title: Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV.
abstract: 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.affiliation: From the Perelman School of Medicine, University of Pennsylvania, Philadelphia (P.T., I.F., M.K., R.G.C., G.B.-S., G.P., W.-T.H., B.L.L., C.H.J.); Albert Einstein College of Medicine, Bronx, NY (D.S.); and Sangamo BioSciences, Richmond, CA (W.W.T., S.Q.W., G.L., S.K.S., R.T.S., M.A.G., G.N., M.C.H., P.D.G., D.G.A.).
authors.forename: Pablo
authors.initials: P
authors.lastname: Tebas
authors.forename: David
authors.initials: D
authors.lastname: Stein
authors.forename: Winson W
authors.initials: WW
authors.lastname: Tang
authors.forename: Ian
authors.initials: I
authors.lastname: Frank
authors.forename: Shelley Q
authors.initials: SQ
authors.lastname: Wang
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: S Kaye
authors.initials: SK
authors.lastname: Spratt
authors.forename: Richard T
authors.initials: RT
authors.lastname: Surosky
authors.forename: Martin A
authors.initials: MA
authors.lastname: Giedlin
authors.forename: Geoff
authors.initials: G
authors.lastname: Nichol
authors.forename: Michael C
authors.initials: MC
authors.lastname: Holmes
authors.forename: Philip D
authors.initials: PD
authors.lastname: Gregory
authors.forename: Dale G
authors.initials: DG
authors.lastname: Ando
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Collman
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Binder-Scholl
authors.forename: Gabriela
authors.initials: G
authors.lastname: Plesa
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Hwang
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D001804:Blood Transfusion, Autologous; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000637:transplantation*; D003131:Combined Modality Therapy; D004279:DNA, Viral / Q000097:blood; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D006678:HIV / Q000235:genetics / Q000302:isolation & purification; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D006801:Humans; D018655:Lymphocyte Count; D017710:Lymphocyte Transfusion; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D019713:Receptors, CCR5 / Q000235:genetics*; D012007:Rectum / Q000276:immunology; D019562:Viral Load
chemical_list: C584933:CCR5 protein, human; D004279:DNA, Viral; D012367:RNA, Viral; D019713:Receptors, CCR5