The cytokine interleukin-15 (IL-15) can exert a range of effects on the immune system, but is particularly important for promoting the proliferation and function of natural killer (NK) cells and CD8 T cells. Some observational studies in HIV have suggested salutary effects of higher IL-15 levels, in one case finding an association with delayed viral load rebound after ART interruption. But attempts at therapeutic administration of the cytokine to SIV-infected macaques have generally produced deleterious effects, including CD4 T cell depletion. More recently, IL-15 has been reexamined in the context of cure research, with laboratory studies demonstrating it can induce latently infected CD4 T cells to produce HIV. There is also increasing interest in therapeutic manipulation of NK cell responses as a means to eliminate the HIV reservoir, a task for which IL-15 may be well suited. A paper published last week in the Journal of Virology reports that an optimized form of IL-15 promoted potent inhibition of HIV by NK cells in humanized mice.
The version of IL-15 used in the study is described as a superagonist, comprising the cytokine bound to part of the receptor with which it interacts. This modified IL-15 is being developed as a cancer therapeutic under the name ALT-803 and, in mice, it has been shown to have superior biological activity (~25-fold greater) and a much longer half-life (~25 hours vs. ~40 minutes) compared to the unaltered cytokine. The new Journal of Virology paper reports that in a humanized mouse model, administration of ALT-803 either one or three days after HIV challenge reduced subsequent virus levels by over 90% (measured up to 21 days later). However, there was no significant effect if the delay in ALT-803 administration was extended to five days after challenge. The researchers used cell transfer experiments to confirm that NK cells, and not CD8 T cells, mediated the inhibition of acute HIV infection in this model. Discussing the results, they state: “to our knowledge, this study is the first reported demonstration that in vivo activation of NK cells can inhibit acute HIV-1 infection.” They also note that the poor outcomes seen previously in the SIV model could be due to unmodified IL-15 producing less antiviral activity and more unwanted effects (e.g. CD4 T cell activation), or might reflect differential responsiveness in macaque compared to human cells.
A dose-escalation pilot trial of ALT-803 in HIV-positive individuals on ART is due to start soon at the University of Minnesota. The primary aim is to evaluate safety and tolerability, but the study will also measure HIV reservoir levels as a secondary endpoint. Due to evidence from animal studies that ALT-803 may be able to invoke NK cell activity against tumors, several phase I trials are already ongoing in people with cancers.
J Virol. 2015 Apr 1. pii: JVI.00563-15. [Epub ahead of print]
Seay K, Church C, Zheng JH, Deneroff K, Ochsenbauer C, Kappes JC, Liu B, Jeng EK, Wong HC, Goldstein H.
Natural killer (NK) cells with anti-HIV-1 activity may inhibit HIV-1 replication and dissemination during acute HIV-1 infection. We hypothesized that the NK cell capacity to suppress acute in vivo HIV-1 infection would be augmented by activating them via treatment with an IL-15 superagonist, IL-15 bound to soluble IL-15Rα, an approach that potentiates human NK cell-mediated killing of tumor cells. In vitro stimulation of human NK cells with a recombinant IL-15 superagonist significantly induced their expression of cytotoxic effector molecules granzyme B and perforin, their degranulation upon exposure to K562 cells as indicated by cell-surface expression of CD107a and their capacity to lyse K562 cells and HIV-1-infected T cells. The impact of IL-15 superagonist-induced activation of human NK cells on acute in vivo HIV-1 infection was investigated using hu-spl-PBMC-NSG mice, NOD-SCID-IL2rγ-/- mice intrasplenically injected with human PBMCs, which develop productive in vivo infection after intrasplenic inoculation with HIV-1. IL-15 superagonist treatment potently inhibited acute HIV-1 infection in hu-spl-PBMC-NSG mice even when delayed until three days after intrasplenic HIV-1 inoculation. Removal of NK cells from the human PBMCs prior to intrasplenic injection into NSG mice completely abrogated IL-15 superagonist-mediated suppression of in vivo HIV-1 infection. Thus, the in vivo activation of NK cells, integral mediators of the innate immune response, by treatment with an IL-15 superagonist increases their anti-HIV activity and enables them to potently suppress acute in vivo HIV-1 infection. These results indicate that in vivo activation of NK cells may represent a new immunotherapeutic approach to suppress acute HIV-1 infection.