Heterodimeric interleukin-15 (hetIL-15) is a native stable form of the cytokine that activates and expands cytotoxic T and NK cells. We have reported that hetIL-15 treatment delivered subcutaneously in SHIV infected macaques results in significant decrease in viral RNA within peripheral lymph nodes (LN) and plasma viral loads. In this study, we have expanded the analysis of the hetIL-15 effects on virus-specific CD8+ T cells, as well as the general lymphocyte population, in immunized MamuA01+ rhesus macaques treated with hetIL-15 subcutaneously (sc), intraperitoneally (ip), intravenously (iv) and intramuscularly (im).
Eight DNA-immunized rhesus macaques received injections of hetIL-15 over 2 weeks using increasing doses of cytokine (step-dosing) by four different routes (sc, ip, iv and im). At the end of the treatment, hetIL-15 effects on different lymphocyte populations were monitored by multi-parametric flow cytometry.
All four protocols resulted in systemic expansion of CD8+ T lymphocytes and NK cells with higher granzyme B content. These cells were found in both effector sites, such as liver, vagina and rectum, and secondary lymphoid tissues. A significant increase in cytotoxic effector memory CD8+ T cells was found in lymph nodes from all hetIL-15-treated macaques. CM9 tetramer staining demonstrated that the increase of CD8+ effector T cells in lymphoid organs included actively proliferating SIV-specific T cells with higher granzyme content. Some effects of hetIL-15 treatment were restricted to the specific delivery route. Macaques treated ip showed the highest levels of proliferation in CD8+ lymphocytes obtained from the gastrointestinal tract (duodenum, jejunum, ileum and colon), although the proliferating T cells from the gut did not show any increase in granzyme content.
Step-dose administration of hetIL-15 by four different routes is well-tolerated and results in systemic activation and expansion of virus-specific cytotoxic leukocytes that infiltrate LN and peripheral effector sites. The differences observed between LN and the gastrointestinal tract suggest that tissue-specific homeostatic mechanisms may modulate the response of the tissue-resident lymphocytes to hetIL-15. These results suggest that hetIL-15 could be useful in promoting the entry of cytotoxic T cells into areas of chronic HIV replication and contributing to a functional cure of the infection.