Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-HIV Activity.

Lum JJ1, Nie Z1,2, Sanchez-Dardon J1, Mbisa GL1, Mihowich J2, Hawlay N1, Narayan S1, Kim JE2, Lynch DH3, and Badley AD1,4,*

1Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario (Canada)

2National HIV/AIDS Laboratories, Health Canada, Ottawa, Ontario (Canada)

3Immunex Corporation, Seattle, Washington (USA)

4Mayo Clinic and Foundation, Division of Infectious Diseases, Rochester, MN (USA).

Background: The ability of IL-7 and IL-15 to expand and/or augment effector cell functions may be of therapeutic benefit to HIV infected patients.  The functional effects of these cytokines on innate HIV specific immunity, and their impact on cells harboring HIV are unknown. Material and Methods: We treated human NK cells from HIV+ or - patients with IL-2, -7, or -15 and analyzed TRAIL and TRAIL receptor expression and function.  We also assessed the ability of these cells to reduce the burden of latent HIV via a TRAIL specific mechanism. Results: We demonstrate that both IL-7 and IL-15 augment NK function using cells (CD3-, CD16+, CD56+) from both HIV positive and negative donors.  Whereas IL-7 enhances NK function through transcriptional upregulation of Fas Ligand (FasL), the effect of IL-15 is mediated through upregulation of TNF related apoptosis inducing ligand (TRAIL).  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 PBMC (infectious units per million [IUPM] control NK cells = 6.79, IL-7 treated NK cells = 236.17, IL-15 treated cells = 1.01 [p = 0.01 vs. control]).  In addition, the treatment of PBMC with IL-15 treated but not IL-7 treated NK cells causes undetectable HIV p24 (5/5 cases), HIV RNA (5/5 cases), or HIV DNA (3/5 cases). Conclusion: These results support the concept of adjuvant immunotherapy of HIV infection using either IL-7 or IL-15, but suggest that the NK mediated antiviral effect of IL-15 may be superior.