Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected With HIV

Study Questions:

Can cells be genetically modified with a zinc-finger nuclease (ZFN) to resist infection by human immunodeficiency virus (HIV)?


Twelve patients with aviremic HIV (on antiretroviral therapy) were treated with a single dose of 109 ZFN-modified autologous CD4 T cells; 11-28% of T cells were genetically modified with the ZFN. Six patients interrupted antiretroviral treatment 4 weeks after the T-cell infusion. The primary outcome was safety, and secondary outcomes included measures of immune reconstitution and HIV resistance.


One serious adverse event was attributed to a transfusion reaction. The median CD4 T cell increased from 448 to 1517 cells/mm3 (p < 0.001), and the concentration of CCR5-modified CD4 T cells at 1 week was 250 cells/mm3. This constituted 13.9% of circulating CD4 T cells. Modified cells had an estimated half-life of 48 weeks. During treatment interruption and resultant viremia, the decline in circulating CCR5-modified cells (−1.81 cells per day) was significantly less than the decline in unmodified cells (−7.25 cells per day). The blood level of HIV DNA decreased in most patients.


The authors concluded that CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study.


ZFNs can be used to modify specific genomic sequences. CCR5 is a coreceptor for HIV, and subjects with a CCR5 mutation are resistant to infection. This raises the intriguing possibility that targeted, cell-specific mutations might be induced with ZFN to induce resistance to HIV. This study shows that this strategy can be employed safely and may be useful to create an immune system that is resistant to HIV infection. The implications of this study are far-reaching, as other monogenic diseases might also be treated with similar strategies.

Clinical Topics: Diabetes and Cardiometabolic Disease

Keywords: Mutation, Pyrrolidinones, HIV Infections, Viremia, CD4-Positive T-Lymphocytes

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