Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection
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 ce...
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MDPI AG
2023-01-01
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| Online Access: | https://www.mdpi.com/1999-4915/15/2/365 |
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| author | Shawn A. Abeynaike Tridu R. Huynh Abeera Mehmood Teha Kim Kayla Frank Kefei Gao Cristina Zalfa Angel Gandarilla Leonard Shultz Silke Paust |
| author_facet | Shawn A. Abeynaike Tridu R. Huynh Abeera Mehmood Teha Kim Kayla Frank Kefei Gao Cristina Zalfa Angel Gandarilla Leonard Shultz Silke Paust |
| author_sort | Shawn A. Abeynaike |
| collection | DOAJ |
| description | 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-<i>Prkdc<sup>scid</sup> Il2rg<sup>tm1Wjl</sup></i>/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. |
| first_indexed | 2024-03-11T08:00:50Z |
| format | Article |
| id | doaj.art-8118595d335249e4852c48ee7118dd24 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-11T08:00:50Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-8118595d335249e4852c48ee7118dd242023-11-16T23:48:01ZengMDPI AGViruses1999-49152023-01-0115236510.3390/v15020365Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 InfectionShawn A. Abeynaike0Tridu R. Huynh1Abeera Mehmood2Teha Kim3Kayla Frank4Kefei Gao5Cristina Zalfa6Angel Gandarilla7Leonard Shultz8Silke Paust9Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USAThe Jackson Laboratory, Bar Harbor, ME 04609, USADepartment of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USAMice 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-<i>Prkdc<sup>scid</sup> Il2rg<sup>tm1Wjl</sup></i>/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.https://www.mdpi.com/1999-4915/15/2/365humanized miceNSGNK cellsIL-15HIV-1immunotherapy |
| spellingShingle | Shawn A. Abeynaike Tridu R. Huynh Abeera Mehmood Teha Kim Kayla Frank Kefei Gao Cristina Zalfa Angel Gandarilla Leonard Shultz Silke Paust Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection Viruses humanized mice NSG NK cells IL-15 HIV-1 immunotherapy |
| title | Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection |
| title_full | Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection |
| title_fullStr | Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection |
| title_full_unstemmed | Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection |
| title_short | Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection |
| title_sort | human hematopoietic stem cell engrafted il 15 transgenic nsg mice support robust nk cell responses and sustained hiv 1 infection |
| topic | humanized mice NSG NK cells IL-15 HIV-1 immunotherapy |
| url | https://www.mdpi.com/1999-4915/15/2/365 |
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