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Journal of Virology, November 2009, p. 11188-11195, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00562-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Uterine Natural Killer Cells but Not Blood Natural Killer Cells Inhibit Human Immunodeficiency Virus Type 1 Infection by Secretion of CXCL12 {triangledown}

Teddy F. Mselle,1 Alexandra L. Howell,1,3 Mimi Ghosh,2 Charles R. Wira,2 and Charles L. Sentman1*

Department of Microbiology and Immunology,1 Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire,2 Veterans Affairs Medical Center, White River Junction, Vermont3

Received 18 March 2009/ Accepted 14 May 2009

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-1IIIB, HIV-1NL4.3, and HIV-1HC4 (X4-tropic) or HIV-1BaL (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-1BaL. 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.

* Corresponding author. Mailing address: Department of Microbiology & Immunology, Dartmouth Medical School, Borwell Research Bldg., One Medical Center Drive, Lebanon NH 03756. Phone: (603) 653-0611. Fax: (603) 650-6223. E-mail: Charles.L.Sentman{at}Dartmouth.edu

{triangledown} Published ahead of print on 19 August 2009.

Journal of Virology, November 2009, p. 11188-11195, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00562-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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