CCR5 is the major coreceptor for human immunodeficiency virus ( HIV ). Researchers have 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.
Twelve patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells, were enrolled.
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.
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 less than 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.
In conclusion, CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. ( Xagena )
Tebas P et al, N Engl J Med 2014; 370:901-910