Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection

• Published in: Viruses Vol. 15; no. 2; p. 365
• Main Authors: Abeynaike, Shawn A, Huynh, Tridu R, Mehmood, Abeera, Kim, Teha, Frank, Kayla, Gao, Kefei, Zalfa, Cristina, Gandarilla, Angel, Shultz, Leonard, Paust, Silke
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.01.2023; MDPI
• Subjects: Animal models; Animal models in research; Animals; Antibodies; Antigens; Artificial chromosomes; Bone marrow; Cells; Cloning; Cord blood; Cytokines; Development and progression; Ethanol; Flow cytometry; Genes; Genetic aspects; Graft-versus-host reaction; Health aspects; Hematopoietic Stem Cells; HIV; HIV infection; HIV Infections - therapy; HIV Seropositivity; HIV-1; HIV-1 - genetics; Human immunodeficiency virus; humanized mice; Humans; IL-15; Immune response; Immune system; Immunodeficiency; Immunological research; immunotherapy; Infections; Interleukin 15; Interleukin 15 receptors; Interleukin-15 - genetics; Killer cells; Killer Cells, Natural; Kinases; Laboratories; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Natural killer cells; NK cells; NSG; Physiological aspects; Transgenic mice; United States; Minneapolis Minnesota; United States > US; Chicago Illinois; HIV-1; IL-15; NK cells; NSG; humanized mice; immunotherapy
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v15020365

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- /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.