Lentivector Knockdown of CCR5 in Hematopoietic Stem and Progenitor Cells Confers Functional and Persistent HIV-1 Resistance in Humanized Mice

Myburgh, Renier; Ivic, Sandra; Pepper, Michael Sean; Gers-Huber, Gustavo; Li, Duo; Audigé, Annette; Rochat, Mary-Aude; Jaquet, Vincent; Regenass, Stephan; Manz, Markus G; Salmon, Patrick; Krause, Karl-Heinz; Speck, Roberto F

doi:10.1128/JVI.00277-15

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Title		Lentivector Knockdown of CCR5 in Hematopoietic Stem and Progenitor Cells Confers Functional and Persistent HIV-1 Resistance in Humanized Mice
Authors		Myburgh, Renier Ivic, Sandra Pepper, Michael Sean Gers-Huber, Gustavo Li, Duo Audigé, Annette Rochat, Mary-Aude Jaquet, Vincent Regenass, Stephan Manz, Markus G Salmon, Patrick Krause, Karl-Heinz Speck, Roberto F show all authors [1 - 13]
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
Full text		Article (Published version) (2.6 MB) - Free access
Structures		Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie
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