Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected With HIV

N Engl J Med. 2014 Mar 6;370(10):901-10. doi: 10.1056/NEJMoa1300662.

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.).

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antiretroviral Therapy, Highly Active
  • Blood Transfusion, Autologous
  • CD4-Positive T-Lymphocytes / chemistry
  • CD4-Positive T-Lymphocytes / transplantation*
  • Combined Modality Therapy
  • DNA, Viral / blood
  • Female
  • Genetic Therapy* / adverse effects
  • Genetic Therapy* / methods
  • HIV / genetics
  • HIV / isolation & purification
  • HIV Infections / drug therapy
  • HIV Infections / immunology
  • HIV Infections / therapy*
  • Humans
  • Lymphocyte Count
  • Lymphocyte Transfusion*
  • Male
  • Middle Aged
  • RNA, Viral / blood
  • Receptors, CCR5 / genetics*
  • Rectum / immunology
  • Viral Load

Substances

  • CCR5 protein, human
  • DNA, Viral
  • RNA, Viral
  • Receptors, CCR5

Associated data

  • ClinicalTrials.gov/NCT00842634