IL-15 stimulates the growth activation and tissue dissemination of NK cells and cytotoxic lymphocytes. We have produced and characterized heterodimeric IL-15 (hetIL-15), the authentic form of IL-15 found in the circulation. This formulation is in clinical trials for cancer.
hetIL-15 was purified and its pharmacokinetic and pharmacodynamic properties were evaluated in macaques upon SC administration. Phenotype and functional changes in lymphocyte subsets were monitored by flow cytometry and multiplexed confocal imaging (MCI).
Treatment of SIV or SHIV infected macaques with hetIL-15 resulted in a significant increase of circulating CD8+ effector T cells and NK cells with activated cytotoxic phenotype (Granzyme+). This expanded T lymphocyte population was disseminated to effector sites, and was also present in secondary lymphoid organs where an increased frequency of total CD8 and of Ag-specific effector CD8 T cells could be observed by flow cytometry and imaging (MCI). A subset of CD8 T cells present in lymph nodes expresses CXCR5, indicating ability to migrate into germinal centers where chronically infected CD4+Tfh reside. MCI confirmed the presence of effector CD8 cells in germinal centers and showed that these cells are cytotoxic (GrzmB+) and actively proliferating (Ki67+) in response to hetIL-15.
These results strongly suggest the use of hetIL-15 in chronic HIV/SIV infection. An exciting possibility is the augmentation of immune responses in the areas of residual HIV/SIV persistence, and the combination with therapeutic vaccination, which has resulted in promising reduction in chronic viremia. We test new generation of therapeutic vaccines focusing immune responses on the conserved regions of HIV/SIV in combination with hetIL-15 in an effort to amplify novel cytotoxic responses with no possibility of immune escape.
We explore the potential of IL-15 as a viral reservoir reducing agent in ART-treated SIV infected macaques. hetIL-15 treatment enhances the number, activation and cytotolytic potential of CD8 cells in LN and germinal centers, a known site of virus persistence. hetIL-15 treatment in combination with pDNA vaccine targeting the “Achilles’ heel” of the virus, i.e., the highly conserved regions (CE), in virus sanctuary areas (germinal centers) is a promising HIV eradication strategy.