Human immunodeficiency virus 1 Nef protein downmodulates the ligands of the activating receptor NKG2D and inhibits natural killer cell-mediated cytotoxicity

Journal of General Virology - Tập 88 Số 1 - Trang 242-250 - 2007
Cristina Cerboni1, Francesca Neri2, Nicoletta Casartelli2, Alessandra Zingoni1, David Cosman3, Paolo Rossi4,2, Angela Santoni1, Margherita Doria2
1Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, 00161 Rome, Italy
2Division of Immunology and Infectious Disease, Children's Hospital Bambino Gesù, Piazza S. Onofrio 4, 00165 Rome, Italy
3Amgen, Seattle, WA 98101, USA
4Department of Pediatrics, University Tor Vergata, 00133 Rome, Italy

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

Arold, 2001, Dynamic Nef and Nef dynamics: how structure could explain the complex activities of this small HIV protein, Trends Biochem Sci, 26, 356, 10.1016/S0968-0004(01)01846-1

Bauer, 1999, Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA, Science, 285, 727, 10.1126/science.285.5428.727

Baur, 2004, Functions of the HIV-1 Nef protein, Curr Drug Targets Immune Endocr Metabol Disord, 4, 309, 10.2174/1568008043339749

Bonaparte, 2003, Inability of natural killer cells to destroy autologous HIV-infected T lymphocytes, AIDS, 17, 487, 10.1097/00002030-200303070-00003

Carl, 2001, Modulation of different human immunodeficiency virus type 1 Nef functions during progression to AIDS, J Virol, 75, 3657, 10.1128/JVI.75.8.3657-3665.2001

Casartelli, 2003a, Structural defects and variations in the HIV-1 nef gene from rapid, slow and non-progressor children, AIDS, 17, 1291, 10.1097/00002030-200306130-00003

Casartelli, 2003b, CD4 and major histocompatibility complex class I downregulation by the human immunodeficiency virus type 1 nef protein in pediatric AIDS progression, J Virol, 77, 11536, 10.1128/JVI.77.21.11536-11545.2003

Cerboni, 2001, Synergistic effect of IFN-gamma and human cytomegalovirus protein UL40 in the HLA-E-dependent protection from NK cell-mediated cytotoxicity, Eur J Immunol, 31, 2926, 10.1002/1521-4141(2001010)31:10<2926::AID-IMMU2926>3.0.CO;2-2

Chalupny, 2003, ULBP4 is a novel ligand for human NKG2D, Biochem Biophys Res Commun, 305, 129, 10.1016/S0006-291X(03)00714-9

Chowers, 1994, Optimal infectivity in vitro of human immunodeficiency virus type 1 requires an intact nef gene, J Virol, 68, 2906, 10.1128/JVI.68.5.2906-2914.1994

Cohen, 1999, The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells, Immunity, 10, 661, 10.1016/S1074-7613(00)80065-5

Collins, 1998, HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes, Nature, 391, 397, 10.1038/34929

Cosman, 2001, ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor, Immunity, 14, 123, 10.1016/S1074-7613(01)00095-4

Deacon, 1995, Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients, Science, 270, 988, 10.1126/science.270.5238.988

Doms, 2000, The plasma membrane as a combat zone in the HIV battlefield, Genes Dev, 14, 2677, 10.1101/gad.833300

Eger, 2004, Perturbation of natural killer cell function and receptors during HIV infection, Trends Microbiol, 12, 301, 10.1016/j.tim.2004.05.006

Gasser, 2005, The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor, Nature, 436, 1186, 10.1038/nature03884

Gervaix, 1997, A new reporter cell line to monitor HIV infection and drug susceptibility in vitro, Proc Natl Acad Sci U S A, 94, 4653, 10.1073/pnas.94.9.4653

Geyer, 2001, Structure–function relationships in HIV-1 Nef, EMBO Rep, 2, 580, 10.1093/embo-reports/kve141

Groh, 2002, Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation, Nature, 419, 734, 10.1038/nature01112

Grzesiek, 1996, The CD4 determinant for downregulation by HIV-1 Nef directly binds to Nef. Mapping of the Nef binding surface by NMR, Biochemistry, 35, 10256, 10.1021/bi9611164

Hanna, 1998, Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice, Cell, 95, 163, 10.1016/S0092-8674(00)81748-1

Kirchhoff, 1995, Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection, N Engl J Med, 332, 228, 10.1056/NEJM199501263320405

Lanier, 2005, NK cell recognition, Annu Rev Immunol, 23, 225, 10.1146/annurev.immunol.23.021704.115526

Le Gall, 1998, Nef interacts with the mu subunit of clathrin adaptor complexes and reveals a cryptic sorting signal in MHC I molecules, Immunity, 8, 483, 10.1016/S1074-7613(00)80553-1

Liu, 2001, HIV Nef-mediated cellular phenotypes are differentially expressed as a function of intracellular Nef concentrations, J Biol Chem, 276, 32763, 10.1074/jbc.M101025200

Lodoen, 2005, Viral modulation of NK cell immunity, Nat Rev Microbiol, 3, 59, 10.1038/nrmicro1066

Maier, 2000, Kinetics of CXCR4 and CCR5 up-regulation and human immunodeficiency virus expansion after antigenic stimulation of primary CD4(+) T lymphocytes, Blood, 96, 1853, 10.1182/blood.V96.5.1853

McMichael, 1998, T cell responses and viral escape, Cell, 93, 673, 10.1016/S0092-8674(00)81428-2

Pende, 2001, Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin, Eur J Immunol, 31, 1076, 10.1002/1521-4141(200104)31:4<1076::AID-IMMU1076>3.0.CO;2-Y

Peterlin, 2003, Hide, shield and strike back: how HIV-infected cells avoid immune eradication, Nat Rev Immunol, 3, 97, 10.1038/nri998

Pross, 1986, Assay for NK cell cytotoxicity – their values and pitfalls, In Immunobiology of Natural Killer Cells, 2

Raulet, 2003, Roles of the NKG2D immunoreceptor and its ligands, Nat Rev Immunol, 3, 781, 10.1038/nri1199

Robertson, 1996, Characterization of a cell line, NKL, derived from an aggressive human natural killer cell leukemia, Exp Hematol, 24, 406

Rölle, 2003, Effects of human cytomegalovirus infection on ligands for the activating NKG2D receptor of NK cells: up-regulation of UL16-binding protein (ULBP)1 and ULBP2 is counteracted by the viral UL16 protein, J Immunol, 171, 902, 10.4049/jimmunol.171.2.902

Salih, 2003, Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia, Blood, 102, 1389, 10.1182/blood-2003-01-0019

Schrager, 1999, HIV-1 Nef increases T cell activation in a stimulus-dependent manner, Proc Natl Acad Sci U S A, 96, 8167, 10.1073/pnas.96.14.8167

Schwartz, 1993, Reduced cell surface expression of processed human immunodeficiency virus type 1 envelope glycoprotein in the presence of Nef, J Virol, 67, 3274, 10.1128/JVI.67.6.3274-3280.1993

Welte, 2003, Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein, Eur J Immunol, 33, 194, 10.1002/immu.200390022