title: Vpr overcomes macrophage-specific restriction of HIV-1 Env expression and virion production.
abstract: The HIV-1 accessory protein Vpr enhances infection of primary macrophages through unknown mechanisms. Recent studies demonstrated that Vpr interactions with the cellular DCAF1-DDB1-CUL4 E3 ubiquitin ligase complex limit activation of innate immunity and interferon (IFN) induction. We describe a restriction mechanism that targets the HIV-1 envelope protein Env, but is overcome by Vpr and its interaction with DCAF1. This restriction is active in the absence of Vpr in HIV-1-infected primary macrophages and macrophage-epithelial cell heterokaryons, but not epithelial cell lines. HIV-1-infected macrophages lacking Vpr express more IFN following infection, target Env for lysosomal degradation, and produce fewer Env-containing virions. Conversely, Vpr expression reduces IFN induction, rescues Env expression, and enhances virion release. Addition of IFN or silencing DCAF1 reduces the amount of cell-associated Env and virion production in wild-type HIV-1-infected primary macrophages. These findings provide insight into an IFN-stimulated macrophage-specific restriction pathway targeting HIV-1 Env that is counteracted by Vpr.
authors.affiliation: Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mashiba
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Collins
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Valeri H
authors.initials: VH
authors.lastname: Terry
authors.affiliation: Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: klcollin@umich.edu.
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Collins
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007372:Interferons / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000821:virology*; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D014771:Virion / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; D007372:Interferons; D044767:Ubiquitin-Protein Ligases; C530533:DCAF1 protein, human; D017346:Protein Serine-Threonine Kinases