Lentivector knockdown of CCR5 in hematopoietic stem and progenitor cells confers functional and persistent HIV-1 resistance in humanized mice
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Date
Authors
Myburgh, Renier
Ivic, Sandra
Gers-Huber, Gustavo
Li, Duo
Audige, Annette
Rochat, Mary-Aude
Jaquet, Vincent
Regenass, Stephan
Manz, Markus G.
Pepper, Michael Sean
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Journal ISSN
Volume Title
Publisher
American Society for Microbiology
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.
Description
Keywords
Hematopoietic stem and progenitor cells (HSPCs), Gene-engineered CD34(+), HIV-1-resistant immune system, CCR5 knockdown, HIV gene therapy, microRNA (miRNA)
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Citation
Myburgh, R, Ivic, S, Pepper, MS, Gers-Huber, G, Li, D, Audige, A, Rochat, MA, Jaquet, V, Regenass, S, Manz, MG, Salmon, P, Krause, KH & Speck, RF 2015, 'Lentivector knockdown of CCR5 in hematopoietic stem and progenitor cells confers functional and persistent HIV-1 resistance in humanized mice', Journal of Virology, vol. 89, no. 3, pp. 6761-6772.