Article abstract
Nature Biotechnology 26, 808 - 816 (2008)
Published online: 29 June 2008 | doi:10.1038/nbt1410
Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases
Elena E Perez1,2, Jianbin Wang3, Jeffrey C Miller3, Yann Jouvenot3,4, Kenneth A Kim3, Olga Liu1, Nathaniel Wang3, Gary Lee3, Victor V Bartsevich3, Ya-Li Lee3, Dmitry Y Guschin3, Igor Rupniewski3, Adam J Waite3, Carmine Carpenito1, Richard G Carroll1, Jordan S Orange2, Fyodor D Urnov3, Edward J Rebar3, Dale Ando3, Philip D Gregory3, James L Riley1, Michael C Holmes3 & Carl H June1
Abstract
Homozygosity for the naturally occurring 
32 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 
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.
- Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, 421 Curie Blvd., Room 554, BRB II/III, Philadelphia, Pennsylvania 19104-6160, USA.
- Children's Hospital of Philadelphia, Division of Allergy and Immunology, Joseph Stokes, Jr. Research Institute, 3615 Civic Center Blvd., Philadelphia, Pennsylvania 19104-4318, USA.
- Sangamo BioSciences, Inc., Point Richmond Tech Center II, 501 Canal Blvd., Suite A100, Richmond, California 94804, USA.
- Present address: Process Science Department, Bayer Hematology/Cardiology, 800 Dwight Way, Berkeley, California 94701, USA.
Correspondence to: Carl H June1 e-mail: cjune@mail.med.upenn.edu
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