title: Human immunodeficiency virus 1 Nef protein downmodulates the ligands of the activating receptor NKG2D and inhibits natural killer cell-mediated cytotoxicity.
abstract: Natural killer (NK) cells are a major component of the host innate immune defence against various pathogens. Several viruses, including Human immunodeficiency virus 1 (HIV-1), have developed strategies to evade the NK-cell response. This study was designed to evaluate whether HIV-1 could interfere with the expression of NK cell-activating ligands, specifically the human leukocyte antigen (HLA)-I-like MICA and ULBP molecules that bind NKG2D, an activating receptor expressed by all NK cells. Results show that the HIV-1 Nef protein downmodulates cell-surface expression of MICA, ULBP1 and ULBP2, with a stronger effect on the latter molecule. The activity on MICA and ULBP2 is well conserved in Nef protein variants derived from HIV-1-infected patients. In HIV-1-infected cells, cell-surface expression of NKG2D ligands increased to a higher extent with a Nef-deficient virus compared with wild-type virus. Mutational analysis of Nef showed that NKG2D ligand downmodulation has structural requirements that differ from those of other reported Nef activities, including HLA-I downmodulation. Finally, data demonstrate that Nef expression has functional consequences on NK-cell recognition, causing a decreased susceptibility to NK cell-mediated lysis. These findings provide a novel insight into the mechanisms evolved by HIV-1 to escape from the NK-cell response.
authors.affiliation: Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, 00161 Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cerboni
authors.affiliation: Division of Immunology and Infectious Disease, Children's Hospital Bambino Gesù, Piazza S. Onofrio 4, 00165 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Neri
authors.affiliation: Division of Immunology and Infectious Disease, Children's Hospital Bambino Gesù, Piazza S. Onofrio 4, 00165 Rome, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Casartelli
authors.affiliation: Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, 00161 Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zingoni
authors.affiliation: Amgen, Seattle, WA 98101, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cosman
authors.affiliation: Department of Pediatrics, University Tor Vergata, 00133 Rome, Italy.|Division of Immunology and Infectious Disease, Children's Hospital Bambino Gesù, Piazza S. Onofrio 4, 00165 Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rossi
authors.affiliation: Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, 00161 Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.affiliation: Division of Immunology and Infectious Disease, Children's Hospital Bambino Gesù, Piazza S. Onofrio 4, 00165 Rome, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Doria
mesh_terms: D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D015693:Gene Products, nef / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D054311:nef Gene Products, Human Immunodeficiency Virus
chemical_list: D015693:Gene Products, nef; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D054311:nef Gene Products, Human Immunodeficiency Virus