Center for Cell and Gene Therapy, Takara Bio Inc, Seta, Otsu, Shiga, Japan.
Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, Ibaraki, Japan.
Mol Ther Nucleic Acids. 2014 Jun 10;3(6):e168. doi: 10.1038/mtna.2014.20.
MazF, an endoribonuclease encoded by Escherichia coli, specifically cleaves the ACA (adenine-cytosine-adenine) sequence of single-stranded RNAs. Conditional expression of MazF under the control of the HIV-1 LTR promoter rendered CD4(+) T cells resistant to HIV-1 replication without affecting cell growth. To investigate the safety, persistence and efficacy of MazF-modified CD4(+) T cells in a nonhuman primate model in vivo, rhesus macaques were infected with a pathogenic simian/human immunodeficiency virus (SHIV) and transplanted with autologous MazF-modified CD4(+) T cells. MazF-modified CD4(+) T cells were clearly detected throughout the experimental period of more than 6 months. The CD4(+) T cell count values increased in all four rhesus macaques. Moreover, the transplantation of the MazF-modified CD4(+) T cells was not immunogenic, and did not elicit cellular or humoral immune responses. These data suggest that the autologous transplantation of MazF-modified CD4(+) T cells in the presence of SHIV is effective, safe and not immunogenic, indicating that this is an attractive strategy for HIV-1 gene therapy.
MazF，一种由大肠杆菌编码的内切核酸酶，特异性切割单链 RNA 的 ACA（腺嘌呤-胞嘧啶-腺嘌呤）序列。在 HIV-1 LTR 启动子的控制下条件表达 MazF，使 CD4(+) T 细胞能够抵抗 HIV-1 复制而不影响细胞生长。为了在体内非人类灵长类动物模型中研究 MazF 修饰的 CD4(+) T 细胞的安全性、持久性和疗效，恒河猴感染了致病性的猿猴/人免疫缺陷病毒 (SHIV)，并移植了自体 MazF 修饰的 CD4(+) T 细胞。在超过 6 个月的实验期间，明显检测到 MazF 修饰的 CD4(+) T 细胞。所有四只恒河猴的 CD4(+) T 细胞计数值均增加。此外，MazF 修饰的 CD4(+) T 细胞的移植没有免疫原性，也没有引起细胞或体液免疫反应。这些数据表明，在 SHIV 存在的情况下自体移植 MazF 修饰的 CD4(+) T 细胞是有效、安全且无免疫原性的，表明这是一种有吸引力的 HIV-1 基因治疗策略。
