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

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 spec... Full description

Journal Title: Nature biotechnology 2008-07, Vol.26 (7), p.808-816
Main Author: June, Carl H
Other Authors: 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 , S Orange, Jordan , Urnov, Fyodor D , Rebar, Edward J , Ando, Dale , Gregory, Philip D , Riley, James L , Holmes, Michael C
Format: Electronic Article Electronic Article
Language: English
Subjects:
HIV
Publisher: New York, NY: Nature Publishing Group
ID: ISSN: 1087-0156
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title: Establishment of HIV-1 resistance in CD4 + T cells by genome editing using zinc-finger nucleases
format: Article
creator:
  • June, Carl H
  • 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
  • S Orange, Jordan
  • Urnov, Fyodor D
  • Rebar, Edward J
  • Ando, Dale
  • Gregory, Philip D
  • Riley, James L
  • Holmes, Michael C
subjects:
  • Adoptive Transfer - methods
  • Animals
  • Article
  • Biological and medical sciences
  • Biotechnology
  • CD4-Positive T-Lymphocytes - enzymology
  • CD4-Positive T-Lymphocytes - transplantation
  • Cells, Cultured
  • Cellular biology
  • Chromosome Mapping - methods
  • Deoxyribonucleases - genetics
  • Fundamental and applied biological sciences. Psychology
  • Genetic engineering
  • Genetic Engineering - methods
  • Genomics
  • Health. Pharmaceutical industry
  • HIV
  • HIV Infections - prevention & control
  • HIV Infections - surgery
  • Human immunodeficiency virus
  • Humans
  • Immunity, Innate
  • Immunology
  • Industrial applications and implications. Economical aspects
  • Infections
  • Mice
  • Miscellaneous
  • Treatment Outcome
  • virus diseases
  • Zinc Fingers - genetics
ispartof: Nature biotechnology, 2008-07, Vol.26 (7), p.808-816
description: 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.
language: eng
source:
identifier: ISSN: 1087-0156
fulltext: no_fulltext
issn:
  • 1087-0156
  • 1546-1696
url: Link


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titleEstablishment of HIV-1 resistance in CD4 + T cells by genome editing using zinc-finger nucleases
creatorJune, Carl H ; 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 ; S Orange, Jordan ; Urnov, Fyodor D ; Rebar, Edward J ; Ando, Dale ; Gregory, Philip D ; Riley, James L ; Holmes, Michael C
creatorcontribJune, Carl H ; 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 ; S Orange, Jordan ; Urnov, Fyodor D ; Rebar, Edward J ; Ando, Dale ; Gregory, Philip D ; Riley, James L ; Holmes, Michael C
descriptionHomozygosity 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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subjectAdoptive Transfer - methods ; Animals ; Article ; Biological and medical sciences ; Biotechnology ; CD4-Positive T-Lymphocytes - enzymology ; CD4-Positive T-Lymphocytes - transplantation ; Cells, Cultured ; Cellular biology ; Chromosome Mapping - methods ; Deoxyribonucleases - genetics ; Fundamental and applied biological sciences. Psychology ; Genetic engineering ; Genetic Engineering - methods ; Genomics ; Health. Pharmaceutical industry ; HIV ; HIV Infections - prevention & control ; HIV Infections - surgery ; Human immunodeficiency virus ; Humans ; Immunity, Innate ; Immunology ; Industrial applications and implications. Economical aspects ; Infections ; Mice ; Miscellaneous ; Treatment Outcome ; virus diseases ; Zinc Fingers - genetics
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8Lee, Gary
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22Holmes, Michael C
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descriptionHomozygosity 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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titleEstablishment of HIV-1 resistance in CD4 + T cells by genome editing using zinc-finger nucleases
authorJune, Carl H ; 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 ; S Orange, Jordan ; Urnov, Fyodor D ; Rebar, Edward J ; Ando, Dale ; Gregory, Philip D ; Riley, James L ; Holmes, Michael C
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18HIV Infections - surgery
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abstractHomozygosity 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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