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Mol Ther Nucleic Acids. 2018 Sep 7;12:793-804. doi: 10.1016/j.omtn.2018.07.017. Epub 2018 Aug 4.

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

Author information

1
Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
2
AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
3
Watanabe Laboratory, Department of Life Science Frontier, Center for iPS Cell Research and Application (CiRA), Kyoto University, Shogoin, Sakyo-ku, 606-8501 Kyoto, Japan.
4
Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
St Vincent's Centre for Applied Medical Research (AMR), St Vincent's Hospital, Darlinghurst, NSW 2010, Australia. Electronic address: k.suzuki@amr.org.au.
6
Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: kaneko.shin@cira.kyoto-u.ac.jp.

Abstract

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.

KEYWORDS:

HIV-1; NF-κB; induced pluripotent stem cells; macrophage; siRNA; transcriptional-gene-silencing

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