Generation of HIV-Resistant Macrophages from IPSCs by Using Transcriptional Gene Silencing and Promoter-Targeted RNA

• Published in: Molecular therapy. Nucleic acids Vol. 12; pp. 793 - 804
• Main Authors: Higaki, Kei, Hirao, Masako, Kawana-Tachikawa, Ai, Iriguchi, Shoichi, Kumagai, Ayako, Ueda, Norihiro, Bo, Wang, Kamibayashi, Sanae, Watanabe, Akira, Nakauchi, Hiromitsu, Suzuki, Kazuo, Kaneko, Shin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.09.2018; Elsevier Limited; American Society of Gene & Cell Therapy; Elsevier
• Subjects: Acquired immune deficiency syndrome; AIDS; Deoxyribonucleic acid; DNA; DNA methylation; Drug resistance; Gene silencing; Gene therapy; Heterochromatin; Highly active antiretroviral therapy; HIV; HIV-1; Human immunodeficiency virus; induced pluripotent stem cells; Infections; Lymphocytes; macrophage; Macrophages; NF-κB; Pathogenesis; Pluripotency; R&D; Replication; Research & development; Ribonucleic acid; RNA; RNA-mediated interference; siRNA; Stem cells; Studies; transcriptional-gene-silencing; Transplantation; Viruses; United States > US; Japan; HIV-1; NF-κB; macrophage; induced pluripotent stem cells; siRNA; transcriptional-gene-silencing
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2018.07.017

Highly active antiretroviral therapy (HAART) has markedly prolonged the prognosis of HIV-1 patients. However, lifelong dependency on HAART is a continuing challenge, and an effective therapeutic is much desired. Recently, introduction of short hairpin RNA (shRNA) targeting the HIV-1 promoter was found to suppress HIV-1 replication via transcriptional gene silencing (TGS). The technology is expected to be applied with hemato-lymphopoietic cell transplantation of HIV patients to suppress HIV transcription in transplanted hemato-lymphopoietic cells. Combination of the TGS technology with new cell transplantation strategy with induced pluripotent stem cell (iPSC)-derived hemato-lymphopoietic cells might contribute to new gene therapy in the HIV field. In this study, we evaluated iPSC-derived macrophage functions and feasibility of TGS technology in macrophages. Human iPSCs were transduced with shRNAs targeting the HIV-1 promoter region (shPromA) by using a lentiviral vector. The shPromA-transfected iPSCs were successfully differentiated into functional macrophages, and they exhibited strong protection against HIV-1 replication with alteration in the histone structure of the HIV-1 promoter region to induce heterochromatin formation. These results indicated that iPS-derived macrophage is a useful tool to investigate HIV infection and protection, and that the TGS technology targeting the HIV promoter is a potential candidate of new gene therapy.