title: Virion-associated Vpr of human immunodeficiency virus type 1 triggers activation of apoptotic events and enhances fas-induced apoptosis in human T cells.
abstract: Human immunodeficiency virus type 1 (HIV-1) Vpr protein exists in three different forms: soluble, intracellular, and virion associated. Previous studies showed that virion-associated Vpr induces apoptosis in activated peripheral blood mononuclear cells (PBMCs) and Jurkat T cells, but these studies were conducted in the presence of other de novo-expressed HIV proteins that may have had additive proapoptotic effects. In this report, we show that virion-associated Vpr triggers apoptosis through caspases 3/7 and 9 in human T cells independently of other HIV de novo-expressed proteins. In contrast to a previous study, we also detected the activation of caspase 8, the initiator caspase of the death receptor pathway. However, activation of all caspases by virion-associated Vpr was independent of the Fas death receptor pathway. Further analyses showed that virion-associated Vpr enhanced caspase activation in Fas-mediated apoptosis in Jurkat T cells and human activated PBMCs. Thus, our results indicate for the first time that viral particles that contain virion-associated Vpr can cause apoptosis in the absence of other de novo-expressed viral factors and can act in synergy with the Fas receptor pathway, thereby enhancing the apoptotic process in T cells. These findings suggest that virion-associated Vpr can contribute to the depletion of CD4(+) lymphocytes either directly or by enhancing Fas-mediated apoptosis during acute HIV-1 infection and in AIDS.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angeles, David Geffen School of Medicine, 615 Charles E. Young Dr. South, BSRB 173, Los Angeles, CA 90095, USA.
authors.forename: Hubert
authors.initials: H
authors.lastname: Arokium
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kamata
authors.forename: Irvin
authors.initials: I
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D004789:Enzyme Activation; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014771:Virion / Q000378:metabolism*; D019014:fas Receptor / Q000276:immunology*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D019014:fas Receptor; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; D020169:Caspases
references.citation: Blood. 1999 May 1;93(9):3053-63
references.pmid: 10216102
references.citation: Virology. 1995 Feb 1;206(2):935-44
references.pmid: 7531918
references.citation: Virology. 2007 Mar 15;359(2):243-52
references.pmid: 17056089
references.citation: Blood. 1999 Feb 1;93(3):1000-10
references.pmid: 9920849
references.citation: Virology. 2000 Oct 10;276(1):16-26
references.pmid: 11021990
references.citation: Cell Death Differ. 2003 Jan;10(1):26-35
references.pmid: 12655293
references.citation: Oncogene. 2002 Jul 11;21(30):4613-25
references.pmid: 12096338
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3369-74
references.pmid: 16492778
references.citation: Blood. 1997 Mar 15;89(6):2060-6
references.pmid: 9058728
references.citation: J Virol. 2008 Jun;82(12):5672-82
references.pmid: 18385244
references.citation: J Immunol. 2003 Mar 1;170(5):2629-37
references.pmid: 12594291
references.citation: Apoptosis. 2007 May;12(5):803-13
references.pmid: 17294081
references.citation: PLoS Pathog. 2006 Dec;2(12):e127
references.pmid: 17140287
references.citation: Nature. 1995 Jun 8;375(6531):497-500
references.pmid: 7539892
references.citation: J Virol. 1995 Nov;69(11):6705-11
references.pmid: 7474080
references.citation: J Acquir Immune Defic Syndr (1988). 1990;3(1):11-8
references.pmid: 2136707
references.citation: Apoptosis. 2003 Mar;8(2):115-28
references.pmid: 12766472
references.citation: J Biol Chem. 2007 Sep 14;282(37):27046-27057
references.pmid: 17620334
references.citation: J Virol. 1996 Jan;70(1):199-206
references.pmid: 8523526
references.citation: Nature. 1988 Jun 2;333(6172):457-61
references.pmid: 3374586
references.citation: Cell. 1998 Aug 21;94(4):481-90
references.pmid: 9727491
references.citation: J Biol Chem. 1999 Mar 26;274(13):9083-91
references.pmid: 10085158
references.citation: Cell Death Differ. 2002 Nov;9(11):1212-9
references.pmid: 12404120
references.citation: J Immunol. 1997 Mar 1;158(5):2456-63
references.pmid: 9036997
references.citation: J Virol. 1997 Jul;71(7):5579-92
references.pmid: 9188632
references.citation: Genes Dev. 1998 Jan 15;12(2):175-85
references.pmid: 9436978
references.citation: J Virol. 1995 Nov;69(11):6873-9
references.pmid: 7474102
references.citation: Nat Med. 1997 Oct;3(10):1117-23
references.pmid: 9334723
references.citation: Immunology. 1996 Apr;87(4):581-5
references.pmid: 8675212
references.citation: Biochem Biophys Res Commun. 2006 Sep 29;348(3):1101-6
references.pmid: 16904642
references.citation: Science. 2001 Nov 2;294(5544):1105-8
references.pmid: 11691994
references.citation: J Neurovirol. 2002 Apr;8(2):86-99
references.pmid: 11935461
references.citation: Nature. 2005 Apr 28;434(7037):1093-7
references.pmid: 15793563
references.citation: Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10873-7
references.pmid: 7971975
references.citation: J Virol. 1999 Jan;73(1):592-600
references.pmid: 9847364
references.citation: J Virol. 2000 Apr;74(7):3105-11
references.pmid: 10708425
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9571-6
references.pmid: 8790371
references.citation: J Exp Med. 2001 Feb 19;193(4):509-19
references.pmid: 11181702
references.citation: J Virol. 1995 Oct;69(10):6304-13
references.pmid: 7666531
references.citation: J Clin Invest. 2003 May;111(10):1547-54
references.pmid: 12750404
references.citation: J Virol. 1999 Jan;73(1):92-100
references.pmid: 9847311
references.citation: J Virol. 1998 Jun;72(6):4686-93
references.pmid: 9573232
references.citation: Nat Rev Immunol. 2003 Sep;3(9):745-56
references.pmid: 12949498
references.citation: Blood. 1996 Sep 1;88(5):1741-6
references.pmid: 8781430
references.citation: J Biol Chem. 2002 Oct 4;277(40):37820-31
references.pmid: 12095993
references.citation: J Virol. 2007 Apr;81(8):4367-70
references.pmid: 17267494
references.citation: J Virol. 2000 Oct;74(20):9717-26
references.pmid: 11000244
references.citation: Oncogene. 1996 Aug 1;13(3):487-93
references.pmid: 8760290
references.citation: Annu Rev Cell Dev Biol. 2005;21:35-56
references.pmid: 16212486
references.citation: J Biol Chem. 1999 Jan 15;274(3):1541-8
references.pmid: 9880531
references.citation: Clin Dev Immunol. 2007;2007:93462
references.pmid: 18317535
references.citation: J Virol. 2008 Sep;82(18):9265-72
references.pmid: 18596088
references.citation: EMBO J. 1998 Mar 16;17(6):1675-87
references.pmid: 9501089
references.citation: J Immunol. 1996 Mar 15;156(6):2282-93
references.pmid: 8690919
references.citation: Mol Biol Cell. 2004 Apr;15(4):1793-801
references.pmid: 14767062
references.citation: Cytometry. 1995 Jun 15;22(2):111-4
references.pmid: 7587741
references.citation: Virology. 2001 Jul 5;285(2):181-92
references.pmid: 11437653
references.citation: Cell. 2004 Jan 23;116(2):205-19
references.pmid: 14744432
references.citation: Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4595-600
references.pmid: 9539783
references.citation: Nat Med. 1995 Feb;1(2):129-34
references.pmid: 7585008
references.citation: J Intern Med. 2005 Dec;258(6):479-517
references.pmid: 16313474
references.citation: J Clin Invest. 1998 Jul 1;102(1):79-87
references.pmid: 9649560
references.citation: Cancer Res. 2006 Jan 15;66(2):627-31
references.pmid: 16423988
references.citation: J Virol. 1996 Apr;70(4):2516-24
references.pmid: 8642681
references.citation: Oncogene. 2000 Sep 21;19(40):4563-73
references.pmid: 11030145
references.citation: AIDS. 1996 Feb;10(2):131-41
references.pmid: 8838700
references.citation: J Exp Med. 1998 Sep 7;188(5):979-84
references.pmid: 9730899
references.citation: AIDS. 2000 May 26;14(8):939-49
references.pmid: 10853975
references.citation: J Virol. 1999 May;73(5):4101-9
references.pmid: 10196306
references.citation: Cell. 1998 Aug 21;94(4):491-501
references.pmid: 9727492
references.citation: EMBO J. 1992 Sep;11(9):3405-12
references.pmid: 1324171
references.citation: Science. 1995 Apr 21;268(5209):429-31
references.pmid: 7716549
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12039-43
references.pmid: 10518572
references.citation: Nature. 2005 Apr 28;434(7037):1148-52
references.pmid: 15793562
references.citation: Virology. 1994 May 1;200(2):623-31
references.pmid: 8178448
references.citation: J Exp Med. 2000 Jan 3;191(1):33-46
references.pmid: 10620603
references.citation: J Virol. 1995 Nov;69(11):6859-64
references.pmid: 7474100