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Journal of Virology, June 2009, p. 5999-6010, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.02350-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Potential Role of Interleukin-18 in the Immunopathogenesis of AIDS: Involvement in Fratricidal Killing of NK Cells{triangledown}

Alexandre Iannello,1,4,{dagger} Suzanne Samarani,1,4,{dagger} Olfa Debbeche,1,4 Rasheed Ahmad,1,4 Mohamed-Rachid Boulassel,2 Cécile Tremblay,3,4 Emil Toma,3,4 Jean-Pierre Routy,2 and Ali Ahmad1,4*

Laboratory of Innate Immunity, CHU-Sainte-Justine Research Center,1 Division of Infectious Diseases, CHUM-Hotel Dieu,3 Department of Microbiology and Immunology, University of Montreal, Montreal, Quebec H3T 1C5, Canada,4 McGill University Health Center, McGill University, Montreal, Quebec H3A 2T5, Canada2

Received 11 November 2008/ Accepted 23 March 2009

We had shown earlier that the concentrations of circulating interleukin-18 (IL-18) are increased significantly in human immunodeficiency virus (HIV)-infected persons compared to HIV-seronegative healthy subjects. In the present study, we investigated the consequences of these elevated levels of IL-18 on natural killer (NK) cells and the immunopathogenesis of AIDS. We show here an inverse correlation between IL-18 concentrations and absolute numbers of various subsets of NK cells in infected persons. Recombinant human IL-18 caused increased death of a human NK cell line, as well as of primary human NK cells in vitro. The IL-18-mediated cell death was dependent upon Fas-FasL interactions and tumor necrosis factor alpha. IL-18 induced the expression of FasL on NK cells, increased the transcription from the human FasL promoter, reduced the expression of Bcl-XL in NK cells, and increased their sensitivity to FasL-mediated cell death. These results suggest that increased IL-18 concentrations present in the circulation of HIV-infected persons contribute to the immunopathogenesis of AIDS by altering NK cell homeostasis.

* Corresponding author. Mailing address: Laboratory of Innate Immunity, CHU-Sainte-Justine Research Center/Department of Microbiology and Immunology, University of Montreal, 3175 Chemin de la Côte Sainte Catherine, Montreal, Quebec H3T 1C5, Canada. Phone: (514) 345-4931, ext. 6157. Fax: (514) 345-4801. E-mail: ali.ahmad{at}recherche-ste-justine.qc.ca

{triangledown} Published ahead of print on 1 April 2009.

{dagger} A.I. and S.S. contributed equally to this study.

Journal of Virology, June 2009, p. 5999-6010, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.02350-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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