BACKGROUND: CCR5 is the major coreceptor for human immunodeficiency virus (HIV). We investigated whether site-specific modification of the gene ("gene editing")--in this case, the infusion of autologous CD4 T cells in which the CCR5 gene was rendered permanently dysfunctional by a zinc-finger nuclease (ZFN)--is safe. METHODS: We enrolled 12 patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells. The patients had chronic aviremic HIV infection while they were receiving highly active antiretroviral therapy. Six of them underwent an interruption in antiretroviral treatment 4 weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified with the ZFN. The primary outcome was safety as assessed by treatment-related adverse events. Secondary outcomes included measures of immune reconstitution and HIV resistance. RESULTS: One serious adverse event was associated with infusion of the ZFN-modified autologous CD4 T cells and was attributed to a transfusion reaction. The median CD4 T-cell count was 1517 per cubic millimeter at week 1, a significant increase from the preinfusion count of 448 per cubic millimeter (P<0.001). The median concentration of CCR5-modified CD4 T cells at 1 week was 250 cells per cubic millimeter. This constituted 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells. Modified cells had an estimated mean half-life of 48 weeks. During treatment interruption and the resultant viremia, the decline in circulating CCR5-modified cells (-1.81 cells per day) was significantly less than the decline in unmodified cells (-7.25 cells per day) (P=0.02). HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients. CONCLUSIONS: CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00842634.).
BACKGROUND:CCR5 is the major coreceptor for human immunodeficiency virus (HIV). We investigated whether site-specific modification of the gene ("gene editing")--in this case, the infusion of autologous CD4 T cells in which the CCR5 gene was rendered permanently dysfunctional by a zinc-finger nuclease (ZFN)--is safe. METHODS: We enrolled 12 patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells. The patients had chronic aviremic HIV infection while they were receiving highly active antiretroviral therapy. Six of them underwent an interruption in antiretroviral treatment 4 weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified with the ZFN. The primary outcome was safety as assessed by treatment-related adverse events. Secondary outcomes included measures of immune reconstitution and HIV resistance. RESULTS: One serious adverse event was associated with infusion of the ZFN-modified autologous CD4 T cells and was attributed to a transfusion reaction. The median CD4 T-cell count was 1517 per cubic millimeter at week 1, a significant increase from the preinfusion count of 448 per cubic millimeter (P<0.001). The median concentration of CCR5-modified CD4 T cells at 1 week was 250 cells per cubic millimeter. This constituted 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells. Modified cells had an estimated mean half-life of 48 weeks. During treatment interruption and the resultant viremia, the decline in circulating CCR5-modified cells (-1.81 cells per day) was significantly less than the decline in unmodified cells (-7.25 cells per day) (P=0.02). HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients. CONCLUSIONS:CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00842634.).
Authors: H Deng; R Liu; W Ellmeier; S Choe; D Unutmaz; M Burkhart; P Di Marzio; S Marmon; R E Sutton; C M Hill; C B Davis; S C Peiper; T J Schall; D R Littman; N R Landau Journal: Nature Date: 1996-06-20 Impact factor: 49.962
Authors: R Liu; W A Paxton; S Choe; D Ceradini; S R Martin; R Horuk; M E MacDonald; H Stuhlmann; R A Koup; N R Landau Journal: Cell Date: 1996-08-09 Impact factor: 41.582
Authors: O J Cohen; M Vaccarezza; G K Lam; B F Baird; K Wildt; P M Murphy; P A Zimmerman; T B Nutman; C H Fox; S Hoover; J Adelsberger; M Baseler; J Arthos; R T Davey; R L Dewar; J Metcalf; D J Schwartzentruber; J M Orenstein; S Buchbinder; A J Saah; R Detels; J Phair; C Rinaldo; J B Margolick; G Pantaleo; A S Fauci Journal: J Clin Invest Date: 1997-09-15 Impact factor: 14.808
Authors: J Eugen-Olsen; A K Iversen; P Garred; U Koppelhus; C Pedersen; T L Benfield; A M Sorensen; T Katzenstein; E Dickmeiss; J Gerstoft; P Skinhøj; A Svejgaard; J O Nielsen; B Hofmann Journal: AIDS Date: 1997-03 Impact factor: 4.177
Authors: M Samson; F Libert; B J Doranz; J Rucker; C Liesnard; C M Farber; S Saragosti; C Lapoumeroulie; J Cognaux; C Forceille; G Muyldermans; C Verhofstede; G Burtonboy; M Georges; T Imai; S Rana; Y Yi; R J Smyth; R G Collman; R W Doms; G Vassart; M Parmentier Journal: Nature Date: 1996-08-22 Impact factor: 49.962
Authors: S R Riddell; M Elliott; D A Lewinsohn; M J Gilbert; L Wilson; S A Manley; S D Lupton; R W Overell; T C Reynolds; L Corey; P D Greenberg Journal: Nat Med Date: 1996-02 Impact factor: 53.440