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Nat Biotechnol. 2008 Jul;26(7):808-16. doi: 10.1038/nbt1410. Epub 2008 Jun 29.

Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases.

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Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, 421 Curie Blvd., Room 554, BRB II/III, Philadelphia, Pennsylvania 19104-6160, USA.


Homozygosity for the naturally occurring Delta32 deletion in the HIV co-receptor CCR5 confers resistance to HIV-1 infection. We generated an HIV-resistant genotype de novo using engineered zinc-finger nucleases (ZFNs) to disrupt endogenous CCR5. Transient expression of CCR5 ZFNs permanently and specifically disrupted approximately 50% of CCR5 alleles in a pool of primary human CD4(+) T cells. Genetic disruption of CCR5 provided robust, stable and heritable protection against HIV-1 infection in vitro and in vivo in a NOG model of HIV infection. HIV-1-infected mice engrafted with ZFN-modified CD4(+) T cells had lower viral loads and higher CD4(+) T-cell counts than mice engrafted with wild-type CD4(+) T cells, consistent with the potential to reconstitute immune function in individuals with HIV/AIDS by maintenance of an HIV-resistant CD4(+) T-cell population. Thus adoptive transfer of ex vivo expanded CCR5 ZFN-modified autologous CD4(+) T cells in HIV patients is an attractive approach for the treatment of HIV-1 infection.

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