title: Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection.
abstract: HIV-1 entry into CD4(+) T cells requires binding of the virus to CD4 followed by engagement of either the C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4) coreceptor. Pharmacologic blockade or genetic inactivation of either coreceptor protects cells from infection by viruses that exclusively use the targeted coreceptor. We have used zinc-finger nucleases to drive the simultaneous genetic modification of both ccr5 and cxcr4 in primary human CD4(+) T cells. These gene-modified cells proliferated normally and were resistant to both CCR5- and CXCR4-using HIV-1 in vitro. When introduced into a humanized mouse model of HIV-1 infection, these coreceptor negative cells engraft and traffic normally, and are protected from infection with CCR5- and CXCR4-using HIV-1 strains. These data suggest that simultaneous disruption of the HIV coreceptors may provide a useful approach for the long-term, drug-free treatment of established HIV-1 infections.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA;
authors.forename: Chuka A
authors.initials: CA
authors.lastname: Didigu
authors.forename: Craig B
authors.initials: CB
authors.lastname: Wilen
authors.forename: Jianbin
authors.initials: J
authors.lastname: Wang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Duong
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Secreto
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Danet-Desnoyers
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Gregory
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: Michael C
authors.initials: MC
authors.lastname: Holmes
authors.forename: Robert W
authors.initials: RW
authors.lastname: Doms
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology*; D049109:Cell Proliferation; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D015497:HIV-1; D006801:Humans; D008297:Male; D051379:Mice; D019713:Receptors, CCR5 / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics*; D019707:Receptors, Chemokine / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: C584933:CCR5 protein, human; C527276:CXCR4 protein, human; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D004706:Endodeoxyribonucleases