HetIL-15 treatment of rhesus macaques is safe and systemically increases effector cytotoxic lymphocytes that infiltrate the lymph nodes.

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Abstract Background Heterodimeric interleukin-15 (hetIL-15) is presently evaluated in humans for the treatment of cancer. hetIL-15 activates and expands cytotoxic T and NK cells, which suggests that the cytokine could be useful for treating diseases such as malignancies and HIV infection. Methods Rhesus macaques received six s.c. injections of hetIL-15 over 2 weeks using increasing doses of cytokine (step-dosing). Animals were sacrificed after treatment and hetIL-15 effects on lymphocytes isolated from necropsy tissues were monitored by multiparametric flow cytometry and quantitative multiplexed confocal microscopy imaging (Histo-cytometry). Results This regimen was found to be safe in macaques and resulted in systemic proliferation and expansion of CD8+ and NK cells with higher granzyme B content. These expanded cells were found in both effector sites, such as liver, vagina and rectum, and secondary lymphoid tissues. A significant increase in effector memory CD8+ T cells was found in peripheral lymph nodes (LN) from all hetIL-15-treated macaques. Imaging analysis by Histo-cytometry revealed that effector CD8+ T cells infiltrated the B cell follicles where chronically infected follicular helper CD4+ T cells are located. Conclusions Step-dose administration of hetIL-15 is a well-tolerated regimen that results in systemic activation and expansion of cytotoxic leukocytes that infiltrate areas where chronic HIV-infected cells reside. These results suggest that hetIL-15 could be useful in disrupting or eliminating long-term viral reservoirs in HIV-1 infected individuals, contributing to a functional cure of the infection. Work assessing the impact of hetIL-15 on the size of the viral reservoir in sampled LN is currently ongoing.