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Review
. 2013 Nov;208 Suppl 2(Suppl 2):S160-4.
doi: 10.1093/infdis/jit382.

Pre-clinical modeling of CCR5 knockout in human hematopoietic stem cells by zinc finger nucleases using humanized mice

Ursula Hofer  1 , Jill E Henley, Colin M Exline, Orla Mulhern, Evan Lopez, Paula M Cannon
Affiliations
Review

Pre-clinical modeling of CCR5 knockout in human hematopoietic stem cells by zinc finger nucleases using humanized mice

Ursula Hofer et al. J Infect Dis. 2013 Nov.

Abstract

Genetic strategies to block expression of CCR5, the major co-receptor of human immunodeficiency virus type 1 (HIV-1), are being developed as anti-HIV therapies. For example, human hematopoietic stem/precursor cells (HSPC) can be modified by the transient expression of CCR5-targeted zinc finger nucleases (ZFNs) to generate CCR5-negative cells, which could then give rise to HIV-resistant mature CD4(+) T cells following transplantation into patients. The safety and anti-HIV effects of such treatments can be evaluated by transplanting ZFN-treated HSPC into immunodeficient mice, where the extent of human cell engraftment, lineage differentiation and anti-HIV activity arising from the engineered HSPC can be examined. In this way, humanized mice are providing a powerful small animal model for pre-clinical studies of novel anti-HIV therapies.

Keywords: CCR5; HIV; hematopoietic stem cells; humanized mice; zinc finger nucleases.

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Figures

Figure 1.
Figure 1.
A, Schematic showing levels of human immunodeficiency virus type 1 (HIV-1) in blood and a typical response to the initiation of antiretroviral therapy, where virus levels are often suppressed to below the limit of detection in standard assays (shown as open squares). Occasional “blips” of virus replication above this threshold can occur, and a long-lived latent reservoir of uncertain composition persists, that is not cleared by the drug therapy. Upon interruption of therapy, HIV-1 levels rapidly rebound due to this persisting reservoir. B, The introduction of HIV-resistant cells is hypothesized to be able to reduce or even fully control/eradicate HIV-1. Shown is a scenario where antiretroviral drugs are withdrawn as part of a planned treatment interruption to promote the selection of such resistant cells [3], where it is expected that HIV-1 levels could initially increase, until a resistant population is selected that is sufficiently large to exert control.
Figure 2.
Figure 2.
Frequency of human CD45+ leucocytes in spleen and bone marrow (BM) of NSG mice transplanted with 1 million human CD34+ HSPC and necropsied at 20 weeks postengraftment. A, Mice transplanted with fetal liver (FL) HSPC as 1-day-old neonates (n = 10). B, Mice transplanted with mobilized peripheral blood (mPB) HSPC as 1-day-old neonates (n = 33). C, Mice transplanted with mPB HSPC as 8-week-old adults (n = 13). Mean levels of engraftment are indicated by a straight line. Abbreviations: HSPC, hematopoietic stem/precursor cells; NSG, NOD/SCID/IL2rγnull.
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