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Lentivector Knockdown of CCR5 in Hematopoietic Stem and Progenitor Cells Confers Functional and Persistent HIV-1 Resistance in Humanized Mice |
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Published in | Journal of virology. 2015, vol. 89, no. 13, p. 6761-72 | |
Abstract | Gene-engineered CD34(+) hematopoietic stem and progenitor cells (HSPCs) can be used to generate an HIV-1-resistant immune system. However, a certain threshold of transduced HSPCs might be required for transplantation into mice for creating an HIV-resistant immune system. In this study, we combined CCR5 knockdown by a highly efficient microRNA (miRNA) lentivector with pretransplantation selection of transduced HSPCs to obtain a rather pure population of gene engineered CD34(+) cells. Low-level transduction of HSPCs and subsequent sorting by flow cytometry yielded >70% transduced cells. Mice transplanted with these cells showed functional and persistent resistance to a CCR5-tropic HIV strain: viral load was significantly decreased over months, and human CD4(+) T cells were preserved. In one mouse, viral mutations, resulting presumably in a CXCR4-tropic strain, overcame HIV resistance. Our results suggest that HSPC-based CCR5 knockdown may lead to efficient control of HIV in vivo. We overcame a major limitation of previous HIV gene therapy in humanized mice in which only a proportion of the cells in chimeric mice in vivo are anti-HIV engineered. Our strategy underlines the promising future of gene engineering HIV-resistant CD34(+) cells that produce a constant supply of HIV-resistant progeny. | |
Keywords | Animals — Disease Resistance — Gene Knockdown Techniques — Genetic Therapy/methods — Genetic Vectors — HIV Infections/immunology/virology — HIV-1/physiology — Hematopoietic Stem Cells/immunology/virology — Humans — Lentivirus/genetics — Mice, SCID — Receptors, CCR5/metabolism — Receptors, HIV/antagonists & inhibitors — Transplantation — Viral Load — Virus Attachment | |
Identifiers | DOI: 10.1128/JVI.00277-15 PMID: 25903342 | |
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Research group | Radicaux libres et cellules souches embryonnaires (60) | |
Citation (ISO format) | MYBURGH, Renier et al. Lentivector Knockdown of CCR5 in Hematopoietic Stem and Progenitor Cells Confers Functional and Persistent HIV-1 Resistance in Humanized Mice. In: Journal of virology, 2015, vol. 89, n° 13, p. 6761-72. doi: 10.1128/JVI.00277-15 https://archive-ouverte.unige.ch/unige:82441 |