Center for Gene Therapy, Beckman Research Institute of City of Hope, Duarte, California, USA.
Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, California, USA.
J Virol. 2022 Feb 9;96(3):e0139421. doi: 10.1128/JVI.01394-21. Epub 2021 Nov 24.
Humanized mouse models are based on the engraftment of human cells in immunodeficient mouse strains, most notably the NSG strain. Most used models have a major limitation in common, the development of graft-versus-host disease (GVHD). GVHD not only introduces variabilities into the research data but also leads to animal welfare concerns. A new mouse strain, B6.129S-Rag2 CD47 Il2rg/J, which lacks Rag1, IL2rg, and CD47 (triple knockout [TKO]), is resistant to GVHD development. We transplanted TKO mice with human peripheral blood mononuclear cells (PBMCs) to establish a new humanized PBMC (hu-PBMC) mouse model. A cohort of these mice was infected with HIV-1 and monitored for plasma HIV viremia and CD4 T cell depletion. The onset and progression of GVHD were monitored by clinical signs. This study demonstrates that TKO mice transplanted with human PBMCs support engraftment of human immune cells in primary and secondary lymphoid tissues, rectum, and brain. Moreover, the TKO hu-PBMC model supports HIV-1 infection via the intraperitoneal, rectal, or vaginal route, as confirmed by robust plasma HIV viremia and CD4 T cell depletion. Lastly, TKO mice showed a delayed onset of GVHD clinical signs (∼24 days) and exhibited significant decreases in plasma levels of tumor necrosis factor beta (TNF-β). Based on these results, the TKO hu-PBMC mouse model not only supports humanization and HIV-1 infection but also has a delayed onset of GVHD development, making this model a valuable tool in HIV research. Currently, there is no cure or vaccine for HIV infection; thus, continued research is needed to end the HIV pandemic. While many animal models are used in HIV research, none is used more than the humanized mouse model. A major limitation with current humanized mouse models is the development of graft-versus-host disease (GVHD). Here, we describe a novel humanized-PBMC mouse model that has a delayed onset GVHD development and supports and models HIV infection comparably to well-established humanized mouse models.
人源化小鼠模型基于将人类细胞植入免疫缺陷小鼠品系中，其中最著名的是 NSG 品系。大多数使用的模型都有一个共同的主要局限性，即移植物抗宿主病（GVHD）的发展。GVHD 不仅会使研究数据产生变异性，还会导致动物福利问题。一种新的小鼠品系 B6.129S-Rag2 CD47 Il2rg/J，缺乏 Rag1、IL2rg 和 CD47（三重敲除[TKO]），对 GVHD 的发展具有抗性。我们将 TKO 小鼠与人外周血单核细胞（PBMC）移植，建立了一种新的人源化 PBMC（hu-PBMC）小鼠模型。该模型的一组小鼠感染了 HIV-1，并监测血浆 HIV 病毒载量和 CD4 T 细胞耗竭情况。通过临床症状监测 GVHD 的发作和进展。本研究表明，移植人 PBMC 的 TKO 小鼠支持人类免疫细胞在初级和次级淋巴组织、直肠和大脑中的植入。此外，TKO hu-PBMC 模型通过腹腔内、直肠或阴道途径支持 HIV-1 感染，这通过强大的血浆 HIV 病毒载量和 CD4 T 细胞耗竭得到证实。最后，TKO 小鼠出现 GVHD 临床症状（约 24 天）的发作延迟，并表现出肿瘤坏死因子β（TNF-β）血浆水平的显著降低。基于这些结果，TKO hu-PBMC 小鼠模型不仅支持人源化和 HIV-1 感染，而且 GVHD 发展的发作延迟，使其成为 HIV 研究的有价值工具。目前，HIV 感染没有治愈方法或疫苗；因此，需要继续研究以结束 HIV 大流行。虽然许多动物模型用于 HIV 研究，但没有一种模型比人源化小鼠模型使用得更多。当前人源化小鼠模型的一个主要局限性是移植物抗宿主病（GVHD）的发展。在这里，我们描述了一种新型的人源化-PBMC 小鼠模型，该模型具有 GVHD 发作延迟的发展，并支持和模拟 HIV 感染，与成熟的人源化小鼠模型相当。
