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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
Ivic, Sandra
Gers-Huber, Gustavo
Li, Duo
Audigé, Annette
Rochat, Mary-Aude
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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 AnimalsDisease ResistanceGene Knockdown TechniquesGenetic Therapy/methodsGenetic VectorsHIV Infections/immunology/virologyHIV-1/physiologyHematopoietic Stem Cells/immunology/virologyHumansLentivirus/geneticsMice, SCIDReceptors, CCR5/metabolismReceptors, HIV/antagonists & inhibitorsTransplantationViral LoadVirus Attachment
Identifiers
PMID: 25903342
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Article (Published version) (2.6 MB) - public document Free access
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Research group Radicaux libres et cellules souches embryonnaires (60)
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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. https://archive-ouverte.unige.ch/unige:82441

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Deposited on : 2016-04-07

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