The Kirby Institute for infection and immunity in society, University of New South Wales, Sydney, New South Wales, Australia.
Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
AIDS. 2018 Aug 24;32(13):1737-1747. doi: 10.1097/QAD.0000000000001882.
Hematological abnormalities that include changes in bone marrow, such as in anemia and pancytopenia, are common among HIV-infected patients, particularly in the advanced stage of disease. Such abnormalities may be caused by a reduced bone marrow function for hematopoiesis. The aim of this study was to determine whether transcriptional gene silencing can help to preserve the hosts' hematopoietic potential in addition to peripheral CD4+ T cells against CCR5-tropic HIV infection.
NOD/SCID/JAK3null (NOJ) mice were transplanted with human cord-derived CD34+ cells with or without transduction with a lentiviral vector expressing a promoter-targeting shRNA called PromA.
At 16 weeks after transplantation, mice engrafted with CD34+ cells were infected with CCR5-tropic HIV-1JRFL.
At week 2 postinfection, HIV replication was observed in peripheral blood mononuclear cells and splenocytes. In mice transplanted with unmanipulated CD34+ cells, viral replication was accompanied by a loss of peripheral/spleen CD4+CCR5+ T cells. Interestingly, bone marrow CD34+ cells in HIV-infected mice were also depleted, but in a CXCR4-associated manner. Conversely, the lentiviral transfer of PromA in CD34+ cells prior to transplantation rendered the humanized NOJ mice resistant to HIV replication in CD4+ T cells, resulting in better preservation of peripheral/spleen CD4+CCR5+ T cells and bone marrow CD34+ cells at 2 weeks after infection.
These results indicate that stable gene transfer of PromA to hematopoietic stem cells not only limited HIV replication but also led to preservation of different subsets of hematopoietic cells, including bone marrow stem/progenitor cells and CD4+ T cells.
包括骨髓变化在内的血液学异常在 HIV 感染患者中很常见，尤其是在疾病的晚期。这些异常可能是由于骨髓造血功能下降引起的。本研究旨在确定转录基因沉默除了对 CCR5 嗜性 HIV 感染具有保护外周 CD4+T 细胞的作用外，是否还可以帮助保留宿主的造血潜能。
NOD/SCID/JAK3null（NOJ）小鼠接受人脐带来源的 CD34+细胞移植，或用表达启动子靶向 shRNA 的慢病毒载体转导。
移植后 16 周，用 CCR5 嗜性 HIV-1JRFL 感染嵌合有 CD34+细胞的小鼠。
感染后第 2 周，在外周血单核细胞和脾细胞中观察到 HIV 复制。在未处理的 CD34+细胞移植的小鼠中，病毒复制伴随着外周/脾 CD4+CCR5+T 细胞的丧失。有趣的是，感染 HIV 的小鼠骨髓 CD34+细胞也被耗尽，但与 CXCR4 相关。相反，在移植前将 PromA 慢病毒转移到 CD34+细胞中，使人类化的 NOJ 小鼠对 CD4+T 细胞中的 HIV 复制具有抗性，从而在感染后 2 周更好地保留了外周/脾 CD4+CCR5+T 细胞和骨髓 CD34+细胞。
这些结果表明，将 PromA 稳定基因转移到造血干细胞中不仅限制了 HIV 复制，而且还导致不同造血细胞亚群的保留，包括骨髓干细胞/祖细胞和 CD4+T 细胞。
