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 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.
Perez
Elena E
EE
Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, 421 Curie Blvd., Room 554, BRB II/III, Philadelphia, Pennsylvania 19104-6160, USA.
Wang
Jianbin
J
Miller
Jeffrey C
JC
Jouvenot
Yann
Y
Kim
Kenneth A
KA
Liu
Olga
O
Wang
Nathaniel
N
Lee
Gary
G
Bartsevich
Victor V
VV
Lee
Ya-Li
YL
Guschin
Dmitry Y
DY
Rupniewski
Igor
I
Waite
Adam J
AJ
Carpenito
Carmine
C
Carroll
Richard G
RG
Orange
Jordan S
JS
Urnov
Fyodor D
FD
Rebar
Edward J
EJ
Ando
Dale
D
Gregory
Philip D
PD
Riley
James L
JL
Holmes
Michael C
MC
June
Carl H
CH
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*
D003851:Deoxyribonucleases