Editing T Cells

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Science  25 Jul 2008:
Vol. 321, Issue 5888, pp. 467
DOI: 10.1126/science.321.5888.467b

The chemokine receptor CCR5 is one of the major docking sites that HIV uses to enter T cells, and individuals carrying a homozygous deletion mutation in CCR5 are resistant to HIV infection. Hence, interfering with the HIV-CCR5 interaction has become the goal of several small-molecule drug design projects.

Perez et al. have instead taken the approach of disrupting CCR5 by introducing a double-stranded break into the gene itself. Zinc-finger nucleases were designed to bind to and cleave at specific sequences found only in CCR5; endogenous DNA repair pathways have the effect of introducing deletions or insertions that yield a truncated or nonfunctional protein. Cultured human T cells that were transduced with a vector expressing the zinc-finger nucleases were resistant to HIV infection, and long-term expansion of these cells in culture did not reduce their resistance. In a mouse model of acute HIV infection, animals treated with nuclease-modified human T cells had a lower plasma viral load than control mice, along with higher T cell counts, suggesting that genome editing might be used therapeutically to provide a pool of HIV-resistant T cells. — LC

Nat. Biotechnol. 26, 808 (2008).

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