Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection

Blood. 2014 Jan 2;123(1):61-9. doi: 10.1182/blood-2013-08-521229. Epub 2013 Oct 25.


HIV-1 entry into CD4(+) T cells requires binding of the virus to CD4 followed by engagement of either the C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4) coreceptor. Pharmacologic blockade or genetic inactivation of either coreceptor protects cells from infection by viruses that exclusively use the targeted coreceptor. We have used zinc-finger nucleases to drive the simultaneous genetic modification of both ccr5 and cxcr4 in primary human CD4(+) T cells. These gene-modified cells proliferated normally and were resistant to both CCR5- and CXCR4-using HIV-1 in vitro. When introduced into a humanized mouse model of HIV-1 infection, these coreceptor negative cells engraft and traffic normally, and are protected from infection with CCR5- and CXCR4-using HIV-1 strains. These data suggest that simultaneous disruption of the HIV coreceptors may provide a useful approach for the long-term, drug-free treatment of established HIV-1 infections.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / virology*
  • Cell Proliferation
  • Endodeoxyribonucleases / metabolism*
  • Female
  • HEK293 Cells
  • HIV Infections / immunology*
  • HIV Infections / prevention & control
  • HIV Infections / therapy
  • HIV-1
  • Humans
  • Male
  • Mice
  • Receptors, CCR5 / genetics*
  • Receptors, CXCR4 / genetics*
  • Receptors, Chemokine / metabolism
  • Zinc Fingers*


  • CCR5 protein, human
  • CXCR4 protein, human
  • Receptors, CCR5
  • Receptors, CXCR4
  • Receptors, Chemokine
  • Endodeoxyribonucleases