title: Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases.
abstract: 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.
authors.affiliation: Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, 421 Curie Blvd., Room 554, BRB II/III, Philadelphia, Pennsylvania 19104-6160, USA.
authors.forename: Elena E
authors.initials: EE
authors.lastname: Perez
authors.forename: Jianbin
authors.initials: J
authors.lastname: Wang
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Miller
authors.forename: Yann
authors.initials: Y
authors.lastname: Jouvenot
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Kim
authors.forename: Olga
authors.initials: O
authors.lastname: Liu
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Wang
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: Victor V
authors.initials: VV
authors.lastname: Bartsevich
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Lee
authors.forename: Dmitry Y
authors.initials: DY
authors.lastname: Guschin
authors.forename: Igor
authors.initials: I
authors.lastname: Rupniewski
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Waite
authors.forename: Carmine
authors.initials: C
authors.lastname: Carpenito
authors.forename: Richard G
authors.initials: RG
authors.lastname: Carroll
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Fyodor D
authors.initials: FD
authors.lastname: Urnov
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Rebar
authors.forename: Dale
authors.initials: D
authors.lastname: Ando
authors.forename: Philip D
authors.initials: PD
authors.lastname: Gregory
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Michael C
authors.initials: MC
authors.lastname: Holmes
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000637:transplantation*; D002478:Cells, Cultured; D002874:Chromosome Mapping / Q000379:methods; D003851:Deoxyribonucleases / Q000235:genetics*; D005818:Genetic Engineering / Q000379:methods; D015658:HIV Infections / Q000517:prevention & control* / Q000601:surgery*; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D016896:Treatment Outcome; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D003851:Deoxyribonucleases