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Journal of Virology, June 2004, p. 6033-6042, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.6033-6042.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-Human Immunodeficiency Virus Activity

Julian J. Lum,1 David J. Schnepple,2 Zilin Nie,1,2 Jaime Sanchez-Dardon,1 Georgina L. Mbisa,1 Jennifer Mihowich,3 Nanci Hawley,1,2 Shanil Narayan,1 John E. Kim,3 David H. Lynch,4 and Andrew D. Badley1,2,5*

Ottawa Health Research Institute, University of Ottawa,1 National HIV/AIDS Laboratories, Health Canada, Ottawa, Ontario, Canada,3 Immunex Corporation, Seattle, Washington,4 Division of Infectious Diseases,2 Program in Translational Immunovirology and Biodefense, Mayo Clinic and Foundation, Rochester, Minnesota5

Received 11 September 2003/ Accepted 20 January 2004

The ability of interleukin-7 (IL-7) and IL-15 to expand and/or augment effector cell functions may be of therapeutic benefit to human immunodeficiency virus (HIV)-infected patients. The functional effects of these cytokines on innate HIV-specific immunity and their impact on cells harboring HIV are unknown. We demonstrate that both IL-7 and IL-15 augment natural killer (NK) function by using cells (CD3– CD16+ CD56+) from both HIV-positive and -negative donors. Whereas IL-7 enhances NK function through upregulation of Fas ligand, the effect of IL-15 is mediated through upregulation of tumor necrosis factor-related apoptosis-inducing ligand. The difference in these effector mechanisms is reflected by the ability of IL-15-treated but not IL-7-treated NK cells to reduce the burden of replication-competent HIV in autologous peripheral blood mononuclear cells (PBMC) (infectious units per million for control NK cells, 6.79; for IL-7-treated NK cells, 236.17; for IL-15-treated cells, 1.01; P = 0.01 versus control). In addition, the treatment of PBMC with IL-15-treated but not IL-7-treated NK cells causes undetectable HIV p24 (five of five cases), HIV RNA (five of five cases), or HIV DNA (three of five cases). These results support the concept of adjuvant immunotherapy of HIV infection with either IL-7 or IL-15 but suggest that the NK-mediated antiviral effect of IL-15 may be superior.

* Corresponding author. Mailing address: Program in Translational Immunovirology and Biodefense, Division of Infectious Diseases, Mayo Clinic and Foundation, 200 First St. NW, Rochester, MN 55905. Phone: (507) 284-3747. Fax: (507) 284-3757. E-mail: badley.andrew{at}mayo.edu.

Journal of Virology, June 2004, p. 6033-6042, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.6033-6042.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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