title: HIV-1 Vpu Mediates HLA-C Downregulation.
abstract: Many pathogens evade cytotoxic T lymphocytes (CTLs) by downregulating HLA molecules on infected cells, but the loss of HLA can trigger NK cell-mediated lysis. HIV-1 is thought to subvert CTLs while preserving NK cell inhibition by Nef-mediated downregulation of HLA-A and -B but not HLA-C molecules. We find that HLA-C is downregulated by most primary HIV-1 clones, including transmitted founder viruses, in contrast to the laboratory-adapted NL4-3 virus. HLA-C reduction is mediated by viral Vpu and reduces the ability of HLA-C restricted CTLs to suppress viral replication in CD4+ cells in vitro. HLA-A/B are unaffected by Vpu, and primary HIV-1 clones vary in their ability to downregulate HLA-C, possibly in response to whether CTLs or NK cells dominate immune pressure through HLA-C. HIV-2 also suppresses HLA-C expression through distinct mechanisms, underscoring the immune pressure HLA-C exerts on HIV. This viral immune evasion casts new light on the roles of CTLs and NK cells in immune responses against HIV.
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Apps
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA.
authors.forename: Gregory Q
authors.initials: GQ
authors.lastname: Del Prete
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA.
authors.forename: Pramita
authors.initials: P
authors.lastname: Chatterjee
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Lara
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC V67 1Y6, Canada.
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC V67 1Y6, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.affiliation: Department of Infectious Disease, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Neil
authors.affiliation: Department of Infectious Disease, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Pickering
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Schneider
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139-3583, USA.
authors.forename: Alicja
authors.initials: A
authors.lastname: Piechocka-Trocha
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139-3583, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: Host Genetics Section, US Military HIV Research Program, Silver Spring, MD 20910, USA.
authors.forename: Rasmi
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, PA 19104-6076, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, PA 19104-6076, USA.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA.
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD 21702, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139-3583, USA. Electronic address: carringm@mail.nih.gov.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
mesh_terms: D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D003001:Cloning, Molecular; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015236:HLA-C Antigens / Q000276:immunology / Q000378:metabolism*; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D007694:Killer Cells, Natural / Q000276:immunology; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014779:Virus Replication; D000086082:Viroporin Proteins
chemical_list: D015236:HLA-C Antigens; D054298:Human Immunodeficiency Virus Proteins; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins