• Pablo Tebas, David Stein, Winson W Tang, Ian Frank, Shelley Q Wang, Gary Lee, S Kaye Spratt, Richard T Surosky, Martin A Giedlin, Geoff Nichol, Michael C Holmes, Philip D Gregory, Dale G Ando, Michael Kalos, Ronald G Collman, Gwendolyn Binder-Scholl, Gabriela Plesa, Wei-Ting Hwang, Bruce L Levine, and Carl H June.
• 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.).
• N. Engl. J. Med.. 2014 Mar 6;370(10):901-10.

BackgroundCCR5 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.MethodsWe 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.ResultsOne 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.ConclusionsCCR5-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.).

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