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

Elena E. Perez; Jianbin Wang; Jeffrey C. Miller; Yann Jouvenot; Kenneth A. Kim; Olga Liu; Nathaniel Wang; Gary Lee; Victor V. Bartsevich; Ya Li Lee; Dmitry Y. Guschin; Igor Rupniewski; Adam J. Waite; Carmine Carpenito; Richard G. Carroll; Jordan S. Orange; Fyodor D. Urnov; Edward J. Rebar; Dale Ando; Philip D. Gregory; James L. Riley; Michael C. Holmes; Carl H. June

doi:10.1038/nbt1410

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

Elena E. Perez, Jianbin Wang, Jeffrey C. Miller, Yann Jouvenot, Kenneth A. Kim, Olga Liu, Nathaniel Wang, Gary Lee, Victor V. Bartsevich, Ya Li Lee, Dmitry Y. Guschin, Igor Rupniewski, Adam J. Waite, Carmine Carpenito, Richard G. Carroll, Jordan S. Orange, Fyodor D. Urnov, Edward J. Rebar, Dale Ando, Philip D. GregoryJames L. Riley, Michael C. Holmes, Carl H. June

Pediatrics

Research output: Contribution to journal › Article

730 Scopus citations

Abstract

Homozygosity for the naturally occurring Δ32 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.

Original language	English (US)
Pages (from-to)	808-816
Number of pages	9
Journal	Nature Biotechnology
Volume	26
Issue number	7
DOIs	https://doi.org/10.1038/nbt1410
State	Published - Jul 1 2008

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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Perez, E. E., Wang, J., Miller, J. C., Jouvenot, Y., Kim, K. A., Liu, O., Wang, N., Lee, G., Bartsevich, V. V., Lee, Y. L., Guschin, D. Y., Rupniewski, I., Waite, A. J., Carpenito, C., Carroll, R. G., Orange, J. S., Urnov, F. D., Rebar, E. J., Ando, D., ... June, C. H. (2008). Establishment of HIV-1 resistance in CD4⁺ T cells by genome editing using zinc-finger nucleases. Nature Biotechnology, 26(7), 808-816. https://doi.org/10.1038/nbt1410

Establishment of HIV-1 resistance in CD4⁺ T cells by genome editing using zinc-finger nucleases. / Perez, Elena E.; Wang, Jianbin; Miller, Jeffrey C.; Jouvenot, Yann; Kim, Kenneth A.; Liu, Olga; Wang, Nathaniel; Lee, Gary; Bartsevich, Victor V.; Lee, Ya Li; Guschin, Dmitry Y.; Rupniewski, Igor; Waite, Adam J.; Carpenito, Carmine; Carroll, Richard G.; Orange, Jordan S.; Urnov, Fyodor D.; Rebar, Edward J.; Ando, Dale; Gregory, Philip D.; Riley, James L.; Holmes, Michael C.; June, Carl H.

In: Nature Biotechnology, Vol. 26, No. 7, 01.07.2008, p. 808-816.

Research output: Contribution to journal › Article

Perez, EE, Wang, J, Miller, JC, Jouvenot, Y, Kim, KA, Liu, O, Wang, N, Lee, G, Bartsevich, VV, Lee, YL, Guschin, DY, Rupniewski, I, Waite, AJ, Carpenito, C, Carroll, RG, Orange, JS, Urnov, FD, Rebar, EJ, Ando, D, Gregory, PD, Riley, JL, Holmes, MC & June, CH 2008, 'Establishment of HIV-1 resistance in CD4⁺ T cells by genome editing using zinc-finger nucleases', Nature Biotechnology, vol. 26, no. 7, pp. 808-816. https://doi.org/10.1038/nbt1410

Perez, Elena E. ; Wang, Jianbin ; Miller, Jeffrey C. ; Jouvenot, Yann ; Kim, Kenneth A. ; Liu, Olga ; Wang, Nathaniel ; Lee, Gary ; Bartsevich, Victor V. ; Lee, Ya Li ; Guschin, Dmitry Y. ; Rupniewski, Igor ; Waite, Adam J. ; Carpenito, Carmine ; Carroll, Richard G. ; Orange, Jordan S. ; Urnov, Fyodor D. ; Rebar, Edward J. ; Ando, Dale ; Gregory, Philip D. ; Riley, James L. ; Holmes, Michael C. ; June, Carl H. / Establishment of HIV-1 resistance in CD4⁺ T cells by genome editing using zinc-finger nucleases. In: Nature Biotechnology. 2008 ; Vol. 26, No. 7. pp. 808-816.

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abstract = "Homozygosity for the naturally occurring Δ32 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.",

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