title: Cell Surface Proteomic Map of HIV Infection Reveals Antagonism of Amino Acid Metabolism by Vpu and Nef.
abstract: Critical cell surface immunoreceptors downregulated during HIV infection have previously been identified using non-systematic, candidate approaches. To gain a comprehensive, unbiased overview of how HIV infection remodels the T cell surface, we took a distinct, systems-level, quantitative proteomic approach. >100 plasma membrane proteins, many without characterized immune functions, were downregulated during HIV infection. Host factors targeted by the viral accessory proteins Vpu or Nef included the amino acid transporter SNAT1 and the serine carriers SERINC3/5. We focused on SNAT1, a β-TrCP-dependent Vpu substrate. SNAT1 antagonism was acquired by Vpu variants from the lineage of SIVcpz/HIV-1 viruses responsible for pandemic AIDS. We found marked SNAT1 induction in activated primary human CD4+ T cells, and used Consumption and Release (CoRe) metabolomics to identify alanine as an endogenous SNAT1 substrate required for T cell mitogenesis. Downregulation of SNAT1 therefore defines a unique paradigm of HIV interference with immunometabolism.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. Electronic address: njm25@cam.ac.uk.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Matheson
authors.affiliation: Department of Infectious Diseases, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sumner
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Wals
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Radu
authors.initials: R
authors.lastname: Rapiteanu
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Weekes
authors.affiliation: Department of Infectious Diseases, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Raphael
authors.initials: R
authors.lastname: Vigan
authors.affiliation: Department of Infectious Diseases, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Weinelt
authors.affiliation: Helmholtz Center Munich, Institute of Virology, 85764 Neuherberg, Germany; Institute of Medical Virology and Epidemiology of Viral Diseases, University Clinic Tübingen, 72076 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schindler
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Antrobus
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: Ana S H
authors.initials: AS
authors.lastname: Costa
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.affiliation: The Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Department of Infectious Diseases, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Stuart J D
authors.initials: SJ
authors.lastname: Neil
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. Electronic address: pjl30@cam.ac.uk.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry* / Q000821:virology; D002462:Cell Membrane / Q000737:chemistry*; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000032:analysis*; D020543:Proteome / Q000032:analysis; D040901:Proteomics / Q000379:methods; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D000596:Amino Acids; D054298:Human Immunodeficiency Virus Proteins; D008565:Membrane Proteins; D020543:Proteome; D054334:Viral Regulatory and Accessory Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins