title: Impaired plasmacytoid dendritic cell (PDC)-NK cell activity in viremic human immunodeficiency virus infection attributable to impairments in both PDC and NK cell function.
abstract: Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections impair plasmacytoid dendritic cell (PDC) and natural killer (NK) cell subset numbers and functions, though little is known about PDC-NK cell interactions during these infections. We evaluated PDC-dependent NK cell killing and gamma interferon (IFN-gamma) and granzyme B production, using peripheral blood mononuclear cell (PBMC)-based and purified cell assays of samples from HCV- and HIV-infected subjects. CpG-enhanced PBMC killing and IFN-gamma and granzyme B activity (dependent on PDC and NK cells) were impaired in viremic HIV infection. In purified PDC-NK cell culture experiments, CpG-enhanced, PDC-dependent NK cell activity was cell contact and IFN-alpha dependent, and this activity was impaired in viremic HIV infection but not in HCV infection. In heterologous PDC-NK cell assays, impaired PDC-NK cell killing activity was largely attributable to an NK cell defect, while impaired PDC-NK cell IFN-gamma-producing activity was attributable to both PDC and NK cell defects. Additionally, the response of NK cells to direct IFN-alpha stimulation was defective in viremic HIV infection, and this defect was not attributable to diminished IFN-alpha receptor expression, though IFN-alpha receptor and NKP30 expression was closely associated with killer activity in viremic HIV infection but not in healthy controls. These data indicate that during uncontrolled HIV infection, PDC-dependent NK cell function is impaired, which is in large part attributable to defective IFN-alpha-induced NK cell activity and not to altered IFN-alpha receptor, NKP30, NKP44, NKP46, or NKG2D expression.
authors.affiliation: Department of Medicine, Case Western Reserve University Center for AIDS Research, University Hospitals of Cleveland, OH, USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Conry
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Milkovich
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Yonkers
authors.forename: Benigno
authors.initials: B
authors.lastname: Rodriguez
authors.forename: Helene B
authors.initials: HB
authors.lastname: Bernstein
authors.forename: Robert
authors.initials: R
authors.lastname: Asaad
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Heinzel
authors.forename: Magdalena
authors.initials: M
authors.lastname: Tary-Lehmann
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
authors.forename: Donald D
authors.initials: DD
authors.lastname: Anthony
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D018899:CpG Islands; D003603:Cytotoxins / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D053804:Granzymes / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D014766:Viremia / Q000276:immunology*
chemical_list: D003603:Cytotoxins; D016898:Interferon-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D053804:Granzymes
references.citation: J Immunol. 2007 Apr 1;178(7):4436-44
references.pmid: 17372001
references.citation: Hepatology. 2004 Aug;40(2):335-45
references.pmid: 15368438
references.citation: Clin Immunol. 2001 Nov;101(2):201-10
references.pmid: 11683579
references.citation: N Engl J Med. 1989 Jun 29;320(26):1731-5
references.pmid: 2543925
references.citation: Blood. 2005 Jul 15;106(2):609-16
references.pmid: 15802534
references.citation: J Immunol. 2004 Sep 15;173(6):3594-8
references.pmid: 15356102
references.citation: J Immunol. 2008 Jun 15;180(12):7785-91
references.pmid: 18523242
references.citation: J Immunol. 2005 Jan 15;174(2):727-34
references.pmid: 15634892
references.citation: J Exp Med. 1995 Sep 1;182(3):789-99
references.pmid: 7650485
references.citation: Hepatology. 2006 Mar;43(3):573-80
references.pmid: 16496327
references.citation: Immunol Today. 1992 Oct;13(10):392-5
references.pmid: 1418374
references.citation: Eur J Immunol. 1999 May;29(5):1656-66
references.pmid: 10359120
references.citation: Eur J Immunol. 2001 Dec;31(12):3546-56
references.pmid: 11745374
references.citation: J Immunol. 2004 Nov 15;173(10):6072-81
references.pmid: 15528343
references.citation: J Immunol. 2003 Dec 1;171(11):5663-7
references.pmid: 14634071
references.citation: Nat Genet. 2002 Aug;31(4):429-34
references.pmid: 12134147
references.citation: J Clin Invest. 2007 Nov;117(11):3316-29
references.pmid: 17948125
references.citation: Immunity. 2004 Jul;21(1):107-19
references.pmid: 15345224
references.citation: J Immunol. 2007 Aug 15;179(4):2642-50
references.pmid: 17675528
references.citation: J Immunol. 2002 Jun 1;168(11):5764-70
references.pmid: 12023377
references.citation: Pediatr AIDS HIV Infect. 1996 Feb;7(1):31-6
references.pmid: 11361470
references.citation: Science. 2004 Aug 6;305(5685):872-4
references.pmid: 15297676
references.citation: Blood. 2006 Dec 1;108(12):3851-8
references.pmid: 16873676
references.citation: Clin Immunol Immunopathol. 1989 May;51(2):294-302
references.pmid: 2539283
references.citation: Blood. 2004 Nov 15;104(10):3267-75
references.pmid: 15242871
references.citation: J Infect Dis. 2004 Dec 1;190(11):1919-26
references.pmid: 15529255
references.citation: J Exp Med. 2002 Feb 4;195(3):327-33
references.pmid: 11828007
references.citation: J Allergy Clin Immunol. 1990 Feb;85(2):453-9
references.pmid: 2303649
references.citation: J Immunol. 2004 Apr 15;172(8):4907-16
references.pmid: 15067070
references.citation: J Immunol. 2004 Oct 15;173(8):5305-11
references.pmid: 15470077
references.citation: J Immunol. 2007 Oct 1;179(7):4608-15
references.pmid: 17878358
references.citation: Immunol Lett. 1994 May;40(2):83-8
references.pmid: 8088876
references.citation: Proc Natl Acad Sci U S A. 2002 May 14;99(10):7015-20
references.pmid: 12011460
references.citation: Virology. 2009 Apr 25;387(1):59-66
references.pmid: 19251297
references.citation: J Immunol. 1984 Nov;133(5):2743-7
references.pmid: 6207244
references.citation: Clin Exp Immunol. 1997 Sep;109(3):451-7
references.pmid: 9328121
references.citation: N Engl J Med. 1983 Jan 13;308(2):79-83
references.pmid: 6216408
references.citation: J Clin Invest. 1983 Jul;72(1):398-403
references.pmid: 6308051
references.citation: Blood. 2001 Aug 15;98(4):906-12
references.pmid: 11493432
references.citation: Clin Immunol. 2001 May;99(2):232-40
references.pmid: 11318595
references.citation: Immunity. 2007 Apr;26(4):503-17
references.pmid: 17398124
references.citation: J Hepatol. 2001 Nov;35(5):650-7
references.pmid: 11690712
references.citation: Hepatology. 2005 Mar;41(3):643-51
references.pmid: 15726647
references.citation: Hepatology. 2000 Nov;32(5):962-9
references.pmid: 11050046
references.citation: J Immunol. 2002 May 1;168(9):4796-801
references.pmid: 11971031
references.citation: J Immunol. 2007 Aug 15;179(4):2097-104
references.pmid: 17675468
references.citation: J Infect Dis. 2005 Aug 1;192(3):497-503
references.pmid: 15995965
references.citation: Science. 1999 Feb 19;283(5405):1183-6
references.pmid: 10024247
references.citation: Eur J Immunol. 2003 Sep;33(9):2410-8
references.pmid: 12938217
references.citation: Clin Exp Immunol. 2005 Nov;142(2):327-32
references.pmid: 16232220
references.citation: J Hepatol. 2002 Oct;37(4):514-22
references.pmid: 12217606
references.citation: J Exp Med. 1999 Nov 15;190(10):1505-16
references.pmid: 10562324
references.citation: J Immunol. 1987 Feb 1;138(3):884-8
references.pmid: 3805719
references.citation: Blood. 2009 May 28;113(22):5497-505
references.pmid: 19299650
references.citation: Immunity. 2003 Oct;19(4):561-9
references.pmid: 14563320
references.citation: J Virol. 1999 Oct;73(10):8469-75
references.pmid: 10482599
references.citation: J Immunol. 2003 Sep 1;171(5):2366-73
references.pmid: 12928383