number of human genes share multiple characteristics of genes encoding for known restriction factors. Most of them display anti-retroviral activity in transient transfection assays and are expressed in primary CD4+ T cells.
authors.affiliation: École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland. paul.mclaren@epfl.ch.|Swiss Institute of Bioinformatics, 1005, Lausanne, Switzerland. paul.mclaren@epfl.ch.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McLaren
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany. ali.gawanbacht@uni-ulm.de.
authors.forename: Ali
authors.initials: A
authors.lastname: Gawanbacht
authors.affiliation: Institute of Microbiology, University of Lausanne, 1011, Lausanne, Switzerland. nitisha.pyndiah@chuv.ch.
authors.forename: Nitisha
authors.initials: N
authors.lastname: Pyndiah
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany. christian.krapp@uni-ulm.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Krapp
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany. dominik.hotter@uni-ulm.de.
authors.forename: Dominik
authors.initials: D
authors.lastname: Hotter
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany. silvia.kluge@uni-ulm.de.
authors.forename: Silvia F
authors.initials: SF
authors.lastname: Kluge
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany. nicola-goetz@web.de.
authors.forename: Nicola
authors.initials: N
authors.lastname: Götz
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany. Jessica.Heilmann1@gmx.net.
authors.forename: Jessica
authors.initials: J
authors.lastname: Heilmann
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany. katharina.mack@uni-ulm.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mack
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany. daniel.sauter@uni-ulm.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sauter
authors.affiliation: Institute of Microbiology, University of Lausanne, 1011, Lausanne, Switzerland. Danielle.thompson@unil.ch.
authors.forename: Danielle
authors.initials: D
authors.lastname: Thompson
authors.affiliation: Institute of Microbiology, University of Lausanne, 1011, Lausanne, Switzerland. Jeremie.perreaud@unil.ch.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Perreaud
authors.affiliation: Swiss Institute of Bioinformatics, 1005, Lausanne, Switzerland. antonio.rausell@isb-sib.ch.|Institute of Microbiology, University of Lausanne, 1011, Lausanne, Switzerland. antonio.rausell@isb-sib.ch.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rausell
authors.affiliation: Institute of Microbiology, University of Lausanne, 1011, Lausanne, Switzerland. Miguel.munoz@chuv.ch.
authors.forename: Miguel
authors.initials: M
authors.lastname: Munoz
authors.affiliation: Institute of Microbiology, University of Lausanne, 1011, Lausanne, Switzerland. angela.ciuffi@chuv.ch.
authors.forename: Angela
authors.initials: A
authors.lastname: Ciuffi
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany. frank.kirchhoff@uni-ulm.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
authors.affiliation: J. Craig Venter Institute, La Jolla, , CA 92037, , USA. atelenti@jcvi.org.
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D020869:Gene Expression Profiling; D005820:Genetic Testing; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate