title: In Vivo Activation of Human NK Cells by Treatment with an Interleukin-15 Superagonist Potently Inhibits Acute In Vivo HIV-1 Infection in Humanized Mice.
abstract: 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 capacity of NK cells to suppress acute in vivo HIV-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 vitro stimulation 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 acute in vivo HIV-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 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 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 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.
  
  
  OBJECTIVE
  Epidemiological studies have indicated that NK cells contribute to the control of HIV-1 infection, and in vitro studies have demonstrated that NK cells can selectively kill HIV-1-infected cells. We demonstrated that in vivo activation 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 of in vivo HIV-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 vivo immunostimulation 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.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Kieran
authors.initials: K
authors.lastname: Seay
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Candice
authors.initials: C
authors.lastname: Church
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Zheng
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Deneroff
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA Birmingham Veterans Affairs Medical Center, Research Service, Birmingham, Alabama, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.affiliation: Altor BioScience Corporation, Miramar, Florida, USA.
authors.forename: Bai
authors.initials: B
authors.lastname: Liu
authors.affiliation: Altor BioScience Corporation, Miramar, Florida, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Jeng
authors.affiliation: Altor BioScience Corporation, Miramar, Florida, USA.
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA harris.goldstein@einstein.yu.edu.
authors.forename: Harris
authors.initials: H
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control*; D006801:Humans; D019409:Interleukin-15 / Q000037:antagonists & inhibitors*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID
chemical_list: C569274:IL15 protein, human; D019409:Interleukin-15
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