In VivoActivation of Human NK Cells by Treatment with an Interleukin-15 Superagonist Potently Inhibits AcuteIn VivoHIV-1 Infection in Humanized Mice

Abstract

ABSTRACTNatural killer (NK) cells with anti-HIV-1 activity may inhibit HIV-1 replication and dissemination during acute HIV-1 infection. We hypothesized that the capacity of NK cells to suppress acutein vivoHIV-1 infection would be augmented by activating them via treatment with an interleukin-15 (IL-15) superagonist, IL-15 bound to soluble IL-15Rα, an approach that potentiates human NK cell-mediated killing of tumor cells.In vitrostimulation of human NK cells with a recombinant IL-15 superagonist significantly induced their expression of the 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 acutein vivoHIV-1 infection was investigated by using hu-spl-PBMC-NSG mice, NOD-SCID-IL2rγ−/−(NSG) mice intrasplenically injected with human peripheral blood mononuclear cells (PBMCs) which develop productivein vivoinfection 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 3 days after intrasplenic HIV-1 inoculation. Removal of NK cells from human PBMCs prior to intrasplenic injection into NSG mice completely abrogated IL-15 superagonist-mediated suppression ofin vivoHIV-1 infection. Thus, thein vivoactivation 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 acutein vivoHIV-1 infection. These results indicate thatin vivoactivation of NK cells may represent a new immunotherapeutic approach to suppress acute HIV-1 infection.IMPORTANCEEpidemiological studies have indicated that NK cells contribute to the control of HIV-1 infection, andin vitrostudies have demonstrated that NK cells can selectively kill HIV-1-infected cells. We demonstrated thatin vivoactivation of NK cells by treatment with an IL-15 superagonist that potently stimulates the antitumor activity of NK cells markedly inhibited acute HIV-1 infection in humanized mice, even when activation of NK cells by IL-15 superagonist treatment is delayed until 3 days after HIV-1 inoculation. NK cell depletion from PBMCs prior to their intrasplenic injection abrogated the suppression ofin vivoHIV-1 infection observed in humanized mice treated with the IL-15 superagonist, demonstrating that activated human NK cells were mediating IL-15 superagonist-induced inhibition of acute HIV-1 infection. Thus,in vivoimmunostimulation of NK cells, a promising therapeutic approach for cancer therapy, may represent a new treatment modality for HIV-1-infected individuals, particularly in the earliest stages of infection.