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Updated: Nov 3, 2025
Chronic, Acute, and Reactivated HIV Infection in Humanized Immunodeficient Mouse Models
Published on: December 3, 2019
Human Microglia Extensively Reconstitute in Humanized-BLT Mice With Human Interleukin-34 Transgene and Support HIV-1
Jianshui Zhang1,2, Saroj Chandra Lohani1,2, Yilun Cheng1,2
1School of Biological Sciences, University of Nebraska-Lincoln, NE, United States.
Abstract:
Humanized bone marrow-liver-thymic (hu-BLT) mice develop a functional immune system in periphery, nevertheless, have a limited reconstitution of human myeloid cells, especially microglia, in CNS. Further, whether bone marrow derived hematopoietic stem and progenitor cells (HSPCs) can enter the brain and differentiate into microglia in adults remains controversial. To close these gaps, in this study we unambiguously demonstrated that human microglia in CNS were extensively reconstituted in adult NOG mice with human interleukin-34 transgene (hIL34 Tg) from circulating CD34+ HSPCs, nonetheless not in hu-BLT NOG mice, providing strong evidence that human CD34+ HSPCs can enter adult brain and differentiate into microglia in CNS in the presence of hIL34. Further, the human microglia in the CNS of hu-BLT-hIL34 NOG mice robustly supported HIV-1 infection reenforcing the notion that microglia are the most important target cells of HIV-1 in CNS and demonstrating its great potential as an in vivo model for studying HIV-1 pathogenesis and evaluating curative therapeutics in both periphery and CNS compartments.
Insights
Human hematopoietic stem cells can form microglia in the adult brain, but only with human interleukin-34. This breakthrough enables new models for studying HIV-1 in the central nervous system.
Area of Science:
- Immunology
- Neuroscience
- Infectious Diseases
Background:
- Humanized bone marrow-liver-thymic (hu-BLT) mice show limited human myeloid cell reconstitution in the central nervous system (CNS).
- The capacity of adult bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) to enter the brain and differentiate into microglia remains debated.
Purpose of the Study:
- To investigate the potential of human HSPCs to reconstitute microglia in the adult CNS.
- To establish a more comprehensive humanized mouse model for studying HIV-1 pathogenesis in both peripheral and central compartments.
Main Methods:
- Utilized NOG mice genetically engineered with a human interleukin-34 transgene (hIL34 Tg).
- Transplanted human CD34+ HSPCs into adult NOG mice, comparing hIL34 Tg mice with hu-BLT NOG mice.
- Assessed the reconstitution of human microglia in the CNS and peripheral tissues.
- Evaluated the susceptibility of human microglia to HIV-1 infection in the established model.
Main Results:
- Extensive reconstitution of human microglia in the CNS was achieved in adult NOG mice expressing hIL34 Tg from circulating CD34+ HSPCs.
- Microglial reconstitution was not observed in hu-BLT NOG mice lacking the hIL34 Tg.
- Demonstrated that human CD34+ HSPCs can enter the adult brain and differentiate into microglia in the presence of hIL34.
- Human microglia in the CNS of hu-BLT-hIL34 NOG mice supported robust HIV-1 infection.
Conclusions:
- Human interleukin-34 is crucial for the engraftment and differentiation of human HSPCs into microglia within the adult CNS.
- This study provides strong evidence for the potential of human HSPCs to repopulate the adult brain with microglia.
- The developed hu-BLT-hIL34 NOG mouse model is a valuable tool for studying HIV-1 pathogenesis and testing therapeutics targeting both CNS and peripheral infections.
