The use of immunodeficient mice transplanted with human hematopoietic stem cells is an accepted approach to study human-specific infectious diseases such as HIV-1 and to investigate multiple aspects of human immune system development. However, mouse and human are different in sialylation patterns of proteins due to evolutionary mutations of the CMP-N-acetylneuraminic acid hydroxylase (CMAH) gene that prevent formation of N-glycolylneuraminic acid from N-acetylneuraminic acid. How changes in the mouse glycoproteins’ chemistry affect phenotype and function of transplanted human hematopoietic stem cells and mature human immune cells in the course of HIV-1 infection are not known. We mutated mouse CMAH in the NOD/scid-IL2Rγc−/− (NSG) mouse strain, which is widely used for the transplantation of human cells, using the CRISPR/Cas9 system. The new strain provides a better environment for human immune cells. Transplantation of human hematopoietic stem cells leads to broad B cells repertoire, higher sensitivity to HIV-1 infection, and enhanced proliferation of transplanted peripheral blood lymphocytes. The mice showed no effect on the clearance of human immunoglobulins and enhanced transduction efficiency of recombinant adeno-associated viral vector rAAV2/DJ8. NSG-cmah−/− mice expand the mouse models suitable for human cells transplantation, and this new model has advantages in generating a human B cell repertoire. This strain is suitable to study different aspects of the human immune system development, provide advantages in patient-derived tissue and cell transplantation, and could allow studies of viral vectors and infectious agents that are sensitive to human-like sialylation of mouse glycoproteins.

中文翻译：

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类人NSG小鼠糖蛋白唾液酸化模式改变人淋巴细胞的表型和对HIV-1感染的敏感性

使用移植有人类造血干细胞的免疫缺陷小鼠是研究人类特异性传染病（例如HIV-1）并研究人类免疫系统发育多个方面的公认方法。但是，由于CMP-N-乙酰神经氨酸羟化酶（CMAH）基因的进化突变会阻止N-乙酰神经氨酸形成N-羟乙酰神经氨酸，因此小鼠和人类的蛋白质唾液酸化方式有所不同。在HIV-1感染过程中，小鼠糖蛋白化学变化如何影响移植的人类造血干细胞和成熟的人类免疫细胞的表型和功能尚不清楚。我们使用CRISPR / Cas9系统突变了NOD /scid-IL2Rγc-/-（NSG）小鼠品系中的小鼠CMAH，该品系被广泛用于人类细胞的移植。新菌株为人类免疫细胞提供了更好的环境。人造血干细胞的移植导致广泛的B细胞库，对HIV-1感染的敏感性更高，并增强了移植的外周血淋巴细胞的增殖。小鼠对人免疫球蛋白的清除没有影响，重组腺相关病毒载体rAAV2 / DJ8的转导效率也没有提高。NSG-cmah-/-小鼠扩展了适用于人类细胞移植的小鼠模型，这种新模型在产生人类B细胞库方面具有优势。该菌株适合研究人类免疫系统发育的不同方面，为患者来源的组织和细胞移植提供了优势，