骨髓内注射cd133阳性造血干细胞制备人源化小鼠:在HIV-1研究中的应用

IF 2 Q4 VIROLOGY Frontiers in virology Pub Date : 2023-06-30 DOI:10.3389/fviro.2023.1192184
T. Koma, T. Odaka, Sung-il Lee, N. Doi, Tomoyuki Kondo, K. Okuma, J. Fujisawa, A. Adachi, Masako Nomaguchi
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引用次数: 0

摘要

动物模型对病毒性疾病的基础和临床研究至关重要。人源化小鼠(用人类造血细胞重建的小鼠)已作为小动物模型有效地用于各种病毒研究。还使用不同的人源化小鼠模型对人类嗜性HIV-1进行了研究。已经使用不同的小鼠品系和植入方法产生了各种人源化小鼠。这些不同的技术影响单个小鼠中人类造血细胞的重建,进而影响HIV-1在体内的复制。在本报告中,我们描述了人源化小鼠的产生方法的细节,即通过骨髓内注射(IBMI)移植人CD133阳性细胞的严重免疫缺陷小鼠(NSG小鼠)。已经表明CD133阳性细胞在体内高度能够产生CD34阳性细胞,IBMI是淋巴和骨髓细胞重新增殖的极好方法。在将CD133阳性细胞移植到骨髓中的人源化小鼠中,人淋巴细胞在移植后3个月增加,CD4阳性细胞稳定增加,直到移植后6-8个月。为了测试我们的系统的实用性,在移植后6-8个月,将CXCR4嗜性和CCR5嗜性HIV-1克隆腹膜内接种到所得的人源化小鼠中。在以相同剂量的病毒接种后,CCR5嗜性HIV-1接种小鼠的血浆病毒载量比CXCR4嗜性HIV-接种小鼠更早达到峰值(接种后2-3周vs 5-10周)。虽然在CXCR4嗜性HIV-1接种小鼠的病毒血症高峰或高峰之前观察到CD4阳性细胞的快速减少,但在CCR5嗜性HIV-接种小鼠中CD4阳性阳性细胞逐渐减少。在以相同剂量的病毒接种后,与亲代病毒相比,Nef缺失的嗜R5 HIV-1在接种的小鼠中表现出迟缓的生长动力学(接种后约8周vs 2-3周),这似乎反映了原代细胞中复制潜力的降低。总之,除了迄今为止报道的人源化小鼠外,我们通过用IBMI方法移植CD133阳性细胞产生的人源性小鼠将是了解体内HIV-1生物学的合适原型模型。
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Humanized mice generated by intra-bone marrow injection of CD133-positive hematopoietic stem cells: application to HIV-1 research
Animal models are essential for basic and clinical research on virus diseases. Humanized mice (mice reconstituted with human hematopoietic cells) have been effectively used for various virus studies as small animal models. Studies on human-tropic HIV-1 have also been performed using different humanized mouse models. Various humanized mice have been generated using distinct mouse strains and engraftment methods. These different techniques affect the reconstitution of human hematopoietic cells in individual mice, and in turn the HIV-1 replication in vivo. In this report, we describe the details of the generation method of humanized mice, i.e., severely immunodeficient mice (NSG mice) transplanted with human CD133-positive cells via intra-bone marrow injection (IBMI). It has been shown that the CD133-positive cells are highly capable to generate CD34-positive cells in vivo and IBMI is an excellent methodology for lymphoid and myeloid cell repopulation. In humanized mice transplanted with CD133-positive cells into the bone marrow, human lymphocytes were increased 3 months after the transplantation and a steady increase in CD4-positive cells was observed until 6–8 months after the transplantation. In order to test the utility of our system, CXCR4-tropic and CCR5-tropic HIV-1 clones were intraperitoneally inoculated into the resultant humanized mice 6–8 months after the transplantation. Upon inoculation at the same dose of viruses, the plasma viral load in CCR5-tropic HIV-1-inoculated mice peaked earlier than that in CXCR4-tropic HIV-1-inoculated mice (2–3 weeks vs 5–10 weeks post-inoculation). While a rapid decrease in CD4-positive cells was observed at the peak or prior to the peak of viremia for CXCR4-tropic HIV-1-inoculated mice, CD4-positive cells were gradually decreased in CCR5-tropic HIV-1-inoculated mice. Upon inoculation at the same dose of viruses, a Nef-deleted R5-tropic HIV-1 exhibited retarded growth kinetics in the inoculated mice compared to the parental virus (around 8 weeks vs 2–3 weeks post-inoculation), which appears to reflect the decrease in replication potential in primary cells. Taken all together, in addition to the humanized mice reported so far, our humanized mice generated by transplanting CD133-positive cells with the IBMI method would be an appropriate prototype model for understanding HIV-1 biology in vivo.
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