Background:  Successful HAART regimens reduce plasma viremia and restore CD4⁺ T cells to healthy levels, although in some patients immunologic recovery is incomplete, suggesting the need for additional immunotherapy. Interleukin (IL) -7 is a candidate immunotherapeutic that can potentially increase CD4⁺ T cells via homeostatic proliferation. Here we assessed the virologic and immunologic outcome of IL-7 therapy in tissues from ART-treated simian immunodeficiency virus (SIV)⁺ rhesus macaques focusing on naïve, central memory (CM), transitional memory (TM), and effector memory (EM) CD4⁺ and CD8⁺ T cells.

Methods:  IL-7 and ART was administered to 2 groups of SIV_mac239⁺ macaques (n = 3, group A; n = 5, group B)) while a third group received ART alone (PMPA and emtricitabine [FTC]). After documented viremia reduction, monkeys received recombinant simian IL-7 (30 µg/kg), either a single injection (group A) or 3 injections at weekly intervals (group B). Animals received BrdU, and T cells were assessed for BrDU incorporation, proliferation (Ki67), and phenotype using flow cytometry of cells obtained from blood, lymph nodes, and small intestines.

Results:  Plasma viremia in IL-7-ART-treated groups (A, and B) did not differ from ART-only macaques, suggesting no virologic effect of IL-7 in the treated monkeys. Assessment of IL-7-induced proliferation in the single IL-7 dose group (A) resulted in increased proliferation within memory CD4⁺ and CD8⁺ T cells; 3 weekly injections of IL-7 for group B resulted in prolonged Ki67 elevation in the CD4⁺ and CD8⁺ memory T cells than for group A. TM cells in the CD4⁺ and CD8⁺ populations were highly responsive to IL-7 as were CM cells. We also observed increased proliferation in the blood CD4⁺ EM cells, as well as in the naïve CD8⁺ cells. Finally, the triple IL-7 injections in group B induced an elevated BrdU uptake in CD4⁺ and CD8⁺ T cells in blood, lymph nodes, and small intestine. In the small intestine, BrdU incorporation was greater in CD8⁺ memory cells than in the CD4⁺ memory compartment.

Conclusions:  In the context of ART inhibition of SIV infection, we have determined that IL-7 has the ability to increase proliferation in naïve-CD8, CM, TM, and EM-CD4 T cells in vivo. Therefore, IL-7 immunotherapy has a broad spectrum of pro-proliferative activity. We hypothesize that IL-7’s proliferative effect on CM T cells may enable a more robust replenishment of EM T cells at mucosal sites. The assessment of potential long-term benefits of IL-7 administration in these macaques is underway.