title: Virion encapsidated HIV-1 Vpr induces NFAT to prime non-activated T cells for productive infection.
abstract: The majority of T cells encountered by HIV-1 are non-activated and do not readily allow productive infection. HIV-1 Vpr is highly abundant in progeny virions, and induces signalling and HIV-1 LTR transcription. We hence hypothesized that Vpr might be a determinant of non-activated T-cell infection. Virion-delivered Vpr activated nuclear factor of activated T cells (NFAT) through Ca(2+) influx and interference with the NFAT export kinase GSK3β. This leads to NFAT translocation and accumulation within the nucleus and was required for productive infection of unstimulated primary CD4(+) T cells. A mutagenesis approach revealed correlation of Vpr-mediated NFAT activation with its ability to enhance LTR transcription and mediate cell cycle arrest. Upon NFAT inhibition, Vpr did not augment resting T-cell infection, and showed reduced G2/M arrest and LTR transactivation. Altogether, Vpr renders unstimulated T cells more permissive for productive HIV-1 infection and stimulates activation of productively infected as well as virus-exposed T cells. Therefore, it could be involved in the establishment and reactivation of HIV-1 from viral reservoirs and might have an impact on the levels of immune activation, which are determinants of HIV-1 pathogenesis.
authors.affiliation: Institute of Virology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Höhne
authors.affiliation: Institute of Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Businger
authors.affiliation: Institute of Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Anouk
authors.initials: A
authors.lastname: van Nuffel
authors.affiliation: Institute of Virology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bolduan
authors.affiliation: Institute of Virology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Herwig
authors.initials: H
authors.lastname: Koppensteiner
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Baeyens
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
authors.forename: Jolien
authors.initials: J
authors.lastname: Vermeire
authors.affiliation: HIV Translational Research Unit, Department of Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Malatinkova
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium bruno.verhasselt@ugent.be.
authors.forename: Bruno
authors.initials: B
authors.lastname: Verhasselt
authors.affiliation: Institute of Virology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany Institute of Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany michael.schindler@med.uni-tuebingen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Schindler
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D057809:HEK293 Cells; D016325:HIV Long Terminal Repeat; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D050778:NFATC Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014771:Virion / Q000235:genetics* / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D050778:NFATC Transcription Factors; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D002118:Calcium
keywords: HIV-1; NFAT; Vpr; productive T-cell infection