1. Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection
- Author
-
Abeynaike, Shawn A, Huynh, Tridu R, Mehmood, Abeera, Kim, Teha, Frank, Kayla, Gao, Kefei, Zalfa, Cristina, Gandarilla, Angel, Shultz, Leonard, and Paust, Silke
- Subjects
Microbiology ,Biological Sciences ,Regenerative Medicine ,Transplantation ,HIV/AIDS ,Stem Cell Research - Nonembryonic - Human ,Stem Cell Research - Umbilical Cord Blood/ Placenta ,Infectious Diseases ,Stem Cell Research ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Infection ,Mice ,Humans ,Animals ,Mice ,Inbred NOD ,Mice ,Transgenic ,HIV-1 ,Interleukin-15 ,HIV Infections ,HIV Seropositivity ,Killer Cells ,Natural ,Hematopoietic Stem Cells ,Mice ,SCID ,humanized mice ,NSG ,NK cells ,IL-15 ,immunotherapy - Abstract
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.
- Published
- 2023