title: Human uterine natural killer cells but not blood natural killer cells inhibit human immunodeficiency virus type 1 infection by secretion of CXCL12.
abstract: Natural killer (NK) cells derived from the human female reproductive tract (FRT) are phenotypically and functionally distinct from those obtained from peripheral blood. Because the FRT is a primary site of human immunodeficiency virus type 1 (HIV-1) infection in women, we determined whether soluble factors secreted by uterine-derived NK (uNK) cells inhibit HIV-1 infection. Clonal populations of uNK cells were activated with interleukin-12 (IL-12) and IL-15, and conditioned media (CM) from these cultures evaluated for their ability to inhibit infection of cells by HIV-1(IIIB), HIV-1(NL4.3), and HIV-1(HC4) (X4-tropic) or HIV-1(BaL) (R5-tropic) viruses. We found that soluble factors secreted by activated uNK cells significantly inhibited X4-tropic virus infection of TZM-bl cells, peripheral blood mononuclear cells, and primary human endometrial cells, but not infection by HIV-1(BaL). In contrast, CM from peripheral blood NK (bNK) cells did not inhibit HIV-1 infection of cells. Analysis of factors secreted from uNK clones with anti-HIV-1 activity demonstrated significantly higher levels of CXCL12 compared to uNK clones without this activity, and the HIV inhibitory activity was neutralized by antibodies to CXCL12. Collectively, these data demonstrate that human uNK cells release chemokines with anti-HIV-1 activity for X4-tropic strains and this suggest that these chemokines may contribute to the inhibition of X4-tropic strain transmission across mucosal tissues.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
authors.forename: Teddy F
authors.initials: TF
authors.lastname: Mselle
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Howell
authors.forename: Mimi
authors.initials: M
authors.lastname: Ghosh
authors.forename: Charles R
authors.initials: CR
authors.lastname: Wira
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sentman
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000276:immunology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D008875:Middle Aged; D014599:Uterus / Q000166:cytology / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents; D054377:Chemokine CXCL12; D016207:Cytokines
references.citation: J Immunol. 2003 Dec 1;171(11):5663-7
references.pmid: 14634071
references.citation: Clin Exp Immunol. 1990 Mar;79(3):430-5
references.pmid: 1969336
references.citation: J Immunol. 1998 Dec 1;161(11):6433-8
references.pmid: 9834136
references.citation: J Clin Invest. 1996 Jun 15;97(12):2722-7
references.pmid: 8675682
references.citation: Science. 1995 Dec 15;270(5243):1811-5
references.pmid: 8525373
references.citation: Antimicrob Agents Chemother. 2002 Jun;46(6):1896-905
references.pmid: 12019106
references.citation: Biol Reprod. 1994 Mar;50(3):461-6
references.pmid: 8167216
references.citation: Hum Immunol. 1989 Mar;24(3):195-205
references.pmid: 2925453
references.citation: Diagn Clin Immunol. 1988;5(6):297-303
references.pmid: 3219779
references.citation: J Infect Dis. 2003 Apr 1;187(7):1038-45
references.pmid: 12660917
references.citation: Eur J Immunol. 2002 Mar;32(3):879-84
references.pmid: 11870632
references.citation: J Clin Endocrinol Metab. 2004 May;89(5):2470-6
references.pmid: 15126579
references.citation: J Virol. 1999 May;73(5):3608-15
references.pmid: 10196252
references.citation: Antiviral Res. 2007 Feb;73(2):132-9
references.pmid: 16997390
references.citation: J Immunol. 2006 May 15;176(10):6219-24
references.pmid: 16670332
references.citation: Am J Reprod Immunol. 2005 Dec;54(6):322-31
references.pmid: 16305657
references.citation: Cell. 1996 Jun 28;85(7):1135-48
references.pmid: 8674119
references.citation: Nature. 2001 Apr 19;410(6831):968-73
references.pmid: 11309626
references.citation: Hum Reprod Update. 2000 Jan-Feb;6(1):28-36
references.pmid: 10711827
references.citation: Curr Womens Health Rev. 2008 May;4(2):102-117
references.pmid: 19644567
references.citation: Eur J Immunol. 1999 Nov;29(11):3654-62
references.pmid: 10556821
references.citation: Nat Rev Immunol. 2005 Nov;5(11):835-43
references.pmid: 16239902
references.citation: Nature. 1996 Aug 29;382(6594):833-5
references.pmid: 8752281
references.citation: Adv Immunol. 1989;47:187-376
references.pmid: 2683611
references.citation: J Immunol. 2004 Jan 1;172(1):88-96
references.pmid: 14688313
references.citation: Biochem Soc Trans. 1997 May;25(2):687-90
references.pmid: 9191183
references.citation: Clin Immunol. 2007 Jul;124(1):69-76
references.pmid: 17524808
references.citation: Nature. 2009 Feb 5;457(7230):722-5
references.pmid: 18978771
references.citation: AIDS. 2004 Sep 3;18(13):1769-79
references.pmid: 15316337
references.citation: J Leukoc Biol. 2004 Sep;76(3):667-75
references.pmid: 15178706
references.citation: Am J Reprod Immunol. 1997 Nov;38(5):350-9
references.pmid: 9352027
references.citation: Int Immunol. 2008 Nov;20(11):1395-405
references.pmid: 18815119
references.citation: Clin Immunol. 2006 Aug;120(2):138-46
references.pmid: 16624619
references.citation: Blood. 2001 May 15;97(10):3146-51
references.pmid: 11342442
references.citation: J Immunol. 2008 Aug 1;181(3):1869-76
references.pmid: 18641324
references.citation: J Clin Endocrinol Metab. 2003 Apr;88(4):1809-14
references.pmid: 12679478
references.citation: Blood. 1990 Dec 15;76(12):2421-38
references.pmid: 2265240
references.citation: Pathobiology. 1996;64(4):171-9
references.pmid: 9031325
references.citation: J Virol. 2000 Feb;74(4):1648-57
references.pmid: 10644334
references.citation: J Exp Med. 1997 Jul 7;186(1):139-46
references.pmid: 9207008
references.citation: Nature. 1996 Aug 29;382(6594):829-33
references.pmid: 8752280
references.citation: Nature. 1996 Jun 20;381(6584):667-73
references.pmid: 8649512
references.citation: Immunity. 2008 Dec 19;29(6):958-70
references.pmid: 19084435
references.citation: Annu Rev Immunol. 2004;22:405-29
references.pmid: 15032583
references.citation: J Leukoc Biol. 1997 Dec;62(6):693-701
references.pmid: 9400809