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JMG, Mice, Humans, Animals, Mice, Inbred NOD, Mice, Transgenic, HIV-1, Interleukin-15, HIV Infections, HIV Seropositivity, Killer Cells, Natural, Hematopoietic Stem Cells, Mice, SCID

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Viruses. 2023;15(2):365







This work was supported by NIH R01AI161014 (SP), R21AI170555 (SP), DK104218 (LS), OD026440 (LS), CA034196 (LS), AI132963 (LS), and TSRI’s unrestricted funds (to SP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.


Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1.


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